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l p to rt. . e, or a ook e be ” Fall 2009 Inside… Leukemia Cells Flash Fake Protein ‘ID’ to Dupe the Immune System Scientific American...................2 Manage your free subscription online at www.dana.org The Dana Foundation’s IMMUNOLOGY IN THE Killer Parasites’ Genes Decoded BBC News................................3 How the Humble Hydrangea Shrub Could Hold the Key to Curing MS, Diabetes and Arthritis The Daily Mail (London).............4 Professor Jean Dausset The Daily Telegraph (London).....4 FROM THE UNIVERSITIES: Immune System Key Discovered Monash University..............5 FROM THE JOURNALS: A Protein Supports Interferons’ Protective Function Immunity...........................5 Receptor Helps Us Fight Respiratory Virus Infection Nature Immunology.............6 Immunology in the News Vol. 9, No. 3 NEWS Swine Flu Vaccine Works with One Shot Protection occurs in 10 days, study finds. By Rob Stein The Washington Post September 11, 2009 The swine flu vaccine appears to work for adults with just one shot and within 10 days, a major boost to the widespread immunization campaign that officials are planning to protect people against the first influenza pandemic in 41 years, researchers reported Thursday [Sept. 10]. Preliminary data from an Australian study found that a single standard dose could produce an immune response in more than 96 percent of recipients, and U.S. studies indicate that the protection occurs in eight to 10 days, scientists reported. The vaccine also appeared safe. The eagerly awaited findings mark the first results from a flurry of studies that scientists have been rushing to conduct to develop a swine flu vaccine. The findings indicate that plans to inoculate millions of Americans—the most ambitious vaccine campaign in U.S. history—and others worldwide could occur much more quickly and require far less vaccine than officials had feared. “This is good news,” said Anthony S. Fauci of the National Institutes of Health, which is leading the U.S. efforts to develop the vaccine. “This is very good news. If you needed two doses, that would be a major strain on vaccine supplies nationally and globally.” The Department of Health and Human Services plans to release preliminary results Friday [Sept. 11] of its vaccine studies. Fauci would not disclose any details except to say “This is very good news. If you needed two doses, that would be a major strain on vaccine supplies nationally and globally.” —Anthony S. Fauci, director, National Institute of Allergy and Infectious Diseases that the findings are consistent with the Australian study involving 240 patients and that they show the response occurs even more quickly—eight to 10 days—than the 21 days that study found. “The NIH clinical trials results verify and corroborate the exciting results” from the Australian study, Fauci said, adding that there is no reason to suspect vaccine produced (See Swine flu vaccine, pg. 2) 4 Andrew Kahn, Editor William Stilwell, Layout Kenneth Krattenmaker, Director of Production Ralph Steinman, M.D., Scientific Consultant rePrint Requests Must Be Directed to Source Publication. published by dana press, a division of the dana foundation Nicky Penttila, Web Editor Dan Gordon, Deputy Web Editor Editorial Office 900 15th St., NW Washington, DC 20005 DANA is a federally registered trademark. copyright 2009, the dana foundation Sign Up for an E-mail Alert Want to know when the next issue of Immunology in the News posts? Sign up to receive an e-mail alert. Visit www.dana.org/ MemberLogin.aspx. If you have signed in to our Web site before, enter your username and password. Otherwise, register for a new account. Then look for Immunology in the News under “Subscribe to E-mail Newsletter.” Genetic Links to Rare Liver Disease Found Understanding primary biliary cirrhosis may lead to new treatments, researchers say. By Steven Reinberg HealthDay News June 10, 2009 Scientists have found genetic variations that appear to increase the risk of developing primary biliary cirrhosis, a baffling disease that can destroy the liver. Primary biliary cirrhosis is an autoimmune disorder that blocks the bile ducts in the liver. It is a condition that mostly affects women, striking about one in 2,500 Americans. The current treatment works in about half of patients. The other half will need a liver transplant at some time in the course of the disease, according to researchers, but the condition has been known to return even after transplantation. “We have known virtually nothing about what causes primary biliary cirrhosis,” said lead researcher Dr. Katherine Siminovitch, a senior investigator at the Samuel Lunenfeld Research Institute of Mount Sinai Hospital in Toronto. “What we have found are some of the major genetic causes of the disease,” she said. “About half the patients will respond to that treatment, but half won’t. Of the half that won’t, some will be OK, but many won’t and they will have to have a liver transplant,” she explained. “So, we urgently need a new medical therapy.” Siminovitch thinks the findings indicate that drugs already being used to treat other autoimmune diseases might work for primary biliary cirrhosis. “This is terrific for us, because we can now begin to do early trials to see if it will change the outcome of this disease,” she said. It is also possible new, more targeted drugs could be made to treat the disease, she said. In addition, the findings may also make it possible to predict who is likely to develop the disease and possibly prevent it, Siminovitch said. The report is published in the June 11 issue of the New England Journal of Medicine. For the study, Siminovitch’s team analyzed blood samples from patients with primary biliary cirrhosis as well as samples from people who did not have the condition. In the first phase of the study, researchers did a genomewide analysis, comparing the genotypes of 536 patients with primary biliary cirrhosis with 1,536 people who did not have the disease. In the next phase, researchers conducted genetic mapping to confirm the initial results and to identify genetic variations closely associated with primary biliary cirrhosis. “I don’t think this is going to translate to a significant change in therapy in the near term. But it opens the door to scientific investigation of other therapies.” —Scott L. Friedman, chief, division of liver diseases, Mount Sinai School of Medicine Siminovitch’s group found variants of two genes, interleukin 12A (IL12A) and interleukin 12RB2 (IL12RB2), that were strongly linked with the disease. In addition, they confirmed that the human leukocyte antigen (HLA) area of the genome is associated with primary biliary cirrhosis, a link that had been identified before. Dr. Scott L. Friedman, chief of the division of liver diseases at Mount Sinai School of Medicine in New York City and president of the American Association for the Study of Liver Diseases, said the discoveries are an important step in understanding this disease, but the interaction between (See Liver Disease Genes, pg. 2) 4 Immunology in the News Fall 2009 1 (Swine flu vaccine, from pg. 1) 4 by any of the five companies making supplies for the United States would be different. “They are really the same. The seed virus is the same. They are made the same way,” said Fauci, who heads the NIH’s National Institute of Allergy and Infectious Diseases. “Even though they are from different companies, you don’t usually see differences from one company to another.” Results from additional studies will be needed to see whether children and other special groups need one or two doses, he added. Young children usually need two seasonal flu shots because they have not been exposed to the virus before. The National Institutes of Health is conducting a series of studies testing the swine flu vaccine on 4,600 volunteers, including adults, children and pregnant women. “We will hopefully get some information about kids from our trial in a couple of weeks,” Fauci said. The results from CSL Ltd. in Australia will be published in the New England Journal of Medicine but were released online Thursday because of their urgency. The study involved a standard dose of 15 micrograms of vaccine and found that the vaccine produced a strong immune response in more than 96 percent of the subjects. “The concern that people had was that because this was a new virus that this would require two doses for everyone. That would have created a problem of supply,” Fauci said. “This greatly alleviates the problem.” The findings also mean that adults will not have to return for a booster shot, which would (Liver Disease Genes, from pg. 1) 4 genes and environmental triggers is complicated. “I don’t think this is going to translate to a significant change in therapy in the near term,” Friedman said. “But it opens the door to scientific investigation of other therapies.” Dr. Nathan M. Bass, medical director of the liver transplant service for adults at University of California, San Francisco, noted that the study was have greatly complicated the already daunting vaccine effort. The results were welcomed by officials at the World Health Organization, which has been particularly concerned about providing enough vaccine to poorer countries. “If this is true, this is quite encouraging,” said Gregory Hartl, a WHO spokesman. “If you only need one shot instead of two, the vaccine will go twice as far. Twice as many people will be able to get the vaccine.” The Australian findings were released with a second study from the University of Leicester. In that study, 175 British volunteers ages 18 to 50 received another version of the vaccine made by Novartis Corp.—either 7.5 or 15 micrograms of vaccine, along with a substance known as an adjuvant, which can boost a vaccine’s effectiveness. The study found that either dose produced adequate immune response within 14 days. Adjuvants have been used widely in Europe, which could extend the supplies even further. U.S. officials were considering approving an adjuvant in this country if supplies ran low. The strong immune response was somewhat puzzling, Fauci said, especially given the results of a third paper, from the federal Centers for Disease Control and Prevention, that found exposure to the seasonal flu vaccine offered no protection against the swine flu. “The responses you’re seeing suggest that somehow or other there has been some previous exposure to similar viruses or some vaccine that is responsible,” Fauci said. The new virus, known as H1N1, emerged last spring in Mexico and quickly spread around the world, causing at least 2,837 deaths, including at least 556 in the United States so far, and prompting WHO to declare the first influenza pandemic since 1968. The pandemic has sparked a flurry of emergency planning, including a rushed program to develop a vaccine. Because the virus is new, experts thought most people would need one shot followed by a booster several weeks later to produce sufficient protection. Because the first batches of vaccine are not expected until mid-October, that meant the first Americans would not be protected until after the outbreak might have peaked. The federal government has already spent $2 billion to buy 195 million doses of vaccine and plans to purchase enough to vaccinate every American if necessary. Unlike the typical flu, the H1N1 virus has been affecting children and young adults much more often than the seasonal flu. As a result, the top priority for vaccination will be everyone age 6 months to 24 years and people who care for children younger than 6 months. Pregnant women, health-care workers and adults ages 25 to 64 with health problems that put them at risk for complications are also being given high priority. The results from the H1N1 vaccine trials came as top U.S. health officials urged Americans to get vaccinated against the seasonal flu. the first of its kind in primary biliary cirrhosis “that appears to shed light on the mechanism of this uncommon, but puzzling, disease.” “Primary biliary cirrhosis is a distressing condition that mainly affects women, and which has eluded our understanding despite many years of research, although a disorder in immune regulation has been suspected for some time,” Bass said. “The findings of this study suggest that the key problem may rest within the interleukin-12 immunoregulatory signaling pathway, offering a novel new insight into the pathogenesis of primary biliary cirrhosis, with the attendant opportunity to better understand the key mechanisms in the evolution and progression of this disease, and to ultimately develop new therapies based on this understanding,” he said. From The Washington Post, September 11 © 2009 The Washington Post All rights reserved. Used by permission and protected by the Copyright Laws of the United States. The printing, copying, redistribution of the Material without express written permission is prohibited. Copyright 2009 ScoutNews, LLC. Reprinted by permission. Leukemia Cells Flash Fake Protein ‘ID’ to Dupe the Immune System A crucial protein on the surfaces of malignant cells shields them from destruction, but it could also provide a new way to attack cancer. By Mandy Kendrick Scientific American August 6, 2009 Bone marrow continually makes blood stem cells, which turn into new blood cells to replace spent ones, but the process is not perfect: Some blood stem cells can develop into abnormal versions, although the immune system usually stamps them out. In acute myeloid leukemia, however, the immune system seems unable to recognize malformed blood cells, which proliferate quickly and become cancerous. Researchers from Stanford University recently uncovered a mechanism by which these leukemia cells elude the immune system. As described in two papers in Cell, the cancerous pretenders use the same “ID” that blood stem cells use to travel around the body. Their findings may not only have implications for the treatment of this form of leukemia but possibly for other cancers, as well. Acute myeloid leukemia (AML) is the most common type of acute leukemia in adults. The average age of sufferers is 67, according to the American Cancer Society, and the disease has a dismal prognosis: the National Cancer Institute estimates a five-year survival rate of 22.8 percent. Crowding out healthy cells According to Ravindra Majeti, a hematologist at Stanford School of Medicine and an author on both studies, the problem is not necessarily the 2 Immunology in the News Fall 2009 presence of the leukemia cells but how these cells interfere with blood-making. He notes that a person’s bone marrow makes approximately 100 billion new blood cells daily. AML cells grow uncontrollably and over time crowd out the progenitor blood stem cells made by the marrow. “So most of the real problems,” including death, are a result of the body “no longer making blood,” Majeti says, and not because of the cancer cells themselves. The findings may have implications not only for the treatment of acute myeloid leukemia but possibly for other cancers, as well. Once made, these cancerous cells express a protein called CD47 on their surfaces. This protein, which is the same as that shown by normal blood stem cells, serves as a forged passport of sorts that it presents to leave the bone marrow. The security guards of the immune system, the macrophages, sense the CD47 protein and consequently pass the cell as “safe.” Once through the checkpoint, the malignant cells can enter the blood stream and then can spread throughout the body. Furthermore, AML cells produce more CD47 than healthy cells do to mask themselves, ensuring complete protection from the macrophages. And in previous work the group has shown that the more CD47 produced, the worse the prognosis. Exploiting the CD47 protein shield Although CD47 enables cancerous cells to evade the immune system, the protein could also lead to their undoing. In preliminary tests with mice infected with human AML, the Stanford group found an antibody that attaches to the CD47 protein, thereby masking this safety signal. As a result, macrophages attacked and removed the cells. The antibody does not go after normal blood stem cells as frequently, because those cells only express CD47 when they are on the move. The researchers found a second method by which they could exploit the excessive amount of CD47. They were able to separate the cancerous cells from the noncancerous stem cells using a technique called fluorescence activated cell sorting. To do this, the group added a fluorophore, a molecule that emits fluorescent light, to the CD47 antibody. The fluorescing CD47 antibody then attached to any cells that have CD47 present. The cell sorter could separate cells with more fluorescence (the cancerous cells) from those with less fluorescence (noncancerous stem cells). The group hopes that this technique of isolating and removing the leukemia cells can help improve the results of autologous stem cell transplant—using a patient’s own stem cells to restore the blood-producing system after chemotherapy or radiation. Copyright 2009 Scientific American. Reprinted by permission. A Clue in the Multiple Sclerosis Mystery Ralph Steinman, M.D. O ne of the most challenging links between immunology and the nervous system is the disease multiple sclerosis (MS). In people with MS, the immune system attacks myelin, an important material that insulates our nerves and helps conduct electrical signals from cell to cell. Scientists do not yet understand what triggers the attack on myelin. However, in the last two years a sea change has occurred in our understanding of the nature of the “self ” attack after it begins. This new understanding, many of us believe, will lead to new therapies for MS. In this resurging field, a molecule called interleukin-17, or IL-17, is a fulcrum. IL-17 first came on the scene in 1996 in the lab of Jacques Banchereau, this year’s winner of the American Association of Immunologists–Dana Foundation Award in Human Immunology Research. The Banchereau team was not, at the time, focused on MS, but rather on molecules that drive inflammation more broadly. They reported in the Journal of Experimental Medicine their discovery of a new molecule—IL-17— which stimulated the production of phagocytes (white blood cells) to defend against infection. Shortly thereafter, Jay Kolls, now at Louisiana State University, began to identify the helpful roles of IL-17. Kolls was trying to figure out how the body defends against a difficult pneumonia caused by the organism Klebsiella pneumoniae. In 2001, Kolls proved that IL-17 was needed to defend against this bug. The IL-17 field has taken off in the years since. Scientists identified a major new pathway in which immune T cells—a subtype of white blood cells— commit to making IL-17. These “Th17” cells help our bodies resist not only Klebsiella, but other scourges such as Staphylococcus aureus and the fungus Candida albicans. Th17 cells and IL-17 are important; people with genetic deficiencies in the Th17 pathway suffer from corresponding infections. That’s the protective role of IL-17. But what about the downside? Thanks to more superb immunology from several quarters, we now realize that Th17 cells bring about certain types of autoimmunity, and MS is a leading example. Much of current MS research on IL-17 is in a mouse model that has been vital for the development of most existing therapies for human MS. In addition, scientists already are looking for Th17 cells in samples from MS patients. Notably, immunologists quickly figured out some key molecules that teach T cells to become Th17 in nature. They identified other interleukins, such as IL-6 and IL-23, that drive the Th17 cells. Furthermore, the intricate genetic program of the Th17 cell is being illuminated. This program allows Th17 cells to make many products in addition to IL-17 whose relevance was previously obscure. Now there is great potential to develop agents to block the elements of the newly discovered Th17 pathway in people with MS and other forms of autoimmunity. A sea change has occurred in our understanding of the nature of the “self” attack after it begins. This new understanding, many of us believe, will lead to new therapies for MS. But what about the enigma? How does this Th17 pathway get triggered in the first place, especially to focus on the brain? Federica Sallusto and her colleagues identified a major clue in findings they published in the May Nature Immunology. This Swiss team knew that Th17 cells had a special receptor called CCR6 that guides the cells’ movement to wherever an attracting molecule, CCL20, is made. Normally, CCR6 and CCL20 work together to direct Th17 cells to body surfaces to fight infections such as K. pneumoniae, S. aureus and C. albicans. The downside is that parts of the brain, particularly the choroid plexus, are rich in CCL20 and thus also attract Th17 cells. The Nature Immunology research showed that if a mouse has Th17 cells, but these cells cannot get into the choroid plexus, MS is blocked. The step that enables Th17 to enter the brain looks like a pivotal one for figuring out how the autoimmune attack in the brain begins. Clearly the research community is making significant discoveries in its longstanding commitment to figure out MS and to identify new treatments— beginning with steps toward understanding, once and for all, how it starts. Ralph Steinman, M.D., is professor and senior physician at The Rockefeller University in New York City, and is the recipient of the 2007 Albert Lasker Award for Basic Medical Research. He serves as scientific consultant for the Dana Foundation and scientific advisor for Immunology in the News. Killer Parasites’ Genes Decoded BBC News July 16, 2009 Scientists have decoded the genetic blueprint of two parasitic flatworms responsible for thousands of deaths worldwide every year. Schistosoma mansoni and Schistosoma japonicum both cause the debilitating disease schistosomiasis, otherwise known as Bilharzia. “This genome sequence catapults schistosomiasis research into a new era. It provides a foundation for understanding aspects of the parasite’s complex biology as well as a vehicle to immediately identify new targets for drug treatment.” —Matthew Berriman, researcher, Wellcome Trust Sanger Institute The work has already uncovered targets for new treatments for the disease, which causes fever and fatigue. The international study features in the journal Nature. Schistosomiasis cases top 200 million every year, with 20 million people seriously disabled by severe anemia, chronic diarrhea, internal bleeding and organ damage caused by the worms and their eggs, or the immune system reactions they provoke. In sub-Saharan Africa alone it kills 280,000 people each year. Dr. Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases, said: “Chronic infection with Schistosoma parasites makes life miserable for millions of people in tropical countries around the globe, and can lead to death. “New drugs and other interventions are badly needed to reduce the impact of a disease that lowers quality of life and slows economic development.” Since the 1980s, a cheap drug, praziquantel, has been widely distributed to areas where the disease is common. However, although the drug is effective, it does not prevent a person becoming re-infected. There is also a risk that the parasites will become resistant to it. Therefore, developing new drug targets is important. Enzyme targets Researchers working on the genetic blueprint of S. mansoni, the most widespread of the schistosomiasis parasites, found that it was made up of 11,809 genes—about 10 times the size of the malaria parasite genome. In particular, they identified a large number of genes that produce enzymes that break down proteins, giving the parasite its ability bore through tissue. Subsequent analysis revealed 120 enzymes that could potentially be targeted with drugs to disrupt the worm’s metabolism. The researchers also identified 66 drugs already on the market that might also be effective against schistosomiasis. The analysis also found that S. mansoni lacks a key enzyme needed to make essential fats and must rely on its host to provide these—revealing a potential Achilles’ heel that could be exploited for CDC.gov In S. mansoni, the smaller female parasite lives inside the thicker male. drug development. Researcher Dr. Matthew Berriman, of the Wellcome Trust Sanger Institute, said: “This genome sequence catapults schistosomiasis research into a new era. “It provides a foundation for understanding aspects of the parasite’s complex biology as well as a vehicle to immediately identify new targets for drug treatment.” Fellow researcher Dr. Najib El-Sayed, of the University of Maryland, said: “The genome sequence has given us, for the first time, a comprehensive view of the engines that drive the parasite, the strategies that allow it to survive in us, its human host. “It is a catalogue of opportunities.” In a separate study, scientists discovered that S. japonicum, which is largely confined to Asia, had even more genes. Copyright 2009 BBC News, http://news.bbc.co.uk. Reprinted by permission. Immunology in the News Fall 2009 3 How the Humble Hydrangea Shrub Could Hold the Key to Curing MS, Diabetes and Arthritis Fiona MacRae The Daily Mail (London) June 5, 2009 Its bright and beautiful flowers bring a splash of color to gardens all over Britain. But it seems the hydrangea is more than just a pretty bloom. A drug made from its roots could be used to treat a raft of common diseases, researchers say. “Halofuginone may herald a revolution in the treatment of certain types of autoimmune and inflammatory diseases.” —Anjana Rao, Children’s Hospital, Boston The colorful shrub—a staple of Chinese medicine—has the power to “revolutionize” the treatment of multiple sclerosis, psoriasis and some forms of diabetes and arthritis, scientists claimed yesterday. These diseases occur when the immune system attacks the body. Existing treatments are expensive, have to be injected, and do not address the biological cause of the problem. Powerful drugs that suppress the immune system can be used as a last resort but leave patients at risk of infections and other serious side effects. Now it appears that a medicine derived from Obituary Professor Jean Dausset The Daily Telegraph (London) June 23, 2009 Professor Jean Dausset, who has died aged 92, was a Nobel Prize-winning immunologist whose pioneering work helped verify the compatibility of donor and recipient in organ and bone-marrow transplants; his work on genetics helped establish the field of “predictive medicine,” which identifies the predisposition of individuals to certain diseases. Dausset won the Nobel Prize for Medicine in 1980 (shared with George Snell and Baruj Benacerraf ) for a lifetime’s work, the crowning achievement of which was his contribution to the identification of the genetic system known as HLA, for human leukocyte antigen. Identifying the HLA system, by which human tissues belong to compatible and incompatible groups just as blood cells do, was a crucial step forward for transplants. Until Dausset’s discovery, transplants were often marked by organ rejection and short life expectancy for the patient. But identifying HLA had an effect well beyond the already substantial impact on transplants. It became clear that these were the key genes controlling immunity. Their effects are visible in susceptibility to so-called “autoimmune diseases” such as multiple sclerosis, rheumatoid arthritis and insulindependent diabetes, to infectious diseases such as HIV/Aids and to various cancers. According to Dausset’s colleague Laurent Degos, the nature of HLA also meant that it enabled the tracking of genetic heritage in groups of people and was therefore “a precise tool to understand migration and blood relations.” It was with this in mind, that, shortly before he 4 Immunology in the News Fall 2009 the hydrangea’s root could offer an alternative. Experiments found that it blocked the formation of a type of white blood cell involved in autoimmune disease. Crucially, the drug does not seem to affect other kinds of cells vital to the body’s defenses— meaning it does not otherwise inhibit the immune system. Mice with a multiple sclerosis-like disease were far less severely affected when given low doses of the hydrangea-based drug, which is called halofuginone, the journal Science reported. Halofuginone is already used to treat a rare autoimmune disease that affects the skin and internal organs. Much more research would be needed for it to be given the green light to treat other conditions such as rheumatoid arthritis and diabetes. However, scientists say it is a promising avenue of research. Dr. Anjana Rao, of the Children’s Hospital in Boston in the U.S., said: “Halofuginone may herald a revoluZuma press tion in the treatment of certain types Hydrangea: The common shrub could hold the key to combating common autoimmune diseases. of autoimmune and inflammatory diseases.” Her fellow researcher Dr. Mark Sundrud added: medicine and is also a traditional medicine of “This is really the first description of a small moleNorth American Cherokee Indians. cule that interferes with autoimmune pathology but An extract of hydrangea leaf is also said to have is not a general immune suppressant.” anti-malarial properties. Hydrangea root has traditionally been used to Copyright 2009 Daily Mail/ZUMA Press. relieve inflammation and “cleanse” the joints. Reprinted by permission. It is one of the 50 staple herbs of Chinese retired to live permanently in Majorca in 2007, he claimed that one of the four realms to which he had made a significant contribution was “anthropology.” The other three were: “Transplantation, predictive medicine and immune response.” Jean Baptiste Gabriel Joachim Dausset was born on October 19, 1916, in Toulouse. His father was a captain in the French army, serving as a doctor, a career for which Jean was soon marked out. Jean was brought up in Biarritz, until the Daussets settled in Paris when he was 11. It was with a certain inevitability that he began medical studies, which he was completing at the outbreak of war in 1939. Identifying the HLA system, by which human tissues belong to compatible and incompatible groups just as blood cells do, was a crucial step forward for transplants. He was called up to serve as a doctor in Rennes, then Autun, from which he retreated on his motorcycle as the Germans invaded in 1940. His unit fell back to the Alps, and, in the ensuing chaos, Dausset found himself back in Toulouse, from where he headed to North Africa. He made it to Algeria before the French defeat was completed, and he was demobilized. Returning to Paris, he began his medical career. There he met a countess from the Caucasus who was recruiting volunteers to man ambulances in Morocco, a country that Dausset had already toured on his motorcycle before the outbreak of war. Dausset began his irregular ambulance service in 1942, wearing flowing white silk robes in the Arab style, which were emblazoned with the countess’s coat of arms. With the Allied landing in 1942, the ambulance unit joined regular forces and headed to the thick of the fighting in Tunisia. Such was the rivalry between Free French generals Leclerc and Giraud, Dausset remembered, that a unit attached to one once loudly played music to drown out the speech of an officer attached to the other. Dausset, who spent most of his career in research, found working on the front line “horrible.” “The ambulances arrived full of blood,” he recalled later. “I saw my first casualties: Germans, Italians, Arabs. Bizarrely, some of the German wounded refused blood transfusions from Italians, but didn’t mind it from Jews….” In 1944, in the middle of the V-1 bombardment, Dausset got himself transferred to London, where he was issued a medical kit including a plastic bathtub, a small chair, and (contrary to wartime conventions) a machine gun. He landed at Arromanches under incessant rain 10 days after D-Day, in charge of a convoy of medical supplies en route for Paris. With half his load destroyed, he finally arrived—only for his truck to give up the ghost on the Champs-Elysées, from where it was towed to its destination with a length of camouflage netting. Dausset then helped organize blood banks and transfusions for the Allied assault on Germany. After the war, in tandem with Professor Marcel Bessis, he began his medical research in earnest, specializing in the properties of blood cells. “We were regarded as biologists more than doctors,” he said. Their work helped improve the efficacy of transfusions, saving patients, including many women who had sought illegal abortions. As part of the Marshall plan, Dausset went to Boston on a medical exchange program in 1948, but did not enjoy his time there, blaming his shyness and poor English. Despite that, he had established good contacts with British medical researchers—in particular Robin Coombs at the British Society of Immunology. Dausset drew on Coombs’s work to develop the idea that white blood cells could possess the same quality of “autoimmunity” displayed by red blood cells. By 1952 he had observed white blood cells clumping together in response to antibodies, a process known as leuco-agglutination. This early research was carried out in antediluvian, dust-filled laboratories in Paris that, he recalled, “had been abandoned since 1914.” He was soon working towards HLA. “I understood, and little by little was able to prove, that cells of all tissues in an organism have a chemical identity which distinguishes them from cells of another organism of the same species to the point that they are incompatible one with another,” he explained. According to Danny Altmann, professor of immunology at the Department of Infectious Disease and Immunity, Imperial College, the period from the mid-1950s to the mid-1960s was one of intense activity for immunologists and geneticists as they struggled to understand this enormously complex aspect of human genetics—HLA being the most variable family of genes in man. Along with Dausset, others in the field included Jon van Rood, Walter Bodmer, Rose Payne and Paul Terasaki. “A key aspect of Dausset’s contribution was his insight that one would only unravel the secrets of such a diverse group of genes by analyzing large numbers of family ‘pedigrees,’ ” noted Altmann. The extension of this approach was to lead many years later to Dausset’s founding of the Centre d’Etude du Polymorphisme Humain (CEPH), a major, international resource of family DNA samples. This resource became central to many disease genetics studies and contributed to efforts to analyze the human genome. “A key aspect of Dausset’s contribution was his insight.” —Danny Altmann, professor of immunology, Imperial College Dausset, was, however, not purely a pioneering research doctor. He was also a great organizer, contributing actively to the fundamental reorganization of France’s medical system in the late 1950s. For several years he was a government adviser, work that culminated in a law establishing full-time employment in French hospitals and encouraging research. In 1958 he was named assistant professor of hematology at the Faculty of Medicine in Paris, then professor of hematology in 1963, before being appointed head of the immunology department at the Hôpital Saint-Louis. There he devoted himself entirely to research, uncovering the HLA system. He published the results in 1964. Apart from the Nobel Prize, Jean Dausset was subsequently honored with dozens of awards and honorary academic roles. Tall, thin and elegant, he was discreet but willing staunchly to defend his ideas. Outside medicine, he was fond of the plastic arts, collecting examples of work by Surrealist artists and displaying them at a gallery he ran in Paris. Jean Dausset, who died on June 6 in Palma, married, in 1963, Rose Mayoral, with whom he had a son and a daughter. Until the end of his life he was determined that his work in genetics should be used with a strong sense of moral purpose. He feared what he called the “sorcerer’s apprentices” in his profession, and noted that “the temptations of eugenics are close to the temptations of totalitarianism. Both can manipulate humans to create identical beings.” Copyright 2009 The Daily Telegraph. Reprinted by permission. From the Universities Immune System Key Discovered Monash University June 23, 2009 A team of Monash University researchers has discovered the importance of a protein that could improve the way the drug interferon is used to strengthen the human immune system. Published online in the prestigious journal Immunity, the findings show that the protein promyelocytic leukemia zinc finger (PLZF) is a key player in the body’s immune response to disease, increasing our understanding of the function of the immune system. Team leader Professor Bryan Williams, at the Monash Institute of Medical Research, said the findings demonstrate a role for PLZF, not previously recognized, that shows the protein is key to the body’s immunologically important interferon response. “We have shown that interferon stimulates an association between PLZF and co-factors to switch on a decisive subset of interferon-stimulated genes, including those involved in protection against viral infections,” Williams said. Interferon is a naturally produced substance that modulates the immune response and provides protection against viral infections and cancer. It has been developed as a drug over many years and has been used in the treatment of hepatitis, cancer and autoimmune diseases, such as multiple sclerosis. See also the journal article summary by Bryan R.G. Williams below. Although much has been learned about the mechanism of action of interferon, the reason that some patients are more sensitive to treatment with interferon than others has proved difficult to identify. “The results described in the study provide new insights into the mechanisms regulating the action of interferon, and demonstrate that PLZF is an important factor in the immune response and could therefore be used as a possible drug target for both anti-viral and anti-tumor therapy,” Williams said. Copyright 2009 Monash University. Reprinted by permission. From the scientific journals A Protein Supports Interferons’ Protective Function Summary by Bryan R. G. Williams Full text: Immunity June 2009 Interferons are a family of proteins that play an important role in protecting our bodies against dangers such as viral infections and cancer. They are naturally produced by cells in response to an attack, and are a vital component of the innate immune system. How they work is not fully understood, but our recent research solves one piece of the puzzle by showing that a specific protein is crucial. Interferons have proved to be useful in the treatment of a range of viral infections, such as hepatitis B and C. They are also an effective treatment for several cancers, including cancers of the blood and solid tumors. One member of the family, interferon-beta, is used to treat multiple sclerosis. However, some patients are more sensitive to treatment with interferons than others, and not all tumors, infections or inflammatory diseases are responsive to treatment. It is therefore critical to learn more about the action of interferons and develop new therapies. PLZF and interferons Since its initial discovery a half-century ago, scientists have learned much about how interferons work: They switch on a large number of interferonstimulated genes (ISGs) through signaling pathways within cells. Our research has identified a transcription factor that plays an important role in the interferon response. Transcription factors are proteins that bind to DNA and can either activate or repress gene activity, thus either increasing or decreasing the amount of protein a particular gene encodes. Our work involves a transcription factor called promyelocytic leukemia zinc finger (PLZF) protein, which Our discovery of PLZF’s important role in innate immunity provides us with new insights into the way interferons protect us from diseases. is known to be involved in sperm formation and skeletal development as a repressor of gene activity. However, we have discovered a new function for PLZF as an activator of a large subset of interferonstimulated genes (ISGs). We compared the expression of ISGs in two cell lines derived from patients with renal cancer and found that the cell line that was more sensitive to interferon treatment showed a higher expression of a large subset of these ISGs. This same cell line expressed higher levels of PLZF. Appropriately, the subset of ISGs that had a greater response in this cell line contained binding sites for PLZF in their promoters. Promoters are regions of genes that are involved in their activation. We then looked to see whether PLZF played a role in the innate immune response. Cells taken from normal mice and grown in culture with interferon were protected from infection with a virus called the Semliki Forest virus, whereas cells from mice that lacked the gene for PLZF were more susceptible to infection. We also looked at the effect of interferon treatment on the survival times of mice infected with the virus. Normal mice treated with interferon before exposure to the virus survived significantly longer than mice lacking the PLZF gene. Thus PLZF is a key player in the innate immune response. Supporting actors However, we found that normal mice and mice that lacked the PLZF gene still produced the same amount of interferon when they were infected with the virus. Therefore, interferon production alone cannot account for the different responses in mice with or without the PLZF gene. We found an answer in the expression of several ISGs known to be involved in the antiviral response that we had identified as being regulated by PLZF: Their expression was reduced in mice that lacked the PLZF gene. So the antiviral action of interferon depends on the activation of these genes by PLZF. PLZF also is important when interferon activates natural killer cells, another key component of the innate immune response. This type of white blood cell can detect and kill cells that are infected with a virus, as well as tumor cells. After being activated (See Protein Helps Protect, pg. 6) 4 Immunology in the News Fall 2009 5 From the scientific journals (Protein Helps Protect, from pg. 5) 4 by interferon, natural killer cells release proteins called perforin and granzyme B, which cause the destruction of damaged or infected cells. We discovered that natural killer cells from mice lacking the PLZF gene were deficient in their ability to kill tumor cells in response to interferon. These cells were impaired in the production of a chemokine—a type of immune mediator—called CXCL10, which has previously been associated with natural killer cell activity and protection from virus infection. In addition, we found that the production of granzyme B was much lower in natural killer cells from PLZF-deficient mice. We have found that a process called phosphorylation, in which a phosphate group is added to the PLZF protein, is essential to the activation of selected ISGs by PLZF. We also discovered that two co-factors, known as HDAC1 and PML, interact with PLZF and increase the activation of ISGs in response to interferon. We think interferon stimulates the phosphorylation of PLZF and its interaction with these co-factors to form a complex that binds to selected ISGs and activates them. These genes then go on to produce proteins involved in the immune response against viruses. Our discovery of PLZF’s important role in innate immunity provides us with new insights into the way interferons protect us from diseases. This knowledge of the role of PLZF may help us to improve the way interferons are used clinically, including the design of new therapies for patients who currently do not respond to interferon treatment. PLZF thus could be an important target in the development of drugs to treat viral infections and cancers. Original article: “Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity.” Dakang Xu,1,6 Michelle Holko,2,6,7 Anthony J. Sadler,1 Bernadette Scott,1 Shigeki Higashiyama,3 Windy Berkofsky-Fessler,4,8 Melanie J. McConnell,4,9 Pier Paolo Pandolfi,5 Jonathan D. Licht,4 and Bryan R.G. Williams1 1Monash Institute of Medical Research, Monash University, Melbourne, Australia. 2Department of Preventive Medicine, Northwestern University, Chicago, IL 60611, USA. 3Department of Biochemistry and Molecular Genetics, Ehime University Graduate School of Medicine, Shitsukawa, To-on, Ehime 791-0295, Japan. 4Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, 303 E. Superior Street, Lurie 5-123, Chicago, IL 60611, USA. 5Cancer Genetics Program, Beth Israel Deaconess Cancer Center and Department of Medicine and Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA. 6These authors contributed equally to this work. 7Present address: Gene Expression Omnibus, National Center for Biotechnology Information, National Institutes of Health, Bethesda, MD 20892, USA. 8Present address: RNA Therapeutics Department, Hoffmann-La Roche Inc., Nutley, NJ 07110, USA. 9Present address: Malaghan Institute of Medical Research, Wellington, New Zealand. (This is a summary by one of the study’s coauthors. Full text appears in Immunity, June 19, 2009, Vol. 30, No. 6, pp. 802-816.) Receptor Helps Us Fight Respiratory Virus Infection New findings may explain why some people are more susceptible to infections caused by influenza and respiratory syncytial virus. Summary by Santanu Bose Full text: Nature Immunology August 2009 Respiratory syncytial virus (RSV) and flu are leading causes of severe and sometimes deadly respiratory diseases among infants, children, the elderly and people with compromised immune systems. With the recent emergence of various subtypes of flu (such as swine flu) and a high mortality rate among some infants and young children infected with RSV, it is crucial to understand how our immune systems protect us against viruses and why they sometimes fail in that regard. First it is important to understand how cells in our lungs recognize respiratory viruses and mount a defense response to restrict viral spread. The first line of defense during a microbial infection is called the innate immune system. This innate defense mechanism is crucial to diminish the severity of diseases associated with flu and RSV infection, including pneumonia and bronchiolitis. Our immune cells possess biosensor molecules called pattern recognition receptors, or PRRs, that can recognize various components of viruses, known as pathogen associated molecular patterns, or PAMPs. Once a pattern recognition receptor identifies a viral pattern, it relays that information to cellular defense molecules, which then launch an anti-viral response to eliminate the virus from the body. In our current study, we have identified a novel pattern recognition receptor called the NOD2 (nucleotide-binding oligomerization domain–2) protein that can sense both flu and RSV and tell the body to launch a defensive response to combat infection. NOD2 recognizes the virus’s genetic material, a type called single-stranded RNA (ssRNA), and activates the immune response by producing an antiviral protein called interferon-beta (IFN). Findings could affect medicines, vaccines We already knew that NOD2 could detect bacteria and activate the anti-bacterial response, but NOD2 never had been shown to detect viruses or RNA. However, our studies have shown that NOD2 is capable of detecting both viral ssRNA and small synthetic ssRNA (which might be used in medicine or with a vaccine) to activate the anti-viral response. We further demonstrated that NOD2 interacts with a protein called mitochondrial anti-viral signaling protein to activate the IFN-mediated anti-viral response against RSV and flu. We showed how important NOD2 is to the host defense against respiratory virus infection by using mice that lacked NOD2 protein. When challenged with a respiratory virus, mice deficient in NOD2 showed enhanced susceptibility and survived for only 10 days after infection, compared with normal mice that survived seven to eight weeks. In addition, the infected mice that lacked NOD2 showed exaggerated lung disease with severe pneumonia, unlike the normal animals (please see image at right). Thus, NOD2 plays a critical role in host defense against respiratory viruses, by detecting viral ssRNA genome during early infection. NOD2 bound to ssRNA then interacts with a mitochondrial protein MAVS, which activates the anti-viral defense apparatus by producing anti-viral protein IFN. A schematic showing the role of NOD2 in host anti-viral defense is shown at left. Our study is clinically relevant for the development of therapeutics against respiratory viruses. In addition, our work suggests that screening for the presence of the NOD2 gene could identify people who are more susceptible to RSV and flu infections. Because small Bose laboratory A schematic demonstrates the anti-viral defense mechanism of the synthetic ssRNA can activate NOD2 NOD2 receptor. NOD2 recognizes a virus’s genetic material, singleby mimicking the viral ssRNA genome, stranded RNA (ssRNA), and interacts with the mitochondrial anti-viral we could utilize synthetic ssRNA (as a signaling (MAVS) protein. This, in turn, activates a protein called nasal spray or mist) to boost anti-viral interferon regulated factor-3 (IRF3) and the interferon-beta (IFN) gene. response among high-risk individuals, Interferon-beta protects surrounding cells and tissue from infection. 6 Immunology in the News Fall 2009 Bose laboratory Cross-sections of virus-infected mouse lungs illustrate the critical role of the cellular molecule NOD2 in host defense. The cross-section on the left is from a normal mouse with healthy lungs; the one on the right is from a NOD2-deficient mouse with pneumonia. or as part of an adjuvant therapy to enhance vaccine efficiency against the flu. This approach is an attractive method for controlling respiratory virus infection since it does not involve viral components— viruses can mutate in response to an anti-viral drug such as Tamiflu. Apart from therapeutic potential, variations in the NOD2 gene, which are common in humans, may explain why some people are more prone to respiratory virus infections. Future studies will explore whether NOD2 gene variations enhance susceptibility to these infections. Original article: “Activation of innate immune anti-viral response by NOD2.” Ahmed Sabbah,1 Te Hung Chang,1 Rosalinda Harnack,1 Victoria Frohlich,2 Kaoru Tominaga,2,3 Peter H Dube,1 Yan Xiang,1 and Santanu Bose1 1Department of Microbiology and Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. 2Department of Cellular and Structural Biology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. 3Sam and Ann Barshop Institute for Longevity and Aging Studies, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, USA. (This is a summary by one of the study’s coauthors. Full text appears in Nature Immunology, advance online publication, Aug. 23, 2009; doi:10.1038/ni.1782. http://www.nature.com/ ni/journal/vaop/ncurrent/full/ni.1782.html)