Tag: Immunology

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Scientists identify immunological profiles of people who make powerful HIV antibodies

Post author By Vetscite
Post date August 30, 2016

People living with HIV who naturally produce broadly neutralizing antibodies (bNAbs) that may help suppress the virus have different immunological profiles than people who do not, researchers report. While bNAbs cannot completely clear HIV infections in people who have already acquired the virus, many scientists believe a successful preventive HIV vaccine must induce bNAbs. The new findings indicate that bNAb production may be associated with specific variations in individual immune functions that may be triggered by unchecked HIV infection. Defining how to safely replicate these attributes in HIV-uninfected vaccine recipients may lead to better designed experimental vaccines to protect against HIV. The study was supported by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health.

Researchers led by a team at Duke University identified these immunologic variations by studying blood samples collected from people living with HIV by the NIAID-supported Center for HIV/AIDS Vaccine Immunology (CHAVI). The team compared blood samples from the 51 individuals with the highest level of bNAbs with samples taken from 51 individuals with few or no bNAbs present. The analysis performed revealed that many variations in immune cell function triggered by chronic HIV infection are associated with high levels of bNAbs. The specific changes included a higher frequency of antibodies that attack one’s own cells, called autoantibodies; fewer immune regulatory T cells, which were also less active in these individuals; and a higher frequency of memory T follicular helper immune cells.

With this immune system configuration, the activity of antibody-producing immune cells called B cells may be less restricted because they are supported by T follicular helper cells and may be hindered by regulatory T cells. This, in turn, could lead to more efficient production of protective bNAbs against HIV. These findings support approaches to developing an HIV vaccine that involve modifying an individual’s immune system to mimic these conditions through the addition of vaccine boosters called adjuvants or other means.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/07/160729143030.htm Original web page at Science Daily

Tags Human, Immunology, Virology

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* Treating autoimmune disease without harming normal immunity

Post author By Vetscite
Post date July 26, 2016

Preclinical study shows that engineered T cells can selectively target the antibody-producing cells that cause autoimmune disease.

In a study with potentially major implications for the future treatment of autoimmunity and related conditions, scientists from the Perelman School of Medicine at the University of Pennsylvania have found a way to remove the subset of antibody-making cells that cause an autoimmune disease, without harming the rest of the immune system. The autoimmune disease the team studied is called pemphigus vulgaris (PV), a condition in which a patient’s own immune cells attack a protein called desmoglein-3 (Dsg3) that normally adheres skin cells.

Current therapies for autoimmune disease, such as prednisone and rituximab, suppress large parts of the immune system, leaving patients vulnerable to potentially fatal opportunistic infections and cancers.

The Penn researchers demonstrated their new technique by successfully treating an otherwise fatal autoimmune disease in a mouse model, without apparent off-target effects, which could harm healthy tissue. The results are published in an online First Release paper in Science.

“This is a powerful strategy for targeting just autoimmune cells and sparing the good immune cells that protect us from infection,” said co-senior author Aimee S. Payne, MD, PhD, the Albert M. Kligman Associate Professor of Dermatology.

Payne and her co-senior author Michael C. Milone, MD, PhD, an assistant professor of Pathology and Laboratory Medicine, adapted the technique from the promising anti-cancer strategy by which T cells are engineered to destroy malignant cells in certain leukemias and lymphomas.

“Our study effectively opens up the application of this anti-cancer technology to the treatment of a much wider range of diseases, including autoimmunity and transplant rejection,” Milone said.

The key element in the new strategy is based on an artificial target-recognizing receptor, called a chimeric antigen receptor, or CAR, which can be engineered into patients’ T cells. In human trials, researchers remove some of patients’ T cells through a process similar to dialysis and then engineer them in a laboratory to add the gene for the CAR so that the new receptor is expressed in the T cells. The new cells are then multiplied in the lab before re-infusing them into the patient. The T cells use their CAR receptors to bind to molecules on target cells, and the act of binding triggers an internal signal that strongly activates the T cells — so that they swiftly destroy their targets.

The basic CAR T cell concept was first described in the late 1980s, principally as an anti-cancer strategy, but technical challenges delayed its translation into successful therapies. Since 2011, though, experimental CAR T cell treatments for B cell leukemias and lymphomas — cancers in which patients’ healthy B cells turn cancerous — have been successful in some patients for whom all standard therapies had failed.

B cells, which produce antibodies, can also cause autoimmunity. Payne researches autoimmunity, and a few years ago, a postdoctoral researcher in her laboratory, Christoph T. Ellebrecht, MD, took an interest in CAR T cell technology as a potential weapon against B cell-related autoimmune diseases. Soon Payne’s lab teamed up with Milone’s, which studies CAR T cell technology, in the hope of finding a powerful new way to treat these ailments.

“We thought we could adapt this technology that’s really good at killing all B cells in the body to target specifically the B cells that make antibodies that cause autoimmune disease,” said Milone.

“Targeting just the cells that cause autoimmunity has been the ultimate goal for therapy in this field,” noted Payne.

Ellebrecht was first author, the team took aim at pemphigus vulgaris. This condition occurs when a patient’s antibodies attack molecules that normally keep skin cells together. When left untreated, PV leads to extensive skin blistering and is almost always fatal, but in recent decades the condition has been treatable with broadly immunosuppressive drugs such as prednisone, mycophenolate mofetil, and rituximab.

To treat PV without causing broad immunosuppression, the Penn team designed an artificial CAR-type receptor that would direct patients’ T cells to attack only the B cells producing harmful anti-Dsg3 antibodies.

The team developed a “chimeric autoantibody receptor,” or CAAR, that displays fragments of the autoantigen Dsg3 — the same fragments to which PV-causing antibodies and their B cells typically bind, as Payne’s laboratory and others have shown in prior studies. The artificial receptor acts as a lure for the B cells that target Dsg3, bringing them into fatal contact with the therapeutic T cells.

Testing many variants, the team eventually found an artificial receptor design that worked well in cell culture, enabling host T cells to efficiently destroy cells producing antibodies to desmoglein, including those derived from PV patients. The engineered T cells also performed successfully in a mouse model of PV, killing desmoglein-specific B cells and preventing blistering and other manifestations of autoimmunity in the animals.

“We were able to show that the treatment killed all the Dsg3-specific B cells, a proof of concept that this approach works,” Payne said.

T cell therapies can be complicated by many factors. But in these experiments, the Penn scientists’ engineered cells maintained their potency despite the presence of anti-Dsg3 antibodies that might have swarmed their artificial receptors. In addition, there were no signs that the engineered T cells caused side effects by hitting the wrong cellular targets in the mice.

The team now plans to test their treatment in dogs, which can also develop PV and often die from the disease. “If we can use this technology to cure PV safely in dogs, it would be a breakthrough for veterinary medicine, and would hopefully pave the way for trials of this therapy in human pemphigus patients,” Payne said.

Also on the horizon for the Penn scientists are applications of CAAR T cell technology for other types of autoimmunity. The immune rejection that complicates organ transplants, and normally requires long-term immunosuppressive drug therapy, may also be treatable with CAAR T cell technology.

“If you can identify a specific marker of a B cell that you want to target, then in principle this strategy can work,” Payne said.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/06/160630144409.htm Original web page at Science Daily

Tags Cell Biology, Dermatology, Immunology

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Natural metabolite can suppress inflammation

Post author By Vetscite
Post date July 26, 2016

An international research team has revealed a substance produced in humans that can suppress the pro-inflammatory activity of macrophages — specific immune cells. The substance known as itaconate is released in large quantities by macrophages themselves and according to the scientists, acts as an antioxidant and anti-inflammatory agent. These properties make itaconate promising for the treatment of such pathologies as cardiac ischemia, metabolic disorders and autoimmune diseases which may be associated with excessive inflammation or oxidative stress. An international group of scientists from US, Canada, Germany and Russia has revealed a substance produced in humans that can suppress the pro-inflammatory activity of macrophages — specific cells of immune system. The substance known as itaconate is released in large quantities by macrophages themselves, but until now its role remained poorly studied. Now scientists have found evidence that itaconate acts as an antioxidant and anti-inflammatory agent. These properties make itaconate promising for the treatment of pathologies caused by excessive inflammation or oxidative stress. Such conditions may be associated with cardiac ischemia, metabolic disorders and perhaps autoimmune diseases. The findings were published in Cell Metabolism.

The work, which united scientists from Washington University in St. Louis, ITMO University, McGill University and Max Planck Institute of Immunobiology and Epigenetics, was based on the study of macrophages — immune system cells in charge of fighting pathogens. An important feature of macrophages is their ability to switch between different states depending on the concentration of various substances in the body. In total, there are three such states: M0 — neutral, M1 — pro-inflammatory and M2 anti-inflammatory.

M1 macrophages are the first who arrive to fight the infection. As they begin to swallow viruses and bacteria, an intense inflammatory process kicks in. This process may adversely affect the entire organism if the macrophages become overly diligent. Inflammation consumes energy resources of the organism and can lead to numerous complications or even death. That is why in order to mitigate the negative consequences of immune response, it is important to understand how we can reduce the excessive proinflammatory effect of macrophages.

An in-depth study of macrophage metabolism during their transition from inactive to proinflammatory state helped researchers identify the substance that could suppress macrophage-related inflammations. Describing the working mechanism of this substance called itaconate became possible due to a complex map of metabolic pathways in macrophages that was developed by the group.

Itaconate is produced by macrophages when they switch from M0 inactive state to M1 pro-inflammatory state. If the concentration of this substance increases to defined limit, macrophage activation falls. “Itaconate sets the bar controlling M1 macrophage formation,” says Alexey Sergushichev, one of the authors of the paper and PhD student at ITMO University. “Without this substance, the inflammation would increase more than required. In the future, with the help of itaconate, it will be possible to artificially manipulate the transition of macrophages from M0 to M1, meaning the possibility of restraining inflammations. The influence of itaconate on macrophages is a delicate mechanism that can ensure high selectivity of the immune system regulation.”

Prior to the study, guesswork with respect to the function and origin of itaconate generated a lot of speculations. But the new study shows that itaconate plays the role of immune regulator. To understand how itaconate reduces the activity of immune cells, the researchers examined the so-called Krebs cycle, or tricarboxylic acid cycle and cellular respiration (processes of producing of vital substances and energy from the oxidation of glucose in cells). Having done so, the scientists identified two “bottlenecks” that can be influenced to reverse the reaction and send it another way.

The Krebs cycle is preceded by signal transmission between cells through oxygen-sensitive pathways. Itaconate blocks the enzyme called Sdh (succinate dehydrogenase), which not only ensures the functioning of the tricarboxylic acid cycle but also links the cycle to cellular respiration and signaling pathways.

Thus, itaconate acts on both functions of the Sdh enzyme, adjusting the cells’ Krebs cycle and respiration. When the enzyme is blocked in macrophages, both processes become interrupted, and this impairs the cells’ activation. “Noteworthy, itaconate acts as an anti-oxidant and anti-inflammatory agent,” says Vicky Lampropoulou, the lead author of the paper and researcher at the laboratory of Maxim Artyomov at Washington University in St. Louis. “At the same time, itaconate is naturally produced by mammalian immune cells. These features make it attractive for use in adjuvant therapy for numerous diseases, in which excessive inflammation and oxidative stress associate with pathology, like heart ischemia, metabolic disorders and perhaps even autoimmunity.”

The researchers have already demonstrated that they can use itaconate to reach the desired effect in living organisms. Experiments with mice have shown that the substance reduces damage after heart attack, acting by the same mechanism of locking the Sdh enzyme. However, according to the scientists, more work is needed to successfully apply the method to humans.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/06/160630155359.htm Original web page at Science Daily

Tags Cell Biology, Immunology, Rodents/Lags

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New anti-cancer strategy mobilizes both innate and adaptive immune response

Post author By Vetscite
Post date July 26, 2016

Scientists have developed a new vaccine that involves injecting cells that have been modified so that they can stimulate both an innate immune response and the more specific adaptive response, which allows the body to keep memories and attack new tumor cells as they form.

Though a variety of immunotherapy-based strategies are being used against cancer, they are often hindered by the inability of the immune response to enter the immunosuppressive tumor microenvironment and to effectively mount a response to cancer cells. Now, scientists from the RIKEN Center for Integrative Medical Sciences have developed a new vaccine that involves injecting cells that have been modified so that they can stimulate both an innate immune response and the more specific adaptive response, which allows the body to keep memories and attack new tumor cells as they form. In the study published in Cancer Research, they found that the vaccine made it possible for killer CD8+T-cells–important players in the immune response against cancer–to enter the tumor microenvironment and target cancerous cells.

According to Shin-ichiro Fujii, leader of the Laboratory for Immunotherapy, who led the study, “Cancer cells have different sensitivities to the innate or adaptive response, so it important to target both in order to eradicate it. We have developed a special type of modified cell, called aAVC, which we found can do this.”

The aAVC cells are not taken from the subject’s own body but are foreign cells. The cells are modified by adding a natural killer t-cell ligand, which permits them to stimulate natural killer T-cells, along with an antigen associated with a cancer. The group found that when these cells are activated, they in turn promote the maturation of dendritic cells, which act as coordinators of the innate and acquired response. Dendritic cells are key because they allow the activation of immune memory, where the body remembers and responds to a threat even years later.

To find whether it worked in actual bodies, they conducted experiments in mice with a virulent form of melanoma that also expresses a model antigen called OVA. Tests in mice showed, moreover, that aggressive tumors could be shrunken by vaccinating the animals with aAVC cells that were programmed to display OVA antigen. Following the treatment, the tumors in the treated animals were smaller and necrotic in the interior–a sign that the tumor was being attacked by the killer CD8+T-cells.

Fujii continues, “We were interesting in finding a mechanism, and were able to understand that the aAVC treatment led to the development of blood vessels in the tumors that expressed a pair of important adhesion molecules, ICAM-1 and VCAM-1, that are not normally expressed in tumors. This allowed the killer CD8+T cells to penetrate into the tumor.”

They also found that in animals that had undergone the treatment, cancer cells injected even a year later were eliminated. “This indicates,” says Fujii, “that we have successfully created an immune memory that remembers the tumor and attacks it even later.”

Looking to the future, Fujii says, “Our therapy with aAVC is promising because typical immunotherapies have to be tailor-made with the patient’s own cells. In our case we use foreign cells, so they can be made with a stable quality. Because we found that our treatment can lead to the maturation of dendritic cells, immunotherapy can move to local treatment to more systemic treatment based on immune memory.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/07/160701093935.htm Original web page at Science Daily

Tags Cell Biology, Immunology, Rodents/Lags

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* Droppings activate the immune system in nestlings

Post author By Vetscite
Post date July 12, 2016

Until now, it was believed that birds removed droppings from their nests to avoid the appearance of parasites. A recent investigation contradicts this hypothesis, concluding that feces activate the immune system of blackbird chicks and only attract insects.

In the animal world, strict rules are followed to deal with sources of contamination and potential dangers such as predation. In the case of birds, parents remove their chicks’ droppings from the nest on a daily basis to conserve hygiene. A new study carried out in Spain and published in the journal Frontiers in Zoology demonstrates that the presence of feces in nests attracts insects and provokes the activation of nestlings’ immune systems. This provides important information on the reason for this sanitation behaviour.

Until now, the predominant hypothesis in ornithology (the branch of zoology dedicated to the study of birds) was that birds removed droppings from the nest in order to avoid attracting parasite species to the nest. However, the new research refutes this. “Our study demonstrates that parasites being attracted by feces does not appear to be the reason for which evolution has favoured this behaviour, despite this having been traditionally assumed to be the case,” Juan Diego Ibáñez-Álamo said, the paper’s main author and an investigator at the Spanish National Scientific Research Council’s (CSIC) Doñana Biological Station and at the University of Groningen (Netherlands).

The scientists ran three different experiments using insect traps, artificial nests and real blackbird nests in order to observe the attractant effect of droppings on parasites.

Although the experimental predictions were for a higher quantity of parasites when feces were present, “the fecal sacs did not attract a higher number of parasites,” says the researcher.

The chicks’ immune systems were affected by the presence of feces; specifically, there was a change in the ratio of heterophils to lymphocytes (blood cells that fight against pathogens such as parasites), a physiological indicator of birds’ response to stress. “This ratio was significantly higher in nestlings that lived near the fecal sacs than in those which did not have feces near them,” state the authors. The scientists also observed that the chicks’ droppings caused an increase in the appearance of flies and a reduction in the number of acarids. The authors indicate the capacity of flies to act as vectors for the transmission of damaging microorganisms as a cause of immune system activation.

Nestlings produce feces enclosed in a mucous covering. This unique structure, shown in a previous study to function as isolation against bacteria, may also be responsible for preventing parasites being attracted to the nest. “It is possible that the mucus acts as a barrier, blocking the spread of chemical signals that parasites may use to locate the chicks,” says Ibáñez-Álamo. “The findings of our study appear to indicate that microorganisms may play a very significant role in relation to the cleanliness of birds’ nests,” he adds.

Even so, the authors consider this habit of parent birds to be the result of several factors: “We cannot rule out that parental behaviour may be altered by the presence of feces near the nest,” they state. Even predation could be another determinant cause for this behaviour.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/06/160621095548.htm Original web page at Science Daily

Tags Behaviour (Ethology), Birds (pet; ornamental; prey e.g. falcons), Immunology

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Itchy inflammation of mosquito bites helps viruses replicate

Post author By Vetscite
Post date July 12, 2016

Mosquito bite sites are not just itchy, irritating nuisances — they also make viral infections spread by the insects far worse, new research has found.

The study, led by the University of Leeds, found that inflammation where the insect has bitten not only helps a virus such as Zika or dengue establish an infection in the body more quickly, but that it also helps it to spread around the body, increasing the likelihood of severe illness.

“Mosquito bites are not just annoying — they are key for how these viruses spread around your body and cause disease,” said Dr Clive McKimmie, a research fellow at the School of Medicine and senior author of the study.

“We now want to look at whether medications such as anti-inflammatory creams can stop the virus establishing an infection if used quickly enough after the bite inflammation appears.”

In the new research, published in the journal Immunity, the investigators used mouse models to study the bites of the Aedes aegypti mosquito, the species that spreads infections such as Zika, dengue and Chikungunya.

When a mosquito bites, it injects saliva into the skin. The saliva triggers an immune response in which white blood cells called neutrophils and myeloid cells rush to the site.

But instead of helping, some of these cells get infected and inadvertently replicate the virus, the researchers found.

The team injected viruses into the skin of the mice with or without the presence of a mosquito bite at the injection site and compared the reaction.

In the absence of mosquito bites and their accompanying inflammation, the viruses failed to replicate well, whereas the presence of a bite resulted in a high virus level in the skin.

“This was a big surprise we didn’t expect,” said Dr McKimmie, whose team worked alongside colleagues at the University of Glasgow. “These viruses are not known for infecting immune cells.

“And sure enough, when we stopped these immune cells coming in, the bite did not enhance the infection anymore.”

Despite the enormous disease burden of mosquito-borne viral infections — they are responsible for hundreds of millions of cases across the world — there are few specific therapies or vaccines.

“This research could be the first step in repurposing commonly available anti-inflammatory drugs to treat bite inflammation before any symptoms set in,” said Dr McKimmie, whose study was funded by the Medical Research Council.

“We think creams might act as an effective way to stop these viruses before they can cause disease.” He added that if it is proven to be effective, this approach could work against a multitude of other viruses. “Nobody expected Zika, and before that nobody expected Chikungunya,” he said.

“There are estimated to be hundreds of other mosquito-borne viruses out there and it’s hard to predict what’s going to start the next outbreak.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/06/160621132526.htm Original web page at Science Daily

Tags Immunology, Rodents/Lags, Virology

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* New drug clears psoriasis in clinical trials

Post author By Vetscite
Post date June 28, 2016

About 80 percent of patients with moderate to severe psoriasis saw their disease completely or almost completely cleared with a new drug called ixekizumab, according to three large, long-term clinical trials led by Northwestern Medicine.

The results of these phase III trials were compiled in a paper published in the New England Journal of Medicine.

“This group of studies not only shows very high and consistent levels of safety and efficacy, but also that the great majority of the responses persist at least 60 weeks,” said Dr. Kenneth Gordon, a professor of dermatology at Northwestern University Feinberg School of Medicine and first author of the paper.

Affecting about 3 percent of the world’s population, psoriasis is an immune-mediated inflammatory disease that causes itchy, dry and red skin. It is also associated with an increased risk for depression, heart disease and diabetes, among other conditions.

Ixekizumab works by neutralizing a pathway in the immune system known to promote psoriasis.

To test the drug’s efficacy over time — and to help clinicians determine whether its benefits outweigh any risks — the three studies enrolled a total of 3,736 adult patients at more than 100 study sites in 21 countries. All participants had moderate to severe psoriasis, which is defined as covering 10 percent or more of the body. Patients were randomly assigned to receive injections of ixekizumab at various doses or a placebo over a period of more than a year.

The investigators assessed whether the drug reduced the severity of psoriasis symptoms compared to the placebo and evaluated safety by monitoring adverse events. By the 12th week, 76.4 to 81.8 percent of patients has their psoriasis classified as “clear” or “minimal” compared to 3.2% of patients on the placebo. By the 60th week, 68.7 to 78.3 percent of patients had maintained their improvement.

“Based on these findings, we expect that 80 percent of patients will have an extremely high response rate to ixekizumab, and about 40 percent will be completely cleared of psoriasis,” Gordon said. “Ten years ago, we thought complete clearance of this disease was impossible. It wasn’t something we would even try to do. Now with this drug, we’re obtaining response levels higher than ever seen before.”

Adverse events associated with ixekizumab included slightly higher rates of neutropenia (low white blood cell count), yeast infection and inflammatory bowel disease compared to the placebo. The safety of therapy longer than 60 weeks will need to be monitored in the future.

The drug has been approved by the Food and Drug Administration since the trials were completed.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/06/160609174808.htm Original web page at Science Daily

Tags Dermatology, Human, Immunology

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* Fighting cancer with the help of someone else’s immune cells

Post author By Vetscite
Post date June 14, 2016

A new step in cancer immunotherapy: researchers from the Netherlands Cancer Institute and University of Oslo/Oslo University Hospital show that even if one’s own immune cells cannot recognize and fight their tumors, someone else’s immune cells might. Their proof of principle study is published in the journal Science on May 19th.

The study shows that adding mutated DNA from cancer cells into immune stimulating cells from healthy donors create an immune response in the healthy immune cells. Inserting the targeted components from the donor immune cells back into the immune cells of the cancer patients, the researchers were able to make cancer patients’ own immune cells recognize cancer cells.

The extremely rapidly developing field of cancer immunotherapy aims to create technologies that help the body’s own immune system to fight cancer. There are a number of possible causes that can prevent the immune system from controlling cancer cells. First, the activity of immune cells is controlled by many ‘brakes’ that can interfere with their function, and therapies that inactivate these brakes are now being tested in many human cancers. As a second reason, in some patients the immune system may not recognize the cancer cells as aberrant in the first place. As such, helping the immune system to better recognize cancer cells is one of the main focuses in cancer immunotherapy.

Ton Schumacher of the Netherlands Cancer Institute and Johanna Olweus of the University of Oslo and Oslo University Hospital decided to test whether a ‘borrowed immune system’ could “see” the cancer cells of the patient as aberrant. The recognition of aberrant cells is carried out by immune cells called T cells. All T cells in our body scan the surface of other cells, including cancer cells, to check whether they display any protein fragments on their surface that should not be there. Upon recognition of such foreign protein fragments, T cells kill the aberrant cells. As cancer cells harbor faulty proteins, they can also display foreign protein fragments — also known as neo-antigens — on their surface, much in the way virus-infected cells express fragments of viral proteins.

To address whether the T cells of a patient react to all the foreign protein fragments on cancer cells, the research teams first mapped all possible neo-antigens on the surface of melanoma cells from three different patients. In all 3 patients, the cancer cells seemed to display a large number of different neo-antigens. But when the researchers tried to match these to the T cells derived from within the patient’s tumors, most of these aberrant protein fragments on the tumor cells went unnoticed.

Next, they tested whether the same neo-antigens could be seen by T-cells derived from healthy volunteers. Strikingly, these donor-derived T cells could detect a significant number of neo-antigens that had not been seen by the patients’ T cells.

“In a way, our findings show that the immune response in cancer patients can be strengthened; there is more on the cancer cells that makes them foreign that we can exploit. One way we consider doing this is finding the right donor T cells to match these neo-antigens.,” says Ton Schumacher. “The receptor that is used by these donor T-cells can then be used to genetically modify the patient’s own T cells so these will be able to detect the cancer cells.”

“Our study shows that the principle of outsourcing cancer immunity to a donor is sound. However, more work needs to be done before patients can benefit from this discovery. Thus, we need to find ways to enhance the throughput. We are currently exploring high-throughput methods to identify the neo-antigens that the T cells can “see” on the cancer and isolate the responding cells. But the results showing that we can obtain cancer-specific immunity from the blood of healthy individuals are already very promising,” says Johanna Olweus.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/05/160519144556.htm Original web page at Science Daily

Tags Human, Immunology, Oncology

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Putting the brakes on cell’s ‘engine’ could give flu, other vaccines a boost

Post author By Vetscite
Post date June 14, 2016

A relatively unknown molecule that regulates metabolism could be the key to boosting an individual’s immunity to the flu — and potentially other viruses — according to research reported today in the journal Immunity.

The study, led by University of Vermont (UVM) College of Medicine doctoral student Devin Champagne and Mercedes Rincon, Ph.D., a professor of medicine and an immunobiologist, discovered that a protein called methylation controlled J — or MCJ — can be altered to boost the immune system’s response to the flu.

Metabolism is a crucial function that helps keep cells alive. It plays a role in a range of bodily processes — from the conversion of food into energy to the ability to fight off infection. MCJ is the part of the cell that produces energy and enables metabolism.

“It’s the engine of the cell,” says Rincon, who adds that previously, researchers assumed that the mitochondria were constantly active.

She and Champagne discovered that MCJ acts as a braking system in the mitochondria, slowing these organelles down. Without MCJ, the mitochondria are hyperactive.

In the T cells of the body’s immune system, specifically the CD8 T cells that fight viruses and infections, metabolism helps ensure that those bug-fighting cells remain active and don’t tire out. When a virus attacks, CD8 cells detect and kill it while leaving the healthy cells intact.

MCJ controls the metabolism of the CD8 cells. It prevents the mitochondria from generating too much energy and making the CD8 cells so overactive that they kill healthy cells.

A vaccine, such as a flu shot, trains the CD8 cells to identify that virus and destroy it. With a good vaccine, the CD8 cells will “remember” and protect against that virus for a long time.

“The metabolism of immune cells is very important,” explains Rincon. “It is critical to determining effective protection against infection, but also if vaccines will work,” she says.

For their study, Champagne and Rincon generated mutant mice without MCJ and infected both normal mice and mice lacking MCJ with flu virus — imitating a vaccine, so the animals’ CD8 cells would learn to recognize the bug. After four weeks, they took the CD8 cells from the infected mice and injected those cells into other mice. One group received normal CD8 cells; the other group got cells without MCJ.

The researchers gave those new mice very high doses of the same flu virus. The mice with normal CD8 cells all died from the virus, indicating that the “educated” CD8 cells did poorly in protection. In contrast, the mice injected with MCJ-deficient CD8 cells had proper protection and all survived.

Champagne and Rincon concluded that with normal MCJ levels, CD8 cells are not as efficient in fighting virus because their mitochondrial metabolism is not strong enough, so the removal of MCJ (the “mitochondrial brake”) can improve the CD8 cells protection capability — and thus the efficacy of a vaccine.

“Nothing has been shown to do what this protein does,” says Rincon. “Suppressing MCJ will enhance your immune response and protection from an influenza virus and, most likely, protection from other threatening viruses.”

The researchers are now testing potential therapies for fatty liver disease by eliminating MCJ in liver cells. That action speeds up the metabolism process of breaking down lipids and converting fat into energy, thus reducing the presence of the disease, which affects 15 to 20 percent of humans, Rincon says.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/05/160524144703.htm Original web page at Science Daily

Tags Immunology, Rodents/Lags, Vaccinology

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Zika virus may cause microcephaly by hijacking human immune molecule

Post author By Vetscite
Post date June 1, 2016

The U.S. Centers for Disease Control and Prevention recently concluded that Zika virus infection in pregnant women can stunt neonatal brain development, leading to babies born with abnormally small heads, a condition known as microcephaly. Now, for the first time, researchers at University of California San Diego School of Medicine have determined one way Zika infection can damage developing brain cells. The study, published May 6, 2016 in Cell Stem Cell, also shows that inhibiting this mechanism reduces brain cell damage, hinting at a new therapeutic approach to mitigating the effects of prenatal Zika virus infection.

Using a 3D, stem cell-based model of a first-trimester human brain, the team discovered that Zika activates TLR3, a molecule human cells normally use to defend against invading viruses. In turn, hyper-activated TLR3 turns off genes that stem cells need to specialize into brain cells and turns on genes that trigger cell suicide. When the researchers inhibited TLR3, brain cell damage was reduced in this organoid model.

“We all have an innate immune system that evolved specifically to fight off viruses, but here the virus turns that very same defense mechanism against us,” said senior author Tariq Rana, PhD, professor of pediatrics at UC San Diego School of Medicine. “By activating TLR3, the Zika virus blocks genes that tell stem cells to develop into the various parts of the brain. The good news is that we have TLR3 inhibitors that can stop this from happening.”

In the study, Rana’s team first made sure their organoid model was truly representative of the early developing human brain. They found that the model’s stem cells differentiate (specialize) into the various cells of the brain in the same way that they do in the first trimester of human development. The researchers also compared patterns of gene activation in organoid cells to a database of human brain genetic information. They found that, genetically speaking, their organoid model closely resembled fetal brain tissue at eight to nine weeks post-conception.

When the team added a prototype Zika virus strain to the 3D brain model, the organoid shrank. Five days after the infection, healthy, mock-infected brain organoids had grown an average of 22.6 percent. In contrast, the Zika-infected organoids had decreased in size by an average 16 percent.

Rana’s team also noticed that the TLR3 gene was activated in the Zika virus-infected organoids. TLR3 is a protein found both inside and attached to the outside of cells. TLR3’s only job is to act as an antenna, sensing double-stranded RNA specific to viruses. When viral RNA binds TLR3, it kicks off an immune response. To do that, TLR3 helps activate many different genes that aid in fighting an infection. However, in developing brain cells, the researchers found TLR3 activation also influences 41 genes that add up to a double whammy in this model — diminished stem cell differentiation into brain cells and increased cell suicide, a carefully controlled process known as apoptosis.

To determine whether TLR3 activation could be the cause of Zika-induced organoid shrinkage — and therefore perhaps microcephaly — or merely a symptom of it, Rana’s team treated some of the infected organoids with a TLR3 inhibitor. They found that the TLR3 inhibitor significantly tempered Zika virus’ severe effects on brain cell health and organoid size, underscoring TLR3’s role linking infection and brain damage. However, the treated organoids weren’t perfect. As evidenced by their non-smooth outer surfaces, infected but treated organoids still encountered more cell death and disruption than uninfected organoids.

While promising, this research has been conducted only in human and mouse cells growing in the laboratory thus far. In addition, the Zika virus strain used in this study (MR766) originated in Uganda, while the current Zika outbreak in Latin America involves a slightly different strain that originated in Asia.

“We used this 3D model of early human brain development to help find one mechanism by which Zika virus causes microcephaly in developing fetuses,” Rana said, “but we anticipate that other researchers will now also use this same scalable, reproducible system to study other aspects of the infection and test potential therapeutics.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/05/160506132202.htm Original web page at Science Daily

Tags Cell Biology, Immunology, Virology

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Researchers show ‘dirty mice’ could clean up immune system research

Post author By Vetscite
Post date May 17, 2016

Scientists at the University of Minnesota have developed a new way to study mice that better mimics the immune system of adult humans and which could significantly improve ways to test potential therapeutics. Published online in the journal Nature, the researchers describe the limitations of laboratory mice for immunology research and reveal the benefits of what they are calling “dirty mice.”

“Standard lab mice don’t reflect important features of the adult human immune system. We wanted to know whether this is because lab animals are shielded from microbes that normal mice encounter in the wild,” said Stephen Jameson, Ph.D., co-senior author, professor in the Department of Laboratory Medicine and Pathology and member of the Center for Immunology, University of Minnesota. “Lab mice remain critical for basic immunology research, but it was important to find a better way to model the complex immune system of adult humans.”

To do so, the group caught mice in barns or purchased them at pet stores and carefully compared their immune system to that of humans. The free-living, or dirty, mice better mirrored immune cell types and tissue distribution found in adult humans. In contrast, the immune system in lab mice which are sheltered from natural microbial exposure were more strongly matched with newborn humans.

When genetically homogenous lab mice were co-housed with dirty mice this restored more normal microbial experience and allowed the immune system of the lab mice to adapt and better recapitulate the adult human immune system.

“This model could provide an important addition to basic research into immunology and the many biological processes and diseases that are impacted by inflammation,” said David Masopust, Ph.D., co-senior author, associate professor in the Department of Microbiology and Immunology and member of the Center for Immunology, University of Minnesota. “Utilizing this model to test vaccinations and therapeutics for cancer or transplantation may better predict how these will perform in humans.”

The use of standard lab mice has led to numerous breakthroughs in biomedical research, including studies that led to recent advances in cancer immunotherapy. However, this study shows the immune system in lab mice may not be fully normalized without a more complete microbial exposure. Hence these so-called dirty mice offer a substantial advance over current models, providing increased translational potential for human disease and better therapeutic models without sacrificing established and powerful research tools.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/04/160420151554.htm Original web page at Science Daily

Tags Immunology, Rodents/Lags

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Critical to screen patients with rheumatoid arthritis for hearing impairment

Post author By Vetscite
Post date May 17, 2016

Rheumatoid arthritis (RA) is the most common autoimmune arthritis, affecting 1% of the general population. Despite its main articular manifestations, RA can involve extra-articular organs including the auditory system.

HI in RA is multifactorial. Mechanism of injury and predisposing factors are not clearly understood. Sensorineural hearing loss is the most common type in RA patients with a prevalence of 25-72%. Possible pathologies are including: Synovial destruction of incudostapedial and incudomalleolar joints, rheumatoid nodules, auditory neuropathy, destruction of the cochlear hair cells and drug-induced ototoxicity. “Elderly Patients and those with long disease duration, active disease, seropositivity, elevated acute phase reactants and rheumatoid nodules are more likely to have HI,” demonstrated a recent study by Amir Emamifar, Kristine Bjørndal and Inger Marie Jensen Hansen.

Environmental factors for instance smoking, alcohol and noise can deteriorate the condition. Passive smokers are also at risk of HI. Long-term exposure to alcohol affects hearing in RA, causing harmful effects on the cochlear function.

Results of pure tone audiometry revealed that RA patients have high prevalence of HI for all frequencies. Transiently Evoked Otoacoustic Emissions (TEOAEs) test has been used widely to evaluate cochlear function, and is capable of detecting various amounts of decreases in RA patients at an early stage of the disease.

Treatment of HI in RA is empirical. Oral steroids and intensifying Disease-Modifying Antirheumatic Drugs might be an option. Anti-oxidants (eg. vitamin E) may play a protective role for the inner ear. Regular audiometric test and TEOAEs should be performed. Patients will also benefit from the cessation of smoking and alcohol. Like other causes of HI in healthy individuals, HI in RA can also be managed by use of different types of hearing aids and implantable devices.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/04/160422115526.htm Original web page at Science Daily

Tags Human, Immunology

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Treating myasthenia gravis with autologous hematopoietic stem cell transplants

Post author By Vetscite
Post date May 3, 2016

A report on seven cases of severe myasthenia gravis (an autoimmune disease characterized by severe muscle weakness) suggests that autologous hematopoietic stem cell transplantation (when a patient’s own stem cells are used) may result in long-term remission that is symptom and treatment free, according to an article published online by JAMA Neurology.

The study by Harold Atkins, M.D., F.R.C.P.C., of the University of Ottawa and the Ottawa Hospital, Canada, and coauthors reports outcomes at the Ottawa Hospital from 2001 through 2014.

All of the patients who were treated had persistent severe or life-threatening symptoms related to myasthenia gravis (MG), although they had used intensive immunosuppressive therapies.

“The ability to control autoimmunity by autologous HSCT [hematopoietic stem cell transplantation] has been demonstrated in other treatment-refractory autoimmune conditions, including neurologic diseases. … The role of autologous HSCT for MG warrants further exploration with prospective testing,” the authors conclude.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/04/160404133932.htm Original web page at Science Daily

Tags Cell Biology, Human, Immunology

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* On the road to allergy prophylaxis

Post author By Vetscite
Post date May 3, 2016

Researchers of MedUni Vienna succeeded in binding allergens to endogenous, endogenic white blood corpuscles to trigger a tolerance reaction in case of a future, possible contact with the respective allergen. The results in animal models are promising and give rise to hope that it may be possible in future to prevent allergens before they appear — be it by “vaccination” with endogenic cells or other vaccination strategies.

For this purpose, the researchers availed themselves of a method which is, in fact, originally applied in transplantation medicine — namely the triggering of an immunological tolerance reaction for the donor organ. Accordingly, the study, now published in EBioMedicine, is a cooperation between the University Clinic for Surgery (Thomas Wekerle, Ulrike Baranyi) and the Institute for Pathophysiology and Allergy Research of MedUni Vienna (Rudolf Valenta).

The pivotal result: The mice, whose white blood corpuscles were combined with the respective allergens — these are proteins to which the immune system reacts more intensive in case of an allergy — remain consistently resistant also with respect to the allergy. Initially, the cells (white blood corpuscles) are removed, “diluted” with the allergen and subsequently re-injected into the organism together with a biologicum known from rheumatology (effective ingredient Abatacept) and an agent from immunosuppression and oncology (Sirolimus). The allergen, thus introduced, practically sleeps on the cell similar to a “Trojan Horse”; once a contact is established with the allergen, i.e. through grass pollen, the body is immune against this “attack” from the outside.

Thomas Wekerle, expert for transplantation immunology at MedUni Vienna: “The long-term effect gives rise to the hope for our vision of a life-long protection from allergies with a single vaccination. However, it is much too early for an application in the clinic.” This requires further studies over many years. Principally, particularly risk groups could be initially vaccinated — e.g. children, whose parents suffer from allergies. Objective: to prevent the allergy from breaking out at all to avoid severe consequences such as asthma.

In Austria, approximately every fifth person suffers from allergies, tendency rising. “Often, it starts with hay fever, but can frequently lead to asthma up to life-threatening symptoms,” explains allergy researcher Rudolf Valenta. All the more important is the early recognition and respective treatment. The new findings may be a major step in this direction.

As Valenta states, it is practical that there is a virtual map of allergens. “It is known precisely which allergens work at an allergy; thus, one could use this fact to specifically immunise cells and render them tolerant.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/04/160414081841.htm Original web page at Science Daily

Tags Immunology, rodents

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Precision medicine’s potential to define the genetics of autoimmune disease

Post author By Vetscite
Post date April 20, 2016

Precision medicine is an emerging field that aims to deliver highly personalized health care by understanding how individual differences in genetics, environment, and lifestyle impact health and disease.

SLE, commonly called lupus, is a serious, potentially fatal autoimmune disease that the National Institutes of Health reports affects nine times more women than men, and is more likely to strike young African-American, Hispanic, Asian, and Native American women. The disease often begins between the ages of 15 and 44.

“SLE starts when the immune system attacks multiple organ systems in the body, which can result in a complex array of symptoms that are difficult to manage clinically and can lead to organ damage,” said Dr. Edward Wakeland, Chair of Immunology at UT Southwestern and co-senior author of the study posted online recently in the journal eLife. “Our findings support the potential of precision medicine to provide clinically relevant information about genetic susceptibility that may ultimately improve diagnosis and treatment.”

The study also may have implications for other systemic autoimmune diseases, a category of diseases that affect multiple body systems and includes Type 1 diabetes, rheumatoid arthritis, and multiple sclerosis, he said.

Dr. Wakeland and colleagues sequenced millions of DNA base pairs from more than 1,700 people, which allowed precise identification of the genetic variations contributing to SLE, he said. Specifically, the researchers identified 1,206 DNA variations located in 16 different regions of the human genome associated with increased susceptibility to SLE. They then showed that almost all of them (1,199) modify the level of expression of specific molecules that regulate immune responses, he said.

In addition, the two-year study identified many of the specific regulatory variations that were changed in SLE patients and demonstrated that accurately identifying such so-called causal variants increased the accuracy of the genetic association of individual SLE risk genes with susceptibility to SLE.

“Prior to our study, such a comprehensive sequence analysis had not been done and little was known about the exact genetic variations that modify the functions of the genes that cause SLE,” added Dr. Wakeland, who holds the Edwin L. Cox Distinguished Chair in Immunology and Genetics.

The scientists began their comprehensive sequence analysis using the DNA samples of 1,349 American Europeans (773 with SLE disease and 576 without) from sample collections at UT Southwestern, the University of Southern California, UCLA, Oklahoma Medical Research Foundation, and the Université Catholique de Louvain in Belgium.

They then determined the precise DNA sequences at SLE-associated genetic regions scattered throughout the genome. They found that SLE risk is associated with specific clusters of DNA variations, commonly called haplotypes, and that some haplotypes increased the risk for SLE while others provided protection from SLE.

After identifying the sets of DNA variants that increased SLE susceptibility in Caucasians, they used multiple public databases, including the international 1000 Genomes Project (2,504 genomic samples from the global human population) to determine whether these haplotypes also were found in South American, South Asian, African, and East Asian populations.

They discovered that the variants and haplotypes were distributed across subpopulations worldwide. Their findings indicate that many common haplotypes in the immune system are shared at different frequencies throughout the global population, suggesting that these variations in the immune system have ancient origins and persist in populations for long periods, Dr. Wakeland said.

“We thank the many SLE patients and control participants whose sample contributions were essential for these studies,” the researchers wrote.

Dr. Wakeland and colleagues plan to continue the research by obtaining more DNA samples and expanding their analysis to additional SLE risk genes with the goal of obtaining a data set that can be used to predict an individual’s unique risk of SLE, as well as the likelihood of benefiting from specific treatments.

“It is feasible that this same type of genetic analysis will allow the clustering of SLE patients into specific groups, based on their genetic predispositions, which would improve clinical management and potentially allow the development of more targeted therapies,” Dr. Wakeland said.

Earlier this month, UT Southwestern announced that Dr. Wakeland, whose laboratory has long served as the institution’s Genomics and Microarray Core Facility, will be leading a large DNA-sequencing initiative to address important clinical challenges. The new clinical sequencing facility, in collaboration with the Department of Pathology, will provide panel sequencing for cancer and other diagnoses, and eventually expand to whole-exome and whole-genome sequence analysis for a variety of patients. The laboratory will be established in the BioCenter on the East Campus. To commit full effort to this initiative, Dr. Wakeland will step down as Chair of Immunology, but will remain in this role until his successor is named.

“This clinical sequencing core facility will generate laboratory data to be used for the evaluation of patient tumors. I hope we will someday expand to genotyping patients to identify potential susceptibility to autoimmune disease and many other conditions as the field of precision medicine develops,” Dr. Wakeland said.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/03/160318144531.htm Original web page at Science Daily

Tags Human, Immunology

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The up- and downside of caloric restriction for aging and health

Post author By Vetscite
Post date April 20, 2016

It’s already well known that a diet may have a life-extending effect. Researchers from Leibniz Institute on Aging — Fritz Lipmann Institute (FLI) in Jena, Germany, now showed that besides improving the functionality of stem cells in mice, a caloric restriction also leads to a fatale weakening of their immune system — counteracting the life-lengthening effect of a diet. The results are published in the Journal of Experimental Medicine on March, 14. 2016.

Only few years ago, researchers succeeded in prolonging the lifespan of worm C. elegans, fruit fly D. melongaster and rats by almost 50% through a simple caloric restriction — which immediately fueled hopes for having found one key to a longer life also for humans. However, transferring these results to long-lived primates short after was not equally successful and cooled down enthusiasms quite quickly. Now, aging researcher Karl Lenhard Rudolph, Scientific Director at the Leibniz Institute on Aging — Fritz Lipmann Institute (FLI) in Jena, Germany, and his team showed that caloric restriction even has a severe downside. In feeding experiments, the stem cells of mice, which were set on a diet, were found to age slower — but the murine immune system was almost completely cut down. Outside of optimal, sterile laboratory conditions, this could lead to severe live-shortening infections. The results of the study are published in the Journal of Experimental Medicine’s current issue.

The study focused on the effects of caloric restriction on blood stem cells (so-called hematopoietic stem cells, HSC) that are responsible for building red blood cells or lymphocytes (immune cells). Like for any other adult stem cell, HSC functionality decreases with every single cell division — the stem cells age. This is why they stay in a resting phase (quiescence) most of the time and are only activated when a massive cell reproduction is required (e.g. after acute blood loss). In their study, the researchers from Jena investigated how a 30% food restriction effects stem cell aging in mice. One main result was that the HSC stayed in a quiescent state even if simulated stress would have required their activation. This effect was found regardless of how long the diet lasted. Thus, during diet, the blood stem cells did not age at all and their functionality to build new blood cells remained increased even one year after diet.

But the long-term diet had a downside, as well: The mice’s immune system almost completely was cut down. Although the diet had no strong effect on the overall cell number of blood cells, the production of lymphocytes — needed for immune defense — was decreased by up to 75%. As a consequence, mice were particularly prone to bacterial infections.

“The study provides the first experimental evidence that long-term caloric restriction — as intervention to slow down aging — increases stem cell functionality, but results in immune defects in the context of prolonged bacterial infection, too. Thus, positive effects of a diet are not transferable to humans one to one,” Rudolph sums up the study results. Even if — under laboratory conditions — aging of single cells or tissues may be slowed down through a diet, the immune suppression may have fatal consequences in real life. To benefit from caloric restriction or medicinal mimetika aiming at increasing health in the elderly, possible risks of such interventions to come down with life-threatening infections remain to be elucidated. “In sepsis patients, we see a higher survival rate for those with a higher body weight than for patients who are very lean,” Prof. Dr. Michael Bauer, Director of the Center for Sepsis Control and Care at University Hospital Jena (UKJ), concurs.

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/03/160314101759.htm Original web page at Science Daily

Tags Cell Biology, Immunology, Rodents/Lags

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Moments of acute stress can cause molecular alterations in immune response

Post author By Vetscite
Post date April 6, 2016

Chronic psychosocial and emotional stress has well-documented negative effects upon the human immune system, measurably increasing the risk of disease. Much less is known about the health effects of acute but transitory episodes of stress, such as jumping out of an airplane. Do these panic-inducing moments also raise the risk of stress-related conditions and disorders, such as cardiovascular disease, sleep dysfunction, impaired wound healing, depression and obesity?

A team of researchers at University of California, San Diego School of Medicine, Stony Brook University in New York and elsewhere addressed that question by asking study participants to literally jump out of a plane, taking blood samples before and after to measure key immune response indicators. Their findings are published in the March 4 issue of Brain, Behavior and Immunity.

“In our everyday lives, acute stress is manageable and does not cause physiological damage,” said study co-author Brinda Rana, PhD, associate professor in the Department of Psychiatry at UC San Diego School of Medicine. “However, for those who experience it frequently, it can be a risk for chronic diseases and disorders, such as cardiovascular and immune modulated inflammation. And since the health of the immune system is crucial to protection against pathogens and other diseases, it’s important to understand the impact of stressful life events on the ability of our immune system to properly do its job.”

The study involved 39 individuals (24 males, 15 females) who had independently contacted a New York-area skydiving school to schedule a first-time tandem sky dive in which the student skydiver was connected by harness to an instructor who guided the student through the jump, freefall and landing.

All of the participants were healthy adults with no history of cardiac or mental illness. They were divided into two groups: 13 would have their RNA expression profiles measured to understand molecular signatures associated with stress, and 26 would be studied by flow cytometry to access changes in immune cell composition in blood.

Blood sampling was precisely scheduled by the lab of co-author Lilianne R. Mujica-Parodi, PhD, associate professor in the Department of Biomedical Engineering at Stony Brook University. Participants provided a baseline blood sample at 9:15 a.m. within one week prior to or one day after the sky dive. On the day of the skydive, all participants awoke at 6:30 a.m. and arrived at Stony Brook University Hospital at 7:30 a.m. where “pre-boarding” samples were collected at 9:15 a.m., one hour before take-off.

The actual jump occurred at 10:30 a.m., when the airplane reached an altitude of 11,550 feet. Skydivers landed five minutes later, with post-landing samples taken at 10:45 a.m. and again at 11:30 a.m. back at the hospital.

“Our tandem skydive instructor is also a phlebotomist,” said Mujica-Parodi. “He carried the blood draw supplies with him on the jump and was poised to draw blood as soon as the skydivers hit the ground.”

In addition, saliva samples were collected every 15 minutes from 9:15 a.m. to 11:30 a.m. on both the day of the sky dive and the baseline hospital day

Previous research has shown that acute, short-term stress provokes a mixed bag of immune responses, some beneficial, some not. For example, numbers of natural killer cells, which are part of the innate immune response, increase, but skin healing capacity is reduced. The novelty of the study, said Rana, is leveraging advanced computational and molecular tools to assess large-scale immune system responses, to more finely detail the effects of acute, short-term stress.

“Our study is the first to probe the rapid transcriptomic (messenger RNA) changes in white blood cells that occur before and after an acute psychological stressor,” said Rana. “We identified specific genes and pathways involved in both the innate and the adaptive immune response that were dysregulated in response to the acute stress of the sky dive, and which returned rapidly to natural baseline levels one hour after the jump.”

Interestingly, the researchers noted that modules of coordinately expressed genes responding to stress were different between male and female skydivers, which they say may help explain gender differences observed in development of stress related cardiovascular and autoimmune disorders, as well as conditions like post-traumatic stress disorder (which is twice as common in women).

Nadejda Beliakova-Bethell, PhD, first co-author of the study and an assistant project scientist at UC San Diego, with background in infectious diseases, said while the research was exploratory, it laid the foundation for future, more detailed experiments to elucidate the contribution of stressful life events and exposure to pathogens to the functioning of the immune system.

“The immune response to stress is similar to the response to pathogens,” said Beliakova-Bethell. “An instance of an acute stress or infection activates the immune system, while chronic stress or infection results in the exhaustion of the immune system, making it less effective at responding to new stressful events or new pathogens. The effects on the transcriptome of white blood cells, observed in this study, were very transient, returning to baseline levels within one hour after landing, but with repeated acute or chronic stress, these transcriptomic changes would be expected to be more permanent, and may be similar, at least in part, to the effects of chronic viral infection.

“Future studies could make an important contribution to identifying gene targets for developing therapeutic strategies that would help people to cope with the prolonged effects of a stressor or to fight new infections. This would be specifically important for the elderly, who would have accumulated effects of stressors and infections throughout their lifetimes.”

https://www.sciencedaily.com/ Science Daily

https://www.sciencedaily.com/releases/2016/03/160301174009.htm Original web page at Science Daily

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Its complicated: Benefits and toxicity of antiprion antibodies in the brain

Post author By Vetscite
Post date February 23, 2016

Immunotherapy to ameliorate neurodegeneration by targeting brain protein aggregates with antibodies is an area of intense investigation. A study published on January 28th in PLOS Pathogens examines seemingly contradictory earlier results of targeting the prion protein and proposes a cautionary way forward to further test related therapeutic approaches.

Damaging aggregation of proteins in the brain is a hallmark of several neurodegenerative diseases, including Alzheimer and Parkinson diseases. In prion diseases such as Creutzfeld-Jakob disease, aggregates of abnormally folded versions of the PrP protein cause the death of brain cells. The use of anti-PrP antibodies to target such aggregates and mediate their destruction by the immune system has been proposed as a therapy, with the caveat that such antibodies could themselves be toxic.

Prompted by the publication of seemingly contradictory reports on the potential neurotoxicity of antibodies against the prion protein in mice, Adriano Aguzzi from the University of Zurich, Switzerland, and colleagues set out to rigorously test several antibodies side-by-side. The researchers examined whether toxicity was influenced by where and how the antibodies were delivered into the brain, the antibody dose, which area on the PrP protein the antibodies bind to, and the genetic background of the mice.

For several of the antibodies, they found, toxicity depended strictly on the administered dose, results that could explain some of the seemingly different earlier results. Other factors tested, including which target regions (or epitopes) on the PrP protein the antibodies bound to, also seemed to affect the toxicity of at least some antibodies.

Because the researchers observed toxicity for most of the antibodies that bind to the so-called globular region of PrP, they conclude that such antibodies might not be suitable for immunotherapy. In contrast, since no toxicity was found in tests of antibodies against the flexible tail region of PrP, they suggest that those might be more promising candidates.

“In summary,” they say, “these data illustrate that the efficacy profile (i.e. the curative effectiveness versus the potential toxicity) of anti-prion antibodies is complex and depends both on intrinsic factors such as, crucially, the nature of the engaged epitope, and extrinsic factors such as the route of administration. Detailed analyses and mapping of the involved epitopes and–most importantly–appropriate dose-escalation studies in vivo are prerequisite not only for preparing clinical trials in humans, but also to avoid the reporting of contradictory, confusing, and potentially misleading results.”

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2016/01/160128151934.htm Original web page at Science Daily

Tags Immunology, Rodents/Lags, Toxicology

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How herpes virus tricks the immune system

Post author By Vetscite
Post date February 23, 2016

With over half the U.S. population infected, most people are familiar with the pesky cold sore outbreaks caused by the herpes virus. The virus outsmarts the immune system by interfering with the process that normally allows immune cells to recognize and destroy foreign invaders. How exactly the herpes simplex 1 virus pulls off its nifty scheme has long been elusive to scientists.

Now new research from The Rockefeller University sheds light on the phenomenon. A team of structural biologists in Jue Chen’s Laboratory of Membrane Biology and Biophysics have captured atomic images of the virus in action, revealing how it inserts itself into another protein to cause a traffic jam in an important immune system pathway. The findings were published in Nature on January 20.

“This work illustrates a striking example of how a persistent virus evades the immune system,” says Chen. “Once this virus enters the body, it never leaves. Our findings provide a mechanistic explanation for how it’s able to escape detection by immune cells.”

When a virus enters the body, it gets chewed up inside cells, and little pieces end up stuck to the outside of the cell. “These pieces act like a barcode to immune cells, which sense that a pathogen is present, and attack,” says senior research associate and first author of the paper, Michael Oldham.

One piece of the machinery involved in getting bits of virus to the cell’s surface is a protein called TAP. It’s a transporter that acts as a bridge to move the virus pieces across the membrane of the endoplasmic reticulum, a structure within the cell that packages the virus bits. From here they move to the cell’s surface, alerting immune cells to the virus’s presence.

“We knew that TAP was involved in our inability to have an effective immune response to this virus, but no one really knew what TAP looks like, or how it works,” says Chen. “Our findings show exactly how this viral protein jams TAP, which has two effects. One, it precludes the regular protein from binding. Two, it makes the transporter stuck in this conformation.”

It has been notoriously difficult to investigate the structure of proteins embedded in cellular membranes, such as TAP, because the samples are not stable and disintegrate easily. In this study, the researchers used a technique known as cryo-electron microscopy, in which the purified protein is frozen in a thin layer of ice. This stabilizes the sample, allowing scientists to retrieve data and computationally determine the structure.

The usefulness of cryo-EM was previously restricted by its inability to yield detailed molecular structures, but recent breakthroughs in detector technology now allow the capture of structural information at the scale of tenths of nanometers. Through a collaboration with Thomas Walz, head of the Laboratory of Molecular Electron Microscopy at Rockefeller, and using sophisticated cryo-EM tools, Chen’s team was able to investigate TAP’s structure in great detail.

Therapeutics to prevent cold sores is not something that will emerge in the near future, due to the complexities involved in creating a drug specific enough to only affect certain transporters. Accidentally interfering with TAP or other similar transporters in an unintended way would likely disrupt many cellular processes and cause major side effects.

However, understanding the various ways viruses block transporters could be harnessed for treating other diseases. TAP is a member of a family of transporters that are found across human cells, a number of which pump molecules like nutrients and drugs across membranes to various cellular compartments. These transporters often pump chemotherapy drugs out of the compartments they are needed in, rendering the drugs useless. Inhibiting these transporters for a short period of time could allow the chemotherapy to stay where it’s needed and function effectively.

“We haven’t been able to figure out how to block these transporters ourselves,” says Chen, “so we are learning how it’s done from viruses, which we hope will teach us some strategies for inhibition.”

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2016/02/160204094928.htm Original web page at Science Daily

Tags Immunology, Virology

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* Immune response differences might determine severity of West Nile Virus disease

Post author By Vetscite
Post date February 9, 2016

While most West Nile Virus (WNV) infections in humans are asymptomatic and go unnoticed, the virus causes serious and sometimes fatal neurologic illness in some people. A study published on January 21st in PLOS Pathogens suggests that an exaggerated and abnormal immune response contributes to the development of neurologic symptoms following West Nile virus infection.

William Kwok and Eddie James, both from the Benaroya Research Institute at Virginia Mason in Seattle, USA, and colleagues are interested in what determines the different outcomes of WNV infection, and whether differences in the immune response play a role. In this study, they compare the immune responses in samples from 24 blood donors who had earlier asymptomatic infections (confirmed by laboratory tests) with those in blood samples from 16 individuals diagnosed with WNV infections that had caused neuro-invasive disease with neurologic symptoms including confusion, tremors, seizures, paralysis, and vision loss.

Because CD4+ (helper) T cell responses have been shown to be sufficient for protection from WNV challenge (independent of B cells and CD8+ T cells) and crucial for viral clearance from the CNS, the researchers focused on the WNV-specific CD4+ T cell repertoires present in the blood samples.

They observed that older individuals had higher numbers of WNV-specific T cells. In addition, WNV-specific cell lines isolated from older individuals had a higher proportion of T cells that produced IFN-γ, and also a higher proportion that co-produced IFN-γ and IL-4 (both molecules that promote a strong immune response).

Comparing the magnitude and characteristics of WNV-specific CD4+ T cell response in individuals of similar ages with either neuroinvasive disease or asymptomatic infection, the researchers found that, independent of age, individuals with neuroinvasive disease had higher numbers of WNV-specific CD4+ T cells. In addition, those T cells that responded to the virus more frequently co-produced IFN-γ and IL-4. Moreover, the gene expression responses in CD4+ T cells stimulated with WNV differed between individuals with previous asymptomatic infection and those who had neuro-invasive WNV disease.

The researchers conclude that “individuals with neuroinvasive West Nile Virus infections have exaggerated and atypical responses to the virus.” And while they acknowledge several limitations of the study, including the lack of data on the immune response close to the time of infection (the blood samples were drawn months and sometimes years after the diagnosis of WNV infection), they suggest that “immune mediated damage may indeed contribute to neurologic symptoms and pathogenic outcomes in the setting of WNV infection.”

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2016/01/160121145135.htm Original web page at Science Daily

Tags Human, Immunology, Virology

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* Scientists prevent, reverse diabetes-related kidney destruction in animal model

Post author By Vetscite
Post date January 26, 2016

Diabetes is the leading cause of kidney failure, and scientists have found that infusing just a small dose of a cytokine, thought to help cause that failure, can instead prevent or reverse it.

The cytokine IL-17A has long been considered a classic promoter of inflammation, which plays a major role in progression of diabetes-related kidney disease, or diabetic nephropathy, said Dr. Ganesan Ramesh, kidney pathologist at the Vascular Biology Center at the Medical College of Georgia at Augusta University.

His lab was pursuing its role in kidney damage but found that when they deleted the IL-17 gene in mice, then induced diabetes, it resulted in increased kidney injury, Ramesh said. They looked next at patients with severe diabetic nephropathy, and found levels of IL-17A reduced in their blood and urine.

In follow-up studies in animal models of both type 1 and type 2 diabetes, IL-17A’s surprising role grew: When researchers infused a small amount of IL-17A every 48 hours for several weeks, it prevented or reversed diabetic nephropathy in their diabetes models. In fact, the therapy worked best in late-stage diabetic nephropathy, Ramesh said. IL-17A therapy also reduced high levels of fat in the blood, a hallmark of type 2 diabetes that is believed to contribute to related kidney and cardiovascular problems.

“It clearly indicates that IL-17A is protective,” Ramesh said. “It does well for the kidney in suppressing damage in response to diabetes.” Ramesh is corresponding author of the study, published in the Journal of the American Society of Nephrology, which is the first to look at IL-17’s role in chronic kidney disease.

IL-17A seems to protect kidney cells multiple ways, including inducing the anti-inflammatory molecule AMWAP, or activated microglia/macrophage WAP domain protein. The cytokine also appeared to aid survival and regeneration of key kidney cells, including podocytes and epithelial cells in the tubules. Podocytes help the kidney retain important large molecules such as protein, and epithelial cells line tubules where these essentials are reabsorbed.

To date, the MCG research team has seen no ill effects from overexpressing IL-17A in mice kidneys and to some extent in their circulation. Currently, there are no drugs available to increase patients’ IL-17A levels, but there are inhibitors for the cytokine that is considered causative in autoimmune diseases such as Crohn’s. Emerging laboratory and clinical trial data indicate there may need to be drugs that do both.

As examples, in a clinical trial of an antibody for IL-17A in patients with Crohn’s, the drug did not seem to help patients, and, in fact, some patients reported worsening symptoms. However, the National Psoriasis Foundation reports good experience with the use of biologics that block 1L-17 for the skin disorder. Meanwhile, French researchers have shown that giving IL-17A to mice suppressed the development of atherosclerosis, while a deficiency in the cytokine gene accelerated development of the arterial disease associated with inflammation.

The MCG researchers note that whether IL-17 promotes or suppresses inflammation may be related to the level and length of time it’s stimulated. Response may also depend on which of the six different forms of IL-17 is activated, the receptors activated and resulting downstream signaling. In their studies, for example, increasing IL-17C and IL-17E levels did not have the same positive effect on diabetic nephropathy as IL-17A as well as IL-17F.

In follow up to the therapy’s particular success with advanced disease, next steps include examining its impact on essentially destroyed kidneys. “If you can recover function from the dead kidney, you could save millions of people from a lifetime of dialysis,” Ramesh said.

A primary way physicians check kidney function is looking for signs of patients excreting the protein albumin in their urine. Albumin, which is made by the liver, is a major protein in the blood that helps keep blood from leaking out of blood vessels and helps keep other vital substances such as nutrients and hormones in the blood. Well-functioning kidneys retain albumin, and, even on dialysis, patients with diabetic nephropathy secrete a lot of protein in their urine.

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2015/12/151228161255.htm Original web page at Science Daily

Tags Genetics, Immunology, Rodents/Lags

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Land use may weaken amphibians’ capacity to fight infection, disease

Post author By Vetscite
Post date January 13, 2016

Human-made changes to the environment may be damaging the immune systems of a species of frog whose populations have drastically declined since the 1970s, according to a new study by researchers at Case Western Reserve University and the Holden Arboretum.

“These Blanchard’s cricket frogs have nearly gone extinct in their northern range, so we’re almost forensically trying to understand what happened,” said Mike Benard, a biology professor at Case Western Reserve. “This study suggests that changes we are making to the environment have the potential to make animals more susceptible to diseases and therefore may lead to population declines.”

Scientists found that habitat characteristics explained the differences in immune defense traits of frogs between populations. They found that the skin microbiomes ?symbiotic bacterial and fungal communities on the skin ?of frogs from disturbed sites, like residential and agricultural lands, were different from the skin microbiomes of frogs from more natural habitats. They also found natural peptide secretions–proteins frogs secrete from their skin that protect against pathogens–differed between frogs from different environments. Both changes potentially alter the amphibian’s immune defense capabilities. These findings and more are published in the journal Biological Conservation.

Research is increasingly showing that microbiomes in the gut and on the skin and antimicrobial peptides excreted by humans and other animals play important roles in fighting infection and disease.

“We’re seeing a lot of disease-related declines among amphibians, not to mention other groups of animals, such as bats plagued with white-nose syndrome and bees suffering from colony collapse disorder,” said Katherine Krynak, a postdoctoral scholar in Case Western Reserve’s Department of Biology and leader of the study. “This research shows that land use–farming or treating lawns with herbicides, pesticides and fertilizers–can influence traits that protect animals from disease.”

Blanchard’s cricket frogs are about an inch long. They had once been widely spread across Wisconsin, Michigan and northern Ohio, but now only pockets remain in this northern region.

Frogs used in the study were from ponds in various habitats: natural ponds surrounded by forest or prairie, or more disturbed ponds surrounded by houses, on farmed land or near athletic fields, parking lots and golf courses. In addition to considering the physical differences, the researchers tested water chemistry and quality in each pond.

With permission from the states of Ohio and Michigan, Krynak, Benard and David Burke, a scientist and research chair at Holden Arboretum in Kirtland, Ohio, examined samples Krynak had collected from the frogs. Krynak used Q-tip like swabs to obtain samples of the skin microbiome, and then placed the frogs in a solution that gently induced the animals to secrete the antimicrobial peptides.

Krynak and Burke then used molecular methods to examine the community of microbes on the frogs’ skin. Burke, who studies symbiotic interactions between plants and microbial communities, is also an adjunct assistant professor of biology at Case Western Reserve. Krynak and Burke also examined the amount of peptides the frogs produced and how effective the peptides were against an amphibian pathogen they cultured in the lab.

The researchers found microbiome differences between frogs that live in natural areas, such as a pond owned by the Nature Conservancy, and those in ponds surrounded by highly “managed” land, such as farmland or residential properties.

“What we’re seeing is the bacteria on the skin can vary markedly, depending on what people are doing to the environment that the frogs are living in,” Burke said.

A pond’s latitude, conductivity–a proxy for chemical runoff–and size also appear to affect the microbiome.

The amount of natural peptide secretions produced from the frogs’ skin also varied across sites and was influenced by both the size of the pond and the conductivity of the water. Some of the skin secretions have been shown to fight off fungal infections, Krynak said. But in petri dishes in the lab, the growth rate of chytrid fungus, which has been linked to devastating population declines in amphibians worldwide, climbed with increasing Blanchard’s cricket frog natural peptide secretions.

The researchers will further investigate why higher concentrations of peptides appear to allow the killer fungus to grow faster in this species.

“This pattern suggests that in areas where land use increases the amount of the peptides these frogs produce, this particular pathogen could have devastating effects” Krynak said.

The team will also look more directly at how the environment interacts with a population’s genes, changing the expression of traits. “Not only may the environment be altering traits now, but it may be dampening the ability of a population to adapt in the future,” Krynak said.

They are also experimentally isolating factors such as how a commonly used and commercially available glyphosate-based herbicide may alter these immune defense traits.

Environmental alteration of defense traits may explain why different amphibian populations show different levels of resistance to infection and disease.

Krynak said there’s a strong chance that the environment is affecting these traits in other amphibians and wildlife in general.”By improving our understanding of the factors influencing immune defense traits capabilities, we are given the opportunity to make changes to our land management practices to better protect wildlife health” she said “and in all likelihood, our own health as a consequence.”

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2015/12/151216140525.htm Original web page at Science Daily

Tags Amphibians, Dermatology, Immunology

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New stem cell gene correction process puts time on researchers’ side

Post author By Vetscite
Post date December 1, 2015

Researchers from the Morgridge Institute for Research and the Murdoch Children’s Research Institute (MCRI) in Australia have devised a way to dramatically cut the time involved in reprogramming and genetically correcting stem cells, an important step to making future therapies possible.

Led by Sara Howden, a postdoctoral fellow at MCRI and formerly with the Morgridge Institute, the study demonstrates how genetically repaired stem cells can be derived from patient skin cells in as little as two weeks, compared to conventional multi-step approaches that take more than three months.

The key to the advance, published in the journal Stem Cell Reports, is to combine two essential steps in preparing cells for potential therapy. First, adult cells must be reprogrammed to an embryonic cell-like state in order to be differentiated into the cells of interest. Second, the cells need to undergo a sophisticated gene editing process to correct the disease-causing mutation.

Howden and colleagues successfully combined these two steps in skin cells derived from an adult patient with retinal degeneration, and an infant patient with severe immunodeficiency. “The method developed in our study could potentially advance transplant medicine by making gene-corrected cells available to patients in a much more timely manner, and at a lower cost,” says Howden. “It will have implications immediately for researchers working in regenerative medicine.”

Howden completed much of the research in the Morgridge Regenerative Biology Laboratory, led by stem cell pioneer James Thomson. “If you want to conduct therapies using patient-specific iPS cells, the timeline makes it hard to accomplish,” Thomson says. “If you add correcting a genetic defect, it really looks like a non-starter. You have to make the cell line, characterize it, correct it, then differentiate it to the cells of interest.”

Adds Thomson: “In this new approach, Dr. Howden succeeded in combining the reprogramming and the gene correction steps together using the new Cas9/CRISPR technology, greatly reducing the time required.” Howden says the faster process also means the cell culture period is greatly reduced, potentially minimizing the risks associated with culturing cells outside of the human body, such as genome instability or other epigenetic changes.

Induced pluripotent cells (iPS cells) hold great promise for medical research because they can essentially be derived from any individual and are capable of becoming any of the 220 types of cells in the human body. And the ability to efficiently and precisely modify the DNA in these cells offers enormous potential for the development of personalized stem cell therapies that benefit people with many different types of genetic disorders.

Howden says one potential next step is to adapt the protocol to work with blood samples. Not only is a blood draw less invasive than a skin biopsy, it also could further reduce the time to obtain genetically repaired iPS cells. Skin cells need to be expanded for several weeks before initiating reprogramming.

This “fast-tracked process” could be most influential in cases where urgent medical intervention is needed, adds Howden. One example is severe combined immunodeficiency, where children typically die within the first few years of life. However, Howden says scientists still need to derive a long-term source of blood cells from pluripotent stem cells before such treatments are viable.

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2015/11/151112123147.htm Original web page at Science Daily

Tags Genetics, Human, Immunology

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* Vulture’s scavenging secrets: Ironclad stomach, strong immune system

Post author By Vetscite
Post date November 17, 2015

Vultures have a unique genetic make-up allowing them to digest carcasses and guard themselves against constant exposure to pathogens in their diet, according to the first Eurasian vulture genome published in the open access journal Genome Biology. The study also finds that this species of Asian vulture is more closely related to the North American bald eagle than previously thought.

The cinereous vulture or black vulture, Aegypius monachus, is the largest bird of prey, and an iconic bird in the Far East. The species plays a key role in the ecosystem by removing rotting carcasses, thus preventing the spread of disease.

As their feeding habits involve constant exposure to pathogens, vultures are suspected to have strong immune systems, having evolved mechanisms to prevent infection by the microbes found in their diet. Despite the potential interest in the immune system of scavengers, little is known about the genetic variations involved in vultures’ immune processes.

Lead author Jong Bhak from Ulsan National Institute of Science and Technology, South Korea, said: “This is the first Old World vulture genome that has been reported, and we can see that the cinereous vulture has genetic signatures for resisting infection from eating decaying flesh. Understanding the genetic make-up of extreme life forms has potential for improving human health. The immune system genes we’ve identified could be useful targets in humans for protection against infection.”

The team sequenced the genome of a cinereous vulture, and compared it to that of the closely-related bald eagle, the national bird of the United States, to find genetic signatures of the dietary and environmental adaptations that help enable the vulture’s scavenging lifestyle.

Specifically, they found variations in genes related to the regulation of gastric acid secretion, consistent with their ability to digest carcasses. Other genetic variations included several in genes associated with immunity and defense against microbial and viral infections.

These included genes that allow cells to take up microorganisms and target pathogens for ingestion and elimination. The authors suggest that these may play a role in helping the vulture species combat pathogens encountered in their diet and complement the role of gastric secretion.

The term vulture refers to two groups of birds of prey that evolved independently, namely the Old World vultures, found in Africa, Asia and Europe, and the New World vultures, found in the Americas.

By analyzing its full genome, the researchers calculated that the Old World cinereous vulture species diverged from the North American bald eagle species around 18 million years ago. This split is much more recent than the divergence of the Old World and New World vultures around 60 million years ago. The results therefore add further evidence to the hypothesis that the two groups of vultures evolved their similar features and lifestyle independently in different locations.

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2015/10/151021083143.htm Original web page at Science Daily

Tags Birds (pet; ornamental; prey e.g. falcons), Immunology, Physiology (e.g. Exercise Physiology)

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Building immune system memory

Post author By Vetscite
Post date November 17, 2015

Mechanism identified for enhancing immunological memory in helper T cells. Molecular mechanisms that control an immune cell’s ability to remember have been identified by scientists. They found that in helper T (CD4+) cells, the proteins Oct1 and OCA-B work together to put immune response genes on standby so that they are easily activated when the body is re-exposed to a pathogen. The research could inform strategies for developing better vaccines, they say. Vaccines help prevent disease by inducing immunological memory, the ability of immune cells to remember and respond more quickly when re-exposed to the same pathogen. While certain phases of the pathway are well understood, little is known about the role of helper T cells, a “master orchestrator” of the immune response that send signals to activate the immune system.

A study led by the University of Utah School of Medicine has identified molecular mechanisms that control an immune cell’s ability to remember. They found that in helper T (CD4+) cells, the proteins Oct1 and OCA-B work together to put immune response genes on standby so that they are easily activated when the body is re-exposed to a pathogen. The research, which could inform strategies for developing better vaccines, was performed in collaboration with scientists from The Broad Institute and University of Michigan, and published in The Journal of Experimental Medicine.

For immunological memory to be effective, genes that are turned off in immune cells following an infection have to be rapidly turned back on when the body reencounters a pathogen. Previous work in the lab of Dean Tantin, Ph.D., senior author and associate professor in pathology at the University of Utah, showed that the transcription factor Oct1 is required for ‘poising’ Il2, a gene important for immunity, in a state where it can be activated quickly if needed.

“Oct1 is unusual in that it often times doesn’t activate a gene or repress a gene,” explained Tantin. “It can act as an insulator to prevent genes from getting permanently turned off.”

They showed that Oct1 blocks stable repression of genes involved in immunity in resting cells that had been previously activated by a pathogen. Oct1 removed epigenetic tags that ordinarily ensure that Il2 stays turned off. However, Tantin noted that the signaling cues used by Oct1 in activated cells were missing in resting memory T cells that had previously been activated, indicating that there must be another factor needed for Il2 expression.

In this study, Shakya et al. identified OCA-B as being the additional factor required for a robust immune response in resting helper T cells. OCA-B was expressed in activated and re-activated helper T cells and was required, together with Oct1, for removal of repressive epigenetic marks from the Il2 gene. Also, helper T cells from OCA-B deficient mice did not produce as much IL-2 as normal cells when stimulated in culture. The findings demonstrate that OCA-B is required for the activation of Il2, and they present evidence that it additionally regulates a group of 50 — 100 genes in re-stimulated cells.

To further investigate the importance of Oct1 and OCA-B in immunological memory, the researchers examined mice lacking either one of the two genes. Months after infection with a pathogenic virus, OCA-B or Oct1 deficient animals had fewer memory T cells compared to control animals. After reinfection with the same virus, memory cells in the Oct1 and OCA-B deficient animals failed to generate a recall response.

These findings show that Oct1 and OCA-B are involved in memory T cell function and are necessary for the helper cell memory response. Results from this research add to the understanding of how a memory response is generated, which could potentially have therapeutic applications.

“If you had pharmaceutics that could augment this process, you potentially could make better vaccines,” said Tantin. “If you interfered with it, you could inhibit memory formation or function, which might be a valid therapeutic for autoimmunity.” Future studies in his lab will pursue these therapeutic possibilities.

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2015/10/151020145351.htm Original web page at Science Daily

Tags Cell Biology, Immunology

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Immunotherapy for pancreatic cancer boosts survival by more than 75 percent in mice

Post author By Vetscite
Post date November 17, 2015

A new study in mice by researchers at Fred Hutchinson Cancer Research Center has found that a specialized type of immunotherapy — even when used without chemotherapy or radiation — can boost survival from pancreatic cancer, a nearly almost-lethal disease, by more than 75 percent. The findings are so promising, human clinical trials are planned within the next year.

The study, led by Drs. Sunil Hingorani and Phil Greenberg, both members of the Clinical Research Division at Fred Hutch, tested the immunotherapy on mice genetically engineered to grow pancreatic tumors very similar to those of human pancreatic cancer. The mouse model, developed by Hingorani, already has led to a first-in-humans clinical trial that is showing early promise in some patients with advanced pancreatic cancer.

Pancreatic cancer is notoriously difficult to treat, said Hingorani, because it recruits the body’s natural systems to construct both a tough physical barrier around tumors as well as an immune-cloaking device that keeps other, disease-fighting immune cells from recognizing the cancer.

Unlike any other cancer, pancreatic tumors are able to survive with a significantly decreased blood supply. As a consequence, chemotherapy, commonly administered via the bloodstream, has a difficult time getting inside. The tumors not only commonly grow quite large before patients will ever notice something is wrong, but they are very prone to metastasize, or spread to other sites in the body.

The investigators’ new study, published in Cancer Cell, breaches pancreatic cancer’s physical and immunological walls by using immunotherapy, a type of treatment that harnesses or refines the body’s own immune system, to recognize and destroy cancer cells. The researchers devised a therapy using T cells, disease-fighting immune cells, that they engineered in the lab to recognize and attack pancreatic cancer.

T-cell therapy is showing promise as a treatment for several types of blood cancers, based on early results from Fred Hutch and other research centers, but aiming these cells at solid tumors like pancreatic cancer has historically proven more difficult, Hingorani said. Part of the challenge comes from the access to tumor cells — or lack thereof. T-cell therapy is administered through the bloodstream, like chemo. It’s easy enough to see why solid tumors may present more of a challenge to treat with this kind of immunotherapy than blood cancers such as leukemia and lymphoma.

The researchers didn’t think the engineered T cells would stand a chance against pancreatic cancer on their own. But they needed somewhere to start, Greenberg said. But to their surprise, the T cells — engineered to recognize and kill cells bearing a protein called mesothelin, which is overproduced by virtually all pancreatic tumors — got into the mice’s tumors and started attacking them.

In the mouse model of the disease — which is actually slightly more aggressive than the human version, Hingorani said — animals that received T cells engineered to recognize a non-cancerous protein survived on average 54 days after their cancer became detectable. Those that received the mesothelin-directed cells lived an average of 96 days, a 78 percent bump.

Although the researchers weren’t expecting to take this first version of the T-cell therapy to clinic, that’s now their plan. Their team has already built the human version of the special T-cell protein that recognizes mesothelin. They’re planning to launch a phase 1 clinical trial to test the therapy’s safety in patients with advanced pancreatic cancer within the next year.

“As best we can tell, this would be a better therapy than anything that exists for pancreatic cancer right now,” Greenberg said. “It’s hard to be this optimistic without ever having treated a pancreatic cancer patient with this [therapy], but the biology of what we’re doing looks so remarkably true and good.

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2015/10/151029134114.htm Original web page at Science Daily

Tags Immunology, Oncology, Rodents/Lags

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* Reptile pets: Food insects shuttle allergens into homes

Post author By Vetscite
Post date November 17, 2015

Reptiles are often chosen as pets when an allergy risk exists within a family and the choice is made to avoid potentially allergenic pets such as dogs, cats or guinea pigs. Researchers at the Messerli Research Institute, however, recently described a noteworthy clinical case in which an eight-year-old boy developed nightly attacks of severe shortness of breath four months after the purchase of a bearded dragon.

The cause for the allergic reaction turned out not to be the lizard itself but the animal’s food. The grasshoppers used to regularly feed the lizard were revealed to be the source of the allergy.

First author Erika Jensen-Jarolim speaks of the tip of an iceberg: “Even colleagues with allergologic expertise could overlook insects as reptile food as a possible cause of such allergic reactions. Far too little is known about grasshoppers as a potential allergenic source in homes. We do know of cases, however, in which fish food has caused allergies. And insects are often processed in fish food.”

For a long time, the cause of the allergic reaction in the eight-year-old Viennese boy remained unknown. The initial diagnosis was pseudo croup, an infection of the respiratory tract, and severe asthma. Allergy expert Jensen-Jarolim and her team considered the possibility of a pet allergy and chose to also test the reptile food: grasshoppers. An allergy skin test and evidence of specific IgE antibodies finally brought certainty: grasshopper allergens were the cause of the allergic reactions in the child.

“We were in the middle of a study investigating sources of allergies at pet stores. So coming upon the reptile food was pure coincidence,” says Jensen-Jarolim. On Jensen-Jarolim’s advice, the reptile was immediately removed from the boy’s home. The symptoms abated as a result. Four years later, however, the boy exposed himself to the allergen again, which triggered an allergic asthmatic reaction even after all that time.

“We are seeing a shift in the attitude towards reptiles from a pure hobby or biological interest toward a human-animal relationship with an emotional component. It is difficult to estimate the number of reptiles and food animals living in people’s homes and the undisclosed figure is sure to be high,” Jensen-Jarolim believes. She recommends keeping reptile food outside of homes. The reptiles themselves should not be kept in living rooms, as undigested insects end up in the terraria via the faeces. This could result in pet owners inhaling the aggressive allergens, leading to allergies such as asthma or skin inflammations.

“Grasshopper allergies have been nearly unknown to date. With our publication, it is our intention to sensitise the public to this matter. We are especially concerned about people who keep such animals, pet store employees as well as physicians, who should include questions regarding reptile pets and their food as a routine in their allergy diagnostic consultation,” stresses Jensen-Jarolim.

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2015/10/151030105252.htm Original web page at Science Daily

Tags Immunology, Reptiles

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Connecting Alzheimer’s disease, immune system

Post author By Vetscite
Post date October 20, 2015

The role of the immune system in Alzheimer’s disease is a hot topic, but exactly how the two are connected and what interventions could help lower risk remain a mystery. In a new study published in Nature Neuroscience this week, researchers in the Ann Romney Center for Neurologic Diseases at Brigham and Women’s Hospital (BWH) investigate how genetic risk factors for Alzheimer’s disease may influence a key type of immune cell. Their results lay the groundwork for designing better therapeutic strategies and better prediction tools for risk of developing Alzheimer’s disease.

“There’s an emerging theme in Alzheimer’s genetics that the immune system may be strongly involved in the onset of Alzheimer’s disease,” said co-corresponding author Philip De Jager, MD, PhD, who directs the Program in Translational NeuroPsychiatric Genomics at the Ann Romney Center for Neurologic Diseases at BWH. “Before genetic studies, many thought that inflammation was a symptom of or a reaction to the disease, but our study and others build a compelling case that the immune system may be involved in the development of Alzheimer’s disease.”

De Jager and his team examined the levels of key proteins in relation to genetic variants that have been implicated in Alzheimer’s disease in the past. The team looked at blood samples from more than 100 younger, healthy subjects as well as 61 older subjects and measured protein levels in monocytes — immune cells that can travel to various sites throughout the body, including the brain where they differentiate into macrophages, specialized for their new environment, in this case the central nervous system.

One of the most intriguing results the team uncovered is connected to TREM2 — a protein that is a major target of Alzheimer’s disease drug development efforts. A previous study of a population in Iceland found that a rare mutation in the gene encoding TREM2 substantially elevated a person’s risk of Alzheimer’s disease. However, it was unclear whether more TREM2 or less TREM2 led to this heightened risk, and follow-up studies in mice have produced conflicting results.

De Jager and his colleagues found evidence that directly addresses this question, determining that higher levels of TREM2 were associated with increased risk. The team found that a genetic variant tied to a separate protein, CD33, also influenced TREM2 levels. The team’s follow-up studies confirmed that the genetic variant led to more CD33, which in turn led to more TREM2. “One interesting note about these protein associations is that we did not observe them at the mRNA level,” said first author Gail Chan, PhD, a research fellow in the Ann Romney Center for Neurologic Diseases at BWH. “This emphasizes the amount of inter-regulation that a cell does to balance all of the related molecules in order to function correctly.”

“Up until now, it’s been unclear whether it would be beneficial to increase or decrease TREM2 levels,” said co-corresponding author Elizabeth Bradshaw, PhD, of the Ann Romney Center for Neurologic Diseases at BWH. “Further studies are needed to understand the connections we’re uncovering and the roles of these proteins, but we’re clearly seeing evidence that these genetic variants have an effect in this type of immune cell.

As a next step, Bradshaw, De Jager and their colleagues plan to measure CD33 and TREM2 levels in subjects as part of the Brigham Healthy Aging Project to determine if these measurements and others could be part of a diagnostic panel for predicting risk of Alzheimer’s disease.

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2015/09/150928122539.htm Original web page at Science Daily

Tags Genetics, Human, Immunology

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Probiotic formula reverses cow’s milk allergies by changing gut bacteria of infants

Post author By Vetscite
Post date October 6, 2015

The newly tolerant infants had higher levels of several strains of bacteria that produce short chain fatty acids, such as butyrate, which help maintain homeostasis in the gut. The discovery of bacteria that drive tolerance to problem foods like cow’s milk could be crucial to developing new treatments to help children with food allergies.

There has been an unprecedented increase in food allergies in developed countries, rising by as much as 20 percent in the past decade. Allergy to cow’s milk is one of the most common, occurring in up to three percent of children worldwide.

Emerging evidence suggests that modern environmental influences, including widespread antibiotic use, high-fat and low-fiber diets, reduced exposure to infectious diseases, Caesarean birth and formula feeding have altered the mutually beneficial relationship between humans and the bacteria that live in our gastrointestinal tract. This dysbiosis, or skewing of the structure of the microbial community, can predispose genetically susceptible individuals to allergies.

Previous research from collaborator Roberto Berni Canani and his team at the University of Naples showed that infants with cow’s milk allergy who are fed formula containing a form of the milk protein casein, supplemented with the probiotic bacterial species Lactobacillus rhamnosus GG (LGG), develop tolerance at higher rates than those treated with a non-probiotic formula.

“Mouse model work from our laboratory published last year identified a common class of mucus-associated gut bacteria that play a critical role in regulating the access of dietary allergens to the bloodstream” said Cathryn Nagler, PhD, Bunning Food Allergy Professor at the University of Chicago and lead author of the study. “This suggests a novel mechanism by which commensal bacteria regulate allergic responses to food.”

To examine whether probiotic administration modulates gut bacterial composition to enhance acquisition of tolerance to cow’s milk, Nagler and colleagues performed sequence analysis to identify bacteria in stool samples collected from healthy infant subjects, infants with cow’s milk allergy who had been fed the LGG enriched probiotic formula, and those who had been fed the formula without added probiotics.

Overall, the gut microbiome of infants with a cow’s milk allergy was significantly different than healthy controls, suggesting that differences in the structure of the bacterial community indeed influence the development of allergies. Infants treated with the LGG probiotic formula who developed tolerance to cow’s milk also had higher levels of bacteria that produce butyrate than those who were fed the probiotic formula but did not develop tolerance. This further suggests that tolerance is linked to the acquisition of specific strains of bacteria, including Blautia and Coprococcus, which produce butyrate.

“The ability to identify bacterial strains that could be used as novel therapeutics for treating food allergies is a fundamental advance,” said Jack Gilbert, PhD, associate professor in the Department of Ecology & Evolution at the University of Chicago, group leader for microbial ecology at Argonne National Laboratory and co-author of the study. “Translating these findings into clinical treatments is our next goal, and one that is now possible through the new FARE Clinical Network center here at the University of Chicago.”

In July 2015, University of Chicago Medicine was among 22 centers of excellence across the country chosen by Food Allergy Research and Education (FARE) to be inaugural members of its FARE Clinical Network, which is working to accelerate development of therapies and raise the standard of care for people with life-threating food allergies. Led by medical director Christina Ciaccio, MD, assistant professor of pediatrics at the University of Chicago Medicine, the center conducts trials for promising therapies and collaborates with FARE and other centers to establish best practices for the care of patients with food allergies.

The study, “Lactobacillus rhamnosus GG-supplemented formula expands butyrate-producing bacterial strains in food allergic infants,” was supported by the National Institute of Allergy and Infectious Diseases, Food Allergy Research and Education, the Chicago Biomedical Consortium and the Italian Ministry of Health.

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2015/09/150922104647.htm Original web page at Science Daily

Tags Human, Immunology

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Growing up on a farm provides protection against asthma and allergies

Post author By Vetscite
Post date September 22, 2015

Researchers at VIB (a leading life sciences institute in Flanders, Belgium) and Ghent University have successfully established a causal relationship between exposure to so-called farm dust and protection against asthma and allergies. This breakthrough discovery is a major step forward towards the development of an asthma vaccine. The results of the research were published in the journal Science.

It is commonly known that drinking raw cow’s milk can provide protection against allergies. A 14-member research team, led by professors Bart Lambrecht and Hamida Hammad (both associated with VIB and Ghent University) has now established a solid scientific basis for this claim.

Many years ago, it was found that children growing up on farms are far better protected against asthma and allergies. However, until recently, scientists were unable to pinpoint why this is the case.

Prof. Bart Lambrecht (VIB/Ghent University/Ghent University Hospital): “At this point, we have revealed an actual link between farm dust and protection against asthma and allergies. We did this by exposing mice to farm dust extract from Germany and Switzerland. These tests revealed that the mice were fully protected against house dust mite allergy, the most common cause for allergies in humans.

In addition to the causal relationship, the scientists discovered the mechanism behind this: farm dust makes the mucous membrane inside the respiratory tracts react less severely to allergens such as house dust mite.

Prof. Hamida Hammad (VIB/Ghent University): “This effect is created by the A20 protein, which the body produces upon contact with farm dust. When we inactivate the A20 protein in the mucous membrane of the lungs, farm dust is no longer able to reduce an allergic or asthmatic reaction.”

These findings were then tested in patients. The results showed that people suffering from allergies and asthma have a deficiency in the protective protein A20. It explains why they react to allergens so severely.

Prof. Bart Lambrecht (VIB/Ghent University/Ghent University Hospital): “We also assessed a test group of 2,000 children growing up on farms, and found that most of them are protected. Those who are not protected and still develop allergies have a genetic variant of the A20 gene which causes the A20 protein to malfunction.” The team’s conclusions have opened up several possibilities for future research. At the moment, they are trying to identify the active substance in farm dust that is responsible for providing protection. Once this has been identified, the development of a preventive medicine against asthma may be the next step.

Prof. Hamida Hammad (VIB/Ghent University): “We already suspect that to some extent, the answer lies in the endotoxines, which form part of the cell wall of specific bacteria. There are very likely other contributing substances as well. Discovering how farm dust provides this type of protection has certainly put us on the right track towards developing an asthma vaccine and new allergy therapies. However, several years of research are required still before they will be available to patients.” The research was conducted at the VIB Inflammation Research Center, UGent, in partnership with researchers from Munich, Rotterdam and Marseille.

http://www.sciencedaily.com/ Science Daily

http://www.sciencedaily.com/releases/2015/09/150903144647.htm Original web page at Science Daily

Tags Immunology, Rodents/Lags