Tag: Immunology

Antibody treatment reduced levels of HIV in study participants for 28 days. Treating HIV with an antibody can reduce the levels of the virus in people’s bodies — at least temporarily, scientists report on 8 April in Nature. The approach, called passive immunization, involves infusing antibodies into a person’s blood. Several trials are under way in humans, and researchers hope that the approach could help to prevent, treat or even cure HIV. The work is a milestone towards those goals, says Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases in Bethesda, Maryland. “This is an early study, but it’s a study with some impressive results,” he says. Researchers tested four different doses of an HIV antibody called 3BNC117 in 29 people in the United States and Germany. Seventeen of the participants had HIV, and 15 of those were not taking antiretroviral (ARV) drugs at the time of the study. One infusion of the highest dose of antibody, given to 8 participants, cut the amount of virus in their blood by between 8 and 250 times for 28 days. But much work remains to determine whether the approach can produce longer-lasting effects and whether it is practical for clinical use.

Previous studies have shown that passive immunization can reduce levels of HIV in the blood of monkeys and mice, although the approach has not worked as well in humans. But the antibodies used in those earlier clinical tests were of an older generation that could not neutralize many different strains of HIV. Researchers have spent much of the past decade trying to find ‘broadly neutralizing’ antibodies that are more widely effective against the virus, and the 3BNC117 antibody belongs to this class. The price of treatment with this approach is also a concern. Antibodies can cost thousands of dollars for each course of treatment, and the majority of people with HIV are in low- and middle-income countries, some of which are already fighting drug companies over the high cost of antibody medicines. “The practicality, utility and efficacy of this approach are hugely open questions,” says Mitchell Warren, executive director of AVAC, a global organization that advocates HIV prevention and is headquartered in New York City.

Even with improved antibodies, researchers still face a vexing problem: HIV mutates quickly as it replicates in the human body, which can reduce the effectiveness of treatments over time. The study’s authors found that this was true for the single antibody that they tested. In two people who received the highest dose of 3BNC117, the antibody became roughly 80% less effective at neutralizing HIV after 28 days of treatment — probably because the virus changed shape to evade the antibody. As a result, it is unlikely that a single antibody alone could treat people who have HIV, says the study’s lead author, Michel Nussenzweig, an infectious-disease physician and immunologist at the Rockefeller University in New York. Instead, therapies would use combinations of antibodies. Nussenzweig’s group has produced a second HIV antibody and hopes to test it alone and in combination with 3BNC117 this year.

“The goal is a once-a-year shot for prevention and a combination approach for cure,” he says, adding that this immunotherapy approach to treating HIV would resemble treatments now used against cancer. Relying on combinations of antibodies would raise the costs of passive-immunization treatments for HIV. But Warren says that this is not necessarily a deal-breaker, noting that patient advocacy and concessions by drug companies have helped to reduce the high cost of ARV medications over the past two decades. “Some people would have said 10–15 years ago that ARVs were not going to be affordable, either,” he adds.

Nature doi:10.1038/nature.2015.17260

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/antibody-shows-promise-as-treatment-for-hiv-1.17260  Original web page at Nature

Results of a new study by UCLA researchers has found that a groundbreaking new triple combination therapy shows promising signs of more effectively controlling advanced melanoma than previous BRAF + MEK inhibitor or BRAF inhibitor + immunotherapy combos alone, and with increased immune response and fewer side effects. An estimated 70,000 new cases of metastatic melanoma are diagnosed each year in the United States, and of those 8,000 will die of the disease. About 50 percent of these men and women (or 35,000 a year) have a mutated protein called a BRAF mutation, which in most cases allows melanoma to eventually build up a resistance to many drug therapies.

In the new study led by UCLA Jonsson Comprehensive Cancer Center member Dr. Antoni Ribas and colleague Dr. Siwen Hu-Lieskovan, UCLA scientists combined targeted therapies utilizing a BRAF inhibitor (dabrafenib) and MEK inhibitor (trametinib) with immunotherapy. The three together are shown to be more effective treatments by sensitizing the patients’ own immune system to enhance immunotherapy, and reduce the probability of the melanoma eventually developing resistance. This is a significant advance compared to previous drug combination findings, in which a combined BRAF inhibitor (vemurafenib) with immunotherapy (ipilimumab) caused serious liver toxicity in some patients, and the targeted therapies (BRAF and/or MEK inhibitors) became less effective and reactivated cancer cell growth.

“The two drug combination of BRAF and MEK inhibitors works synergistically and decreases the side effects of the BRAF inhibitor or normal cells. We reasoned that this combo would allow us to synergize with immunotherapy without increasing toxicities,” said Ribas, a professor of hematology and oncology. “We have made incredible progress in the last three years of treating advanced melanoma, with six new drug therapies approved by the FDA. Half are immunotherapies and the other half are BRAF or MEK inhibitors. The next step is to figure out how to rationally combine them and merge their benefits in the clinic.” “The triple combination of targeted therapies BRAF (dabrafinib) and MEK (trametinib) inhibitors with immunotherapy (tumor antigen-specific adoptive cell transfer or anti-PD1 antibody) makes immune therapy more effective at killing cancerous tumors and causes less toxicity ” said Hu-Lieskovan, a UCLA clinical instructor of hematology and oncology.

“We’re trying to take advantage of the high response rate of the targeted therapy and durability of the immune therapy to induce a response that lasts in the majority of patients.” Ribas and Hu-Lieskovan have opened two clinical trials to test the effectiveness of the triple combination therapy in advanced melanoma patients. The first reported findings will be presented at the American Society of Clinical Oncology (ASCO) annual meeting in May 2015. The study will be available online March 18th in the journal Science Translational Medicine.

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

http://www.sciencedaily.com/releases/2015/03/150318144334.htm  Original web page at Science Daily

Now scientists at The Scripps Research Institute (TSRI) have captured the first images showing how immune molecules bind to a site on the surface of Marburg virus. The images are like enemy reconnaissance, showing scientists how to target the virus’s weak spots with future treatments. The research team is also the first to describe an antibody that binds to both Marburg and Ebola viruses, paving the way for new antibody treatments to fight an entire family of viruses. “These cross-reactive antibodies are a straightforward route to a therapeutic,” said TSRI Professor Erica Ollmann Saphire, senior author of new study. “You could use these antibodies directly against Marburg virus or — with a bit more engineering — use them to also target Ebola virus.” Their findings were published February 26 in the journal Cell. Marburg virus is spread to humans by bats and can cause massive hemorrhaging and organ failure, just like Ebola virus. In 2005, a Marburg outbreak in Angola killed 329 people, mostly children and health-care workers. Some worry Marburg could cause an even bigger outbreak in the future. “Marburg is just as likely as Ebola to migrate to a densely populated area,” said Saphire.

The new study focuses on an antibody discovered in the blood of a Marburg survivor. By studying how the antibody binds to the virus, the researchers hoped to find new points of attack on Marburg’s surface. The project was a six-year effort in the Saphire lab. Takao Hashiguchi, a former TSRI research associate, and Marnie Fusco, a TSRI research assistant, figured out how to grow crystals of the antibody attached to its viral target. This crystal was then exposed to X-ray diffraction at the Photon Factory synchrotron in Tsukuba, Japan, revealing its shape in three dimensions. The team’s work showed how the antibody attaches to Marburg virus, blocking the virus’s ability to bind to a receptor and get its genetic material into human cells. This was also the first time that Marburg’s glycoprotein had been seen in the form it takes as it infects cells. Marburg and Ebola viruses enter cells the same way, so the researchers wondered if the antibody could also inactivate Ebola virus by binding to the same site. The work of TSRI Staff Scientist Zachary Bornholdt showed that it did bind to Ebola — and provided a crystal structure of the same antibody bound to Ebola virus. The crystal structure also revealed why this cross-reactive antibody was found in a Marburg survivor and not an Ebola survivor, even though the antibody reacts with both viruses. The key was in the flexible, carbohydrate-rich coating on the surface proteins of both viruses.

With the help of researchers at the Lawrence Berkeley National Laboratory, the team used a technique called small-angle X-ray scattering to study the carbohydrate-cloaked versions of the Ebola and Marburg proteins. Their images showed that the carbohydrate-rich regions had different shapes and exposed different surfaces underneath, allowing the body to create an antibody against this exposed region only in Marburg. The new study was published in Cell with a companion paper, led by researcher James E. Crowe Jr. at Vanderbilt University and co-authored by TSRI Associate Professor Andrew Ward and C. Daniel Murin, a TSRI graduate student. This paper shows low-resolution structures of other antibodies with the potential to bind to the same vulnerable receptor on Marburg virus. Ward said the two studies give him hope that a cross-reactive antibody treatment could someday be designed to combat related viruses, such as Sudan virus and Bundibugyo virus, which share the receptor. “We need to be prepared for future outbreaks,” said Ward. “You don’t know which virus is going to break out next,” said Saphire. “This gives us something to work with.”

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

http://www.sciencedaily.com/releases/2015/02/150226122328.htm  Original web page at Science Daily

Investigators with the National Institutes of Health have discovered the genomic switches of a blood cell key to regulating the human immune system. The findings, published in Nature today, open the door to new research and development in drugs and personalized medicine to help those with autoimmune disorders such as inflammatory bowel disease or rheumatoid arthritis. The senior author of the paper, John J. O’Shea, M.D., is the scientific director at NIH’s National Institute of Arthritis and Musculoskeletal and Skin Diseases. The lead author, Golnaz Vahedi, Ph.D., is a postdoctoral fellow in Dr. O’Shea’s lab in the Molecular Immunology and Inflammation Branch. The study was performed in collaboration with investigators led by NIH Director, Francis S. Collins, M.D., Ph.D., in the Medical Genomics and Metabolic Genetics Branch at the National Human Genome Research Institute.

Autoimmune diseases occur when the immune system mistakenly attacks its own cells, causing inflammation. Different tissues are affected in different diseases, for example, the joints become swollen and inflamed in rheumatoid arthritis, and the brain and spinal cord are damaged in multiple sclerosis. The causes of these diseases are not well understood, but scientists believe that they have a genetic component because they often run in families. “We now know more about the genetics of autoimmune diseases,” said NIAMS Director Stephen I. Katz, M.D., Ph.D. “Knowledge of the genetic risk factors helps us assess a person’s susceptibility to disease. With further research on the associated biological mechanisms, it could eventually enable physicians to tailor treatments to each individual.” Identifying autoimmune disease susceptibility genes can be a challenge because in most cases a complex mix of genetic and environmental factors is involved. Genetic studies have shown that people with autoimmune diseases possess unique genetic variants, but most of the alterations are found in regions of the DNA that do not carry genes. Scientists have suspected that the variants are in DNA elements called enhancers, which act like switches to control gene activities.

Dr. O’Shea’s team wondered if the alterations might lie in a newly discovered type of enhancer called a super-enhancer (SE). Earlier work in the laboratory of Dr. Collins and others had shown that SEs are especially powerful switches, and that they control genes important for the function and identity of each individual cell type. In addition, a large number of disease-associated genetic alterations were found to fall within SEs, suggesting that disease occurs when these switches malfunction. Dr. O’Shea’s team began by searching for SEs in T cells, immune cells known to play an important role in rheumatoid arthritis. They reasoned that SEs could serve as signposts to steer them toward potential genetic risk factors for the disease. “Rather than starting off by looking at genes that we already knew were important in T cells, we took an unbiased approach,” said Dr. O’Shea. “From the locations of their super-enhancers, T cells are telling us where in the genome these cells invest their assets–their key proteins–and thereby where we are most likely to find genetic alterations that confer disease susceptibility.” Using genomic techniques, the researchers combed the T cell genome for regions that are particularly accessible to proteins, a hallmark of DNA segments that carry SEs. They identified several hundred, and further analysis showed that they largely control the activities of genes that encode cytokines and cytokine receptors. These types of molecules are important for T cell function because they enable them to communicate with other cells and to mount an immune response.

But the researchers’ most striking observation was that a large fraction of previously identified alterations associated with rheumatoid arthritis and other autoimmune diseases localized to these T cell SEs. Additional experiments provided further evidence for a central role for SEs in rheumatoid arthritis. When the scientists exposed human T cells to a drug used to treat the disease, tofacitinib, the activities of genes controlled by SEs were profoundly affected compared to other genes without SEs. This result suggests that tofacitinib may bring about its therapeutic effects in part by acting on SEs to alter the activities of important T cell genes. “Three types of data–the genetics of rheumatoid arthritis, a genomic feature of T cells, and the pharmacological effects of a rheumatoid arthritis drug–are all pointing to the importance of super-enhancers,” said Dr. Vahedi. “These regions are where we plan to search for insights into the mechanisms that underlie rheumatoid arthritis and other autoimmune diseases, and for novel therapeutic targets for these conditions.”

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

http://www.sciencedaily.com/releases/2015/02/150216131144.htm Original web page at Science Daily

Therapies that make use of a patient’s own T cells, a component of the immune system, are showing promise in the clinic. When immunologist Michel Sadelain launched his first trial of genetically engineered, cancer-fighting T cells in 2007, he struggled to find patients willing to participate. Studies in mice suggested that the approach — isolating and engineering some of a patient’s T cells to recognize cancer and then injecting them back — could work. But Sadelain did not blame colleagues for refusing to refer patients. “It does sound like science fiction,” he says. “I’ve been thinking about this for 25 years, and I still say to myself, ‘What a crazy idea’.” Since then, early results from Sadelain’s and other groups have shown that his ‘crazy idea’ can wipe out all signs of leukaemia in some patients for whom conventional treatment has failed. And today, his group at the Memorial Sloan Kettering Cancer Center in New York City struggles to accommodate the many people who ask to be included in trials of the therapy, known as adoptive T-cell transfer. At the American Society of Hematology (ASH) meeting held in San Francisco, California, on 6–9 December, attendees heard dozens of talks and poster presentations on the promise of engineered T cells — commonly called CAR (chimaeric antigen receptor) T cells — for treating leukaemias and lymphomas. The field has been marred by concerns over safety, the difficulties of manufacturing personalized T-cell therapies on a large scale, and how regulators will view the unusual and complicated treatment. But those fears have been quelled for some former sceptics by data showing years of survival in patients who once had just months to live. “The numbers are pretty stunning,” says Joseph Hedden, an analyst for the London-based market-research firm Datamonitor Healthcare. “Companies have clearly decided that it’s worth the pitfalls of how much this therapy is going to cost to develop.” At least five major pharmaceutical companies have invested in developing CAR-T-cell therapy over the past three years. Such interest from industry is a dramatic turn for a field that once consisted of a handful of academic medical centres. Small biotechnology firms have also sprung up to develop CAR T cells, including Kite Pharmaceuticals of Santa Monica, California, which raised US$127.5 million when it went public in June. And investors pumped $310 million into another CAR-T-cell company, Juno Therapeutics of Seattle, Washington, this year. “There is no doubt there has been a shift,” says Juno chief executive Hans Bishop. Most of these efforts focus on killing the cancerous, antibody-producing B cells behind some leukaemias and lymphomas. Researchers do this by engineering T cells to recognize a protein on the surface of most B cells — CD19 — and attacking cells that display it. Finding proteins that are expressed only on cancer cells can be difficult, and CD19 represents a compromise: the treatment sometimes wipes out all B cells, cancerous and healthy alike, but patients can survive without them. At the ASH meeting, Sadelain and his colleagues reported that this approach left no signs of cancer in all six patients with lymphoma who were enrolled in one trial. In another presentation, immunologist Carl June of the University of Pennsylvania in Philadelphia showed that targeting CD19 reduced cancer burden in 9 of 23 patients with chronic lymphocytic leukaemia. In a more aggressive disease called acute lymphoblastic leukaemia, 27 of 30 patients had no signs of cancer after therapy and the CAR T cells remained in their blood two years later.

But studies also highlight the risks of revving up immune responses. In April, at least five CAR-T-cell trials were halted after a series of patient deaths linked to unusually high levels of a protein called interleukin-6, which promotes inflammation, as well as other inflammatory molecules. Interleukin-6 is part of the body’s normal response to infection. But the intense immune onslaught launched by CAR T cells can send interleukin-6 levels soaring. The trials resumed after investigators adjusted their protocols to better monitor and treat the problem. These safety risks, as well as the difficulty of manufacturing CAR T cells, are still putting many drug companies off, says Andrew Baum, the London-based head of global health-care research for Citi, an investment bank headquartered in New York City. “The bulk of the multinationals are standing back and watching, rather than getting engaged here,” he says. When CAR T cells do reach the market, they will not be cheap. Baum says that some sponsors are tentatively planning to price their therapies higher than bone-marrow transplants, which can exceed $500,000. The cost may be so high, he says, that companies are forced to set up a reimbursement scheme in which they are paid only when a patient benefits from the treatment. Baum estimates that peak sales of CAR-T-cell therapies will reach $10 billion annually, although that amount will depend on what competing therapies emerge and whether the treatment can be extended to other cancers. For now, Sadelain, a scientific founder of Juno Therapeutics, hopes that the attention from industry will spur the field. He remembers his postdoc days, when he struggled to insert genes into T cells and colleagues asked him why he was bothering. “We’ve never had this kind of investment in the field before,” he says. “It’s hard to believe — sometimes I still pinch myself.”

Nature 516, 156 (11 December 2014) doi:10.1038/516156a

http://www.nature.com/news/index.html  Nature

http://www.nature.com/news/immune-cells-boost-cancer-survival-from-months-to-years-1.16519 Original web page at Nature

Contrary to what was previously thought, newborn immune T cells may have the ability to trigger an inflammatory response to bacteria, according to a new study led by King’s College London. Although their immune system works very differently to that of adults, babies may still be able to mount a strong immune defense, finds the study published in the journal Nature Medicine. Our immune system is made up of several different types of immune cells, including neutrophils which play an important role in the frontline defense against infection, and lymphocytes: B cells which produce antibodies, and T cells that target cells infected with viruses and microbes. Up to now, it was generally believed that babies have an immature immune system that doesn’t trigger the same inflammatory response normally seen in adults. Although babies need to protect themselves from the harmful pathogens they are exposed to from birth, it was thought that their T cells were suppressed to some extent to prevent inflammatory damage to the developing child. Sceptical of this notion, the King’s-led study set out to characterize the properties of T cells, examining very small samples of blood in twenty-eight highly premature babies, as they developed over the first few weeks of life. The team discovered that whilst T cells in newborn babies are largely different to those in adults, it is not because they are immunosuppressed; rather, they manufacture a potent anti-bacterial molecule known as IL8 that has not previously been considered a major product of T cells, and that activates neutrophils to attack the body’s foreign invaders. Dr Deena Gibbons, lead author in the Department of Immunobiology at King’s College London, says: “We found that babies have an in-built anti-bacterial defense mechanism that works differently to adults, but nevertheless may be effective in protecting them. This may also be a mechanism by which the baby protects itself in the womb from infections of the mother. The next stage of our work will be to better understand the pathways that result in the immune cells of newborns being so different to those in adults.” This T cell activity could become a target for future treatments aimed at boosting the immune system of neonates in intensive care, where infection is a major risk for morbidity and mortality. Premature babies are also at serious risk of developing inflammatory diseases such as necrotising enterocolitis (NEC), where severe inflammation destroys tissues in the gut. NEC is the most common gastrointestinal surgical emergency in preterm babies, with mortality rates of around 15 to 30 per cent in the UK.

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

http://www.sciencedaily.com/releases/2014/09/140921145104.htm  Original web page at Science Daily

Oral thrush is caused by an overgrowth of a normally present fungus called Candida albicans, which leads to painful white lesions in the mouth, said senior investigator Sarah L. Gaffen, Ph.D., professor, Division of Rheumatology and Clinical Immunology, Pitt School of Medicine. The infection is treatable, but is a common complication for people with HIV, transplant recipients who take drugs to suppress the immune system, chemotherapy patients and babies with immature immune systems. “In previous work, we found the cytokine interleukin-17 (IL-17), a protein involved in immune regulation, must be present to prevent the development of thrush,” Dr. Gaffen said. “But until now, we didn’t know where the IL-17 was coming from.” Typically, IL-17 is produced by immune T-cells that learn to recognize and remove a foreign organism after an initial exposure, known as adaptive immunity. But unlike humans, mice do not normally acquire Candida during birth and are considered immunologically naïve to it. When the researchers exposed the lab animals to Candida, their IL-17 levels rose within 24 hours despite the lack of a T-cell response. This suggested the immune activity was innate, rather than acquired. To find the cell responsible for IL-17 secretion, lead investigator Heather R. Conti, Ph.D., devised a way of applying a scientific technique called flow cytometry to sort for the first time cells gathered from the oral tissues. In the tongue, she identified unusual ones known as natural TH17 cells that looked very much like T-cells but didn’t behave like them. Subsequent tests showed that the novel cells did, indeed, make IL-17 when exposed to Candida. “These cells are part of a natural host defense system that is present at birth and does not require a first exposure to be activated,” Dr. Gaffen explained. “This study demonstrates for the first time that natural TH17 cells protect against infection.” The researchers speculate that the similarities natural TH17 cells share with T-cells make them vulnerable to HIV, chemotherapy and other agents as well, which could explain why certain people are more susceptible to oral thrush. Also, new drugs that block IL-17 soon will be on the market for treatment of rheumatologic conditions, so it’s possible that thrush could be a side effect. The team plans to examine the factors that influence thrush development within the high-risk groups.

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

http://www.sciencedaily.com/releases/2014/09/140908121504.htm  Original web page at Science Daily

Previous studies have shown that stem cells can reduce lung inflammation and restore some function in ARDS, but experts are not sure how this occurs. The new study, which was presented at the European Respiratory Society’s International Congress, brings us a step closer to understanding the mechanisms that occur within an injured lung. ARDS is a life-threatening condition in which the efficiency of the lungs is severely reduced. It is caused by damage to the capillary wall either from illness or a physical injury, such as major trauma. ARDS is characterised by excessive and dysregulated inflammation in the lung and patients require mechanical ventilation in order to breathe. Although inflammation is usually a method by which the body heals and copes with an infection, when the inflammation is dysregulated it can lead to severe damage. Immune cells known as macrophages can coordinate the inflammatory response by driving or suppressing inflammation, depending on the stimulation. The researchers investigated whether stem cells can affect the stimulation of the macrophages and promote the state in which they will suppress the inflammation. They tested this in an animal model using human bone marrow-derived stem cells. Mice were infected with live bacteria to induce acute pneumonia and model the condition of ARDS. The results showed that treatment with stem cells led to significant reductions in lung injury, inflammation and improved bacterial clearance. Importantly, when stem cells were given to animals that had their macrophages artificially removed, the protective effect was gone. This suggests that the macrophages are an important part of the beneficial effects of stem cells seen in this model of ARDS. These results were further supported by experiments where stem cells were applied to human macrophages in samples of fluid taken from lungs of patients with ARDS. Again, the stem cells were able to promote the anti-inflammatory state in the human macrophage cells. The authors have identified several proteins, secreted by the stem cells, that would be responsible for this effect. Dr Anna Krasnodembskaya, lead author of the study from the Queens University Belfast, said: “This is the first study to our knowledge that has looked at how stem cells can change the functional properties of the macrophages in both humans and a mouse model. The findings highlight the advantages of stem cell treatment, as they can actively respond to the local micro-environment and exert multiple beneficial effects. We believe that clinical trials are now needed to test whether this can be an effective treatment for people suffering from ARDS.”

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

http://www.sciencedaily.com/releases/2014/09/140909093711.htm  Original web page at Science Daily

Treating Ebola patients with blood or purified serum of disease survivors should be a priority in the fight against the outbreak in West Africa, an expert panel organized by the World Health Organization (WHO) said on 5 September. The recommendation came at the end of a two-day meeting to determine which experimental Ebola therapies and vaccines should be prioritised for accelerated clinical development. The WHO estimates that roughly 3,700 people have been infected in West Africa, and about 1,850 have died. Marie-Paule Kieny, WHO assistant director-general for health systems and innovation, told reporters that the transfusion of whole blood or purified serum from Ebola survivors was the therapy with the greatest potential to be implemented immediately on a large scale in West Africa — in part because the outbreak’s size means there are many potential donors available. The idea is to transfer antibodies against Ebola from survivors to sufferers, but there is little information on the efficacy of such transfusions. The priority, said Kieny, will be to ensure that collected blood is free of other pathogens and that health-care workers remain safe during transfusions, when they are exposed to Ebola patients’ blood. Efforts to institute proper infrastructure and training are in place are already beginning, she added. No Ebola therapies or vaccines have been approved for human use, but a WHO expert panel said on 11 August that testing and using experimental drugs and vaccines in the outbreak is ethically acceptable provided that every effort is made to gather scientific data on safety and efficacy. That panel said that such actions are justified because of the exceptional nature of this outbreak; for example, it has proven difficult to implement public health measures that have ended past Ebola outbreaks. At the WHO meeting that concluded today, experts also recommended prioritising tests of two candidate vaccines: a chimpanzee adenovirus vaccine (ChAd3) developed by the US National Institute of Allergy and Infectious Diseases (NIAID) and Glaxo SmithKline, and a recombinant vesicular stomatitis virus (rVSV) vaccine developed by the Public Health Agency of Canada and licensed to NewLink Genetics and Profectus Biosciences. Phase I trials of ChAd3 will start this month in the United States, the United Kingdom, Gambia and Mali. The first tests will be on healthy volunteers because areas stricken by Ebola lack infrastructure to do proper trials.

Both the ChAd3 and rVSV vaccines have conferred 100% protection against Ebola in animal studies. The WHO estimates that 800 doses of rVSV are currently available, and some 15,000 doses of ChAd3 should be ready by the end of the year. The WHO has also selected drugs for priority use and testing, basing its decision on those that have shown good efficacy and safety in non-human primates. The chosen treatments include ZMapp, a cocktail of monoclonal antibodies which last week was shown to confer 100% protection in rhesus macaques. On 2 September, the US Department of Health and Human Services announced up to US$42.3 million in funding over 18 months for the drug’s development and manufacturing. Oyewale Tomori, a virologist at Redeemer’s University in Redemption City, Nigeria, says that efforts to test and distribute new therapies and vaccines must not detract from the need to institute basic public health measures in Ebola-stricken areas or to provide supportive care for patients. Few patients in outbreak areas have access to quality care, such as intravenous rehydration, that can greatly reduce mortality. But WHO said on 28 August that it was seeking $490 million to bolster basic public health measures and quality of care in Ebola treatment centres.

Nature doi:10.1038/nature.2014.15854

http://www.nature.com/news/index.html Nature

http://www.nature.com/news/blood-transfusion-called-priority-ebola-therapy-1.15854 Original web page at Nature

Researchers from UCL (University College London) have demonstrated how an interplay between nutrition, metabolism and immunity is involved in the process of aging. The two new studies, supported by the Biotechnology and Biological Sciences Research Council (BBSRC), could help to enhance our immunity to disease through dietary intervention and help make existing immune system therapies more effective. As we age our immune systems decline. Older people suffer from increased incidence and severity of both infections and cancer. In addition, vaccination becomes less efficient with age. In previous BBSRC funded work, Professor Arne Akbar’s group at UCL showed that aging in immune system cells known as ‘T lymphocytes’ was controlled by a molecule called ‘p38 MAPK’ that acts as a brake to prevent certain cellular functions. They found that this braking action could be reversed by using a p38 MAPK inhibitor, suggesting the possibility of rejuvenating old T cells using drug treatment. In a new study published in Nature Immunology the group shows that p38 MAPK is activated by low nutrient levels, coupled with signals associated with age, or senescence, within the cell. It has been suspected for a long time that nutrition, metabolism and immunity are linked and this paper provides a prototype mechanism of how nutrient and senescence signals converge to regulate the function of T lymphocytes. The study also suggests that the function of old T lymphocytes could be reconstituted by blocking one of several molecules involved in the process. The research was conducted at UCL alongside colleagues from Complejo Hospitalario de Navarra, Pamplona, Spain. The second paper, published in The Journal of Clinical Investigation, showed that blocking p38 MAPK boosted the fitness of cells that had shown signs of aging; improving the function of mitochondria (the cellular batteries) and enhancing their ability to divide. Extra energy for the cell to divide was generated by the recycling of intracellular molecules, a process known as autophagy. This highlights the existence of a common signaling pathway in old/senescent T lymphocytes that controls their immune function as well as metabolism, further underscoring the intimate association between aging and metabolism of T lymphocytes. This study was conducted by researchers from UCL, Cancer Research UK, University of Oxford and University of Tor Vergata, Rome, Italy.

Professor Arne Akbar said: “Our life expectancy at birth is now twice as long as it was 150 years ago and our lifespans are on the increase. Healthcare costs associated with aging are immense and there will be an increasing number of older people in our population who will have a lower quality of life due in part to immune decline. It is therefore essential to understand reasons why immunity decreases and whether it is possible to counteract some of these changes. “An important question is whether this knowledge can be used to enhance immunity during aging. Many drug companies have already developed p38 inhibitors in attempts to treat inflammatory diseases. One new possibility for their use is that these compounds could be used to enhance immunity in older subjects. Another possibility is that dietary instead of drug intervention could be used to enhance immunity since metabolism and senescence are two sides of the same coin.”

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http://www.sciencedaily.com/releases/2014/08/140824152345.htm  Original we page at Science Daily

Infants exposed to rodent and pet dander, roach allergens and a wide variety of household bacteria in the first year of life appear less likely to suffer from allergies, wheezing and asthma, according to results of a study conducted by scientists at the Johns Hopkins Children’s Center and other institutions. Previous research has shown that children who grow up on farms have lower allergy and asthma rates, a phenomenon attributed to their regular exposure to microorganisms present in farm soil. Other studies, however, have found increased asthma risk among inner-city dwellers exposed to high levels of roach and mouse allergens and pollutants. The new study confirms that children who live in such homes do have higher overall allergy and asthma rates but adds a surprising twist: Those who encounter such substances before their first birthdays seem to benefit rather than suffer from them. Importantly, the protective effects of both allergen and bacterial exposure were not seen if a child’s first encounter with these substances occurred after age 1, the research found. A report on the study, published on June 6 in the Journal of Allergy and Clinical Immunology, reveals that early exposure to bacteria and certain allergens may have a protective effect by shaping children’s immune responses — a finding that researchers say may help inform preventive strategies for allergies and wheezing, both precursors to asthma. “Our study shows that the timing of initial exposure may be critical,” says study author Robert Wood, M.D., chief of the Division of Allergy and Immunology at the Johns Hopkins Children’s Center. “What this tells us is that not only are many of our immune responses shaped in the first year of life, but also that certain bacteria and allergens play an important role in stimulating and training the immune system to behave a certain way.” The study was conducted among 467 inner-city newborns from Baltimore, Boston, New York and St.   Louis whose health was tracked over three years. The investigators visited homes to measure the levels and types of allergens present in the infants’ surroundings and tested them for allergies and wheezing via periodic blood and skin-prick tests, physical exams and parental surveys. In addition, the researchers collected and analyzed the bacterial content of dust collected from the homes of 104 of the 467 infants in the study.

Infants who grew up in homes with mouse and cat dander and cockroach droppings in the first year of life had lower rates of wheezing at age 3, compared with children not exposed to these allergens soon after birth. The protective effect, moreover, was additive, the researchers found, with infants exposed to all three allergens having lower risk than those exposed to one, two or none of the allergens. Specifically, wheezing was three times as common among children who grew up without exposure to such allergens (51 percent), compared with children who spent their first year of life in houses where all three allergens were present (17 percent). In addition, infants in homes with a greater variety of bacteria were less likely to develop environmental allergies and wheezing at age 3. When researchers studied the effects of cumulative exposure to both bacteria and mouse, cockroach and cat allergens, they noticed another striking difference. Children free of wheezing and allergies at age 3 had grown up with the highest levels of household allergens and were the most likely to live in houses with the richest array of bacterial species. Some 41 percent of allergy-free and wheeze-free children had grown up in such allergen and bacteria-rich homes. By contrast, only 8 percent of children who suffered from both allergy and wheezing had been exposed to these substances in their first year of life. Asthma is one of the most common pediatric illnesses, affecting some 7 million children in the United States, according to the U.S. Centers for Disease Control and Prevention. By the time they turn 3, up to half of all children develop wheezing, which in many cases evolves into full-blown asthma.

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

July 8, 2014

http://www.sciencedaily.com/releases/2014/06/140606091157.htm  Original web page at Science Daily

A team of UniformedServicesUniversity of the Health Sciences (USU) researchers led by Dr. Brian Schaefer, Associate Professor in USU’s Department of Microbiology and Immunology, has demonstrated that the “POLKADOTS signalosome” (named for its dot-like appearance in cells) activates a protein called “NF-kappaB” in T cells. A signalosome is a cluster of proteins that works together inside a cell to control the activity of other proteins. NF-kappaB is a protein that turns on many different T cell functions, including those that contribute to autoimmunity and rejection of transplants. Dr. Schaefer’s team, including lead author, Dr. Suman Paul, had previously shown that the POLKADOTS signalosome, in addition to activating this protein, also limits how much NF-kappaB is turned on. Because the POLKADOTS signalosome is a major point of control for NF-kappaB activation, it may be an attractive target for the design of new drugs to block or regulate T cell functions. Normally, T cells play a key role in maintaining health, by helping to eliminate invading disease-causing bacteria and viruses. However, in some individuals, T cells begin to react against tissues in the body, causing autoimmunity. Also, when a patient receives an organ transplant, T cells will react to that organ and cause transplant rejection, if T cell functions are not successfully blocked. There are currently only a small number of drugs available to treat autoimmunity and transplant rejection, and these drugs do not work for all patients. Inhibiting NF-kappaB activation has long been recognized as a potentially useful strategy for blocking the T cell responses that cause autoimmunity and transplant rejection. However, because NF-kappaB is necessary for a wide variety of important processes throughout the body, directly targeting this protein would lead to many undesired and harmful side effects. Importantly, Dr. Schaefer’s group predicts that drugs that block the activity of the POLKADOTS signalosome would inhibit NF-kappaB only in T cells. This is because the POLKADOTS signalosome appears to be present only in T cells. If successfully produced, drugs that act on the POLKADOTS signalosome may be a powerful new therapy for the treatment of many different autoimmune diseases and transplant rejection.

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

June 10, 2014

http://www.sciencedaily.com/releases/2014/05/140513091117.htm  Original web page at Science Daily

If you’ve ever used a steroid, for example cortisone cream on eczema, you’ll have seen first-hand how efficient steroids are at suppressing the immune response. Normally, when your body senses that immune cells have finished their job, it produces steroids -but which cells actually do that? In this latest study, scientists looked at Th2 immune cells during parasitic infection and saw that at a certain point, these cells produce a steroid called pregnenolone. “We were really surprised to see that these immune cells are producing a steroid. In cell culture, we see that the steroids play a part in regulating T cell proliferation,” says Bidesh Mahata in the Teichmann group at EMBL-EBI and Sanger, who designed the study. “We had already seen that T-helper cells were producing steroids, but initially we were blind — what was going on?” “Because we had access to data from single-cell sequencing experiments, we could conduct deep statistical analyses on a very large and comprehensive dataset,” explains Sarah. “That pointed us to the genes involved in pregnenolone production at the point when Th2 cells are being produced, and we could deduce that the Th2 cells themselves were involved in immunosuppression.” The researchers suggest that bringing the immune system back into balance is an intrinsic part of this particular immune response. “We confirmed our findings experimentally, showing that pregnenolone inhibits both Th cell proliferation and B cell immunoglobulin class switching,” adds Bidesh. “We think this points to the idea that Th2 cells differentiate into steroid-producing cells as part of a larger mechanism to bring the immune system back into balance.” The findings from this study are strengthened by those of the Gelfand group at National Jewish Health in Denver, US. The next step for the Genome Campus group is to figure out how the process starts, what other tissues are involved and which types of infection give rise to this response.

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

June 10, 2014

http://www.sciencedaily.com/releases/2014/05/140508133037.htm  Original web page at Science Daily

Despite a long record of failure, a few immunologists continue to pursue precisely targeted therapies for autoimmune diseases. Ever since Ed Wiley learned that he had type 1 diabetes in 1997, he has fretted over his meals, blood glucose levels and the daily programming of his insulin pump. Wiley, a statistician who lives outside Boulder, Colorado, and works on big data analytics, has learned to live in a state of hypervigilance. Finding the right dose of insulin turned out to be more art than science and, like many with the disease, his control began slipping away with time. By 2008, he says, “my insulin doses just basically didn’t work any more”. Unable to reliably anticipate what he needed, Wiley was having severe hypoglycaemic episodes and was at risk of diabetic seizures and long-term disability. On his endocrinologist’s advice, he enrolled in a clinical trial of a novel drug called BHT-3021. Although technically a vaccine, BHT-3021 is not designed to stimulate an immune response, but rather to shut it down, stopping the body’s errant attack against cells in the pancreas that produce insulin. The goal is to achieve immune tolerance. Drugs that broadly suppress immunity are the standard treatment for autoimmune disorders such as multiple sclerosis (MS), rheumatoid arthritis and lupus. But these drugs can lead to life-threatening infections, and do not address the cause of the disease. Tolerance therapies are different. They aim to target only the immune cells that react to a specific antigen, a substance — in Wiley’s case, the insulin precursor proinsulin — that might trigger a response. “Why shut down a major arm of the immune system, if we’re just trying to restore tolerance to one antigen?” asks immunologist Larry Steinman of StanfordUniversity in California, who developed BHT-3021. This strategy, known as antigen-specific tolerance, is simple in concept. But, so far, dozens of clinical trials have failed to achieve a categorical success. And there is a fine line between calming the immune system and stimulating it, so these efforts risk making a disease worse — as happened in an MS trial some 15 years ago.

BHT-3021 is one of a new wave of treatments conceived by five veterans of the field that promises to do better. Early-stage trials show encouraging results in people with MS and type 1 diabetes. “A number of these approaches really are going to work,” predicts David Wraith, an immunologist at the University of Bristol, UK, and one of the few persisting in pursuing the work. “The science has caught up.” The approaches are varied, but they all rely on the body’s natural ability to distinguish its own substances from those of foreign intruders. When bacteria or viruses invade, some are swallowed by specialized antigen-presenting cells, or APCs. These chop up the bacterial or viral antigens and present them to T cells, white blood cells that orchestrate the immune response. The T cells then proliferate and launch a coordinated attack. APCs also ensure that normal daily maintenance does not turn deadly. As the body’s own cells continuously die and are replenished, APCs mop up the debris and present those self-antigens to T cells along with an array of proteins that signal that these cellular remnants pose no danger. In autoimmunity, for unknown reasons, this protective mechanism goes awry. The new therapies are designed to override this dysfunction by deliberately sending the relevant antigen to tissues where the body is likely to see it as a non-threatening part of itself. Most of the therapies developed so far target MS, which occurs when the immune system attacks the myelin sheath that protects neurons in the brain and spinal cord. Immunologist Stephen Miller of NorthwesternUniversity in Chicago, Illinois, designed a therapy that he and neurologist Roland Martin, now at University Hospital Zurich in Switzerland, began testing in patients in 2009. During the treatment, the patients’ white blood cells are extracted, chemically linked to seven myelin antigens, then reinfused. The cells make their way to the spleen, where they die and release the antigen, which is picked up by APCs.

Read more: http://www.nature.com/news/immunology-a-tolerant-approach-1.14933

http://www.nature.com/news/index.html Nature

April 15, 2014

http://www.nature.com/news/immunology-a-tolerant-approach-1.14933  Original web page at Nature