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  • richardmitnick 7:21 am on September 2, 2016 Permalink | Reply
    Tags: , , Immunology, ,   

    From Caltech: Women in STEM – “Multitasking Protein Keeps Immune System Healthy” Beth Stadtmueller 

    Caltech Logo

    Caltech

    09/01/2016
    Lori Dajose

    1
    Simplified diagram of pIgR binding to an antibody. A) pIgR and an antibody. B) Recognition binding. pIgR chemically recognizes an antibody. C) Conformational change. The pIgR protein opens up. D) The bound state of pIgR and an antibody. Credit: B. Stadtmueller

    2
    Schematic summary highlighting the differences in pIgR structure among fish, birds and humans.
    Credit: B. Stadtmueller

    The polymeric immunoglobulin receptor, or pIgR, is a multitasking protein produced in the lining of mucosal surfaces, such as the intestines. It plays a pivotal role in the body’s immune functions by sequestering bacteria and by assisting antibodies—large proteins that can identify and neutralize specific bacteria and viruses. Now, scientists at Caltech have determined the three-dimensional structure of pIgR, providing important insights into how the protein keeps the immune system running smoothly.

    Beth Stadtmueller, a postdoctoral scholar in the laboratory of Centennial Professor of Biology Pamela Björkman, is the first author on two recent papers describing the findings.

    2
    Beth Stadtmueller

    “Proteins such as pIgR are folded into complicated shapes,” says Stadtmueller. “Having a complete model of a protein is analogous to an architectural model of a building showing scaled dimensions of walls, the locations of windows and doors, angles of the roof, and so on. Understanding the structure of this protein provides information on how it carries out normal functions while also providing a basis to rationally engineer modified proteins with enhanced functions, which could be used as therapeutics.”

    The pIgR protein is best known for attaching to antibodies and ferrying them from the bloodstream to the interior of the intestines, where the antibodies can neutralize pathogens. In mammals such as humans, the group discovered that pIgR looks like five round beads—biologists call these regions “domains”—that are connected to form a tightly closed, triangle-shaped loop. The group also showed that upon encountering an antibody, the pIgR molecule opens up—like changing from a fist to an open hand—to enclose around the antibody and to transport it into the intestines.

    While pIgR is crucial for helping antibodies to function, the protein also has disease-fighting abilities of its own. For example, some molecules of pIgR are released into the intestines where they alone engage bacteria, such as pneumonia-causing Streptococcus pneumoniae.

    The group also studied the structures of pIgR from fish and birds, to see how the protein has changed as vertebrates evolved. In fish, pIgR has only two domains and forms a straight line. In birds, an evolutionary intermediary between fish and humans, the protein has four domains. The group was surprised to find that the shape of the bird pIgR is not fixed in a closed loop or a straight line—it can change freely between closed and open configurations, and can grasp antibodies much like the human protein.

    “The human pIgR is like a door that has to be unlocked to open, whereas the bird pIgR is constantly opening and closing like a revolving door,” Stadtmueller says. “These are very different structures, which are likely to support functions unique to each protein.”

    “The immune system has changed considerably as vertebrates have evolved,” she adds. “Studying pIgR in a spectrum of vertebrates illustrates how the protein architecture has changed to support species-specific defense systems. It helps us to understand why certain immune system functions have evolved and provides a foundation to test their contributions to specific states of health and disease.”

    The three-dimensional structure of human pIgR is described in a March 2016 paper published in the journal eLife, titled The structure and dynamics of secretory component and its interactions with polymeric immunoglobulins. A follow-up study, titled Biophysical and biochemical characterization of avian secretory component provides structural insights into the evolution of the polymeric Ig receptor, describing the structure of avian pIgR, was published in the Journal of Immunology on August 15, 2016. The work was done in collaboration with the Hubbell laboratory at UCLA and supported by grants from the National Institute of Allergy and Infectious Diseases, the Cancer Research Irving Postdoctoral Fellowship, the Jules Stein Professorship Endowment, and the National Institutes of Health.

    See the full article here .

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    The California Institute of Technology (commonly referred to as Caltech) is a private research university located in Pasadena, California, United States. Caltech has six academic divisions with strong emphases on science and engineering. Its 124-acre (50 ha) primary campus is located approximately 11 mi (18 km) northeast of downtown Los Angeles. “The mission of the California Institute of Technology is to expand human knowledge and benefit society through research integrated with education. We investigate the most challenging, fundamental problems in science and technology in a singularly collegial, interdisciplinary atmosphere, while educating outstanding students to become creative members of society.”
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  • richardmitnick 6:29 pm on February 25, 2016 Permalink | Reply
    Tags: a bat, , Australian black flying fox, , Immunology   

    From CSIRO: “Bat super immunity to lethal disease could help protect people” 

    CSIRO bloc

    Commonwealth Scientific and Industrial Research Organisation

    23 February 2016
    Ms Emma Pyers

    For the first time researchers have uncovered a unique ability in bats which allows them to carry but remain unaffected by lethal diseases.

    Bats

    Unlike humans, bats keep their immune systems switched on 24/7 and scientists believe this could hold the key to protecting people from deadly diseases like Ebola.

    Bats are a natural host for more than 100 viruses, some of which are lethal to people, including Middle Eastern Respiratory Syndrome (MERS), Ebola and Hendra virus, however, interestingly bats do not get sick or show signs of disease from these viruses.

    Published today in the journal Proceedings of the National Academy of Sciences (PNAS), this new research examines the genes and immune system of the Australian black flying fox, with surprising results.

    “Whenever our body encounters a foreign organism, like bacteria or a virus, a complicated set of immune responses are set in motion, one of which is the defense mechanism known as innate immunity,” leading bat immunologist at CSIRO’s Australian Animal Health Laboratory Dr Michelle Baker said.

    “We focused on the innate immunity of bats, in particular the role of interferons – which are integral for innate immune responses in mammals – to understand what’s special about how bats respond to invading viruses.

    “Interestingly we have shown that bats only have three interferons which is only a fraction – about a quarter – of the number of interferons we find in people.

    “This is surprising given bats have this unique ability to control viral infections that are lethal in people and yet they can do this with a lower number of interferons.”

    The team also compared two type 1 interferons – alpha and beta.

    The research showed that bats express a heightened innate immune response even when they were not infected with any detectable virus.

    “Unlike people and mice, who activate their immune systems only in response to infection, the bats interferon-alpha is constantly ‘switched on’ acting as a 24/7 front line defence against diseases,” Dr Baker said.

    “In other mammalian species, having the immune response constantly switched on is dangerous – for example it’s toxic to tissue and cells – whereas the bat immune system operates in harmony.”

    While we are familiar of the important role bats play in the eco-system as pollinators and insect controllers, they are also increasingly demonstrating their worth in potentially helping to protect people from infectious diseases.

    “If we can redirect other species’ immune responses to behave in a similar manner to that of bats, then the high death rate associated with diseases, such as Ebola, could be a thing of the past,” Dr Baker said.

    This work builds on previous research undertaken by CSIRO and its partners to better understand bat immunity to help protect Australia and its people from exotic and emerging infectious diseases.

    Led by CSIRO, this international research effort included expertise from CSIRO, Duke-NUS Medical School and the Burnet Institute.

    See the full article here .

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    CSIRO campus

    CSIRO, the Commonwealth Scientific and Industrial Research Organisation, is Australia’s national science agency and one of the largest and most diverse research agencies in the world.

     
  • richardmitnick 4:21 pm on January 18, 2016 Permalink | Reply
    Tags: , Immunology,   

    From Scripps: “TSRI Scientists Solve 3D Structure of Protein that Guides the Immune System” 

    Scripps
    Scripps Research Institute

    January 18, 2016
    No writer credit found
    Office of Communications
    Tel: 858-784-2666
    Fax: 858-784-8136
    press@scripps.edu

    Temp 1
    A new study from The Scripps Research Institute (TSRI) and the Duke University Medical Center reveals the three-dimensional structure of a crucial ion channel, shedding light on its role in the immune system.

    Many cells have microscopic gates, called ion channels, which open to allow the flow of ions across the cell membrane. Thanks to these gates, cells can detect stimuli such as heat, pain, pressure and even spicy food.

    In a new study, researchers from The Scripps Research Institute (TSRI) and the Duke University Medical Center reveal the three-dimensional structure of a crucial ion channel. Their findings depict this channel in more detail than ever before, shedding light on the channel’s possible role in immune functions such as detecting infection and inflammation.

    “Our ability to perceive our environment—which includes sensing temperature and pain—is heavily reliant on these channels. Understanding their 3D structure paves the way for the development of a wide variety of new therapies,” said TSRI biologist Gabe Lander, who was co-senior of author of the study with biochemist Seok-Yong Lee of the Duke University Medical Center.

    The new study was published January 18, 2016, in the journal Nature Structural and Molecular Biology.

    An Important Sensor

    Lander and his colleagues focused on an ion channel called the transient receptor potential vanilloid-2 (TRPV2), which resides within the membranes of cells throughout the body. Previous research had suggested TRPV2 was involved in sensing physical stresses, such as changes in pressure and temperature, as well as in detecting immune challenges and activating the immune system’s T cells.

    In the new study, the researchers used an imaging technique called cryo-electron microscopy, in which a sample is pelted with high-energy electrons. Through the use of new sample preparation techniques, computer programs and a new generation of cameras, researchers at TSRI have improved the potential resolution of cryo-electron microscopy images to the point that TRPV2 could be imaged with near-atomic precision.

    “The fact that the field of cryo-electron microscopy has advanced to where we can now solve the structures of these small membrane-embedded complexes to such high resolution is exciting,” said TSRI Research Associate Mark Herzik Jr., who was co-first author of the study with Lejla Zubcevic of Duke University. “The methodological insights from this study will help advance other projects in the lab.”

    When the researchers compared the structure of TRPV2 with TRPV1, a genetically similar ion channel found only in the nervous system, they noticed some significant differences. TRPV2’s architectural components near the central gate and the peripheral domains were in a previously unobserved configuration. Together, this led the authors to propose that this configuration represents a “desensitized” state, providing a new molecular snapshot of these ion channels at work.

    “The TRVP2 ion channel is likely a global internal sensor—playing an important role in our immune response,” said Lander.

    Lander said the next step is to find the structures of TRPV2 at different stages of opening and closing its gate. With the entire cycle imaged, researchers will have a better idea of how the ion channel works and how it might be manipulated therapeutically to treat autoimmune diseases.

    The other co-authors on the paper, Cryo-electron microscopy structure of the TRPV2 ion channel,” were Ben Chung and Zhirui Liu of the Duke University Medical Center.

    This study was supported by the Duke University Medical Center, the National Institutes of Health (grants R01GM100894, DP2OD008380 and DP2EB020402), the Searle Scholars Program and The Pew Charitable Trusts.

    See the full article here .

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    The Scripps Research Institute (TSRI), one of the world’s largest, private, non-profit research organizations, stands at the forefront of basic biomedical science, a vital segment of medical research that seeks to comprehend the most fundamental processes of life. Over the last decades, the institute has established a lengthy track record of major contributions to the betterment of health and the human condition.

    The institute — which is located on campuses in La Jolla, California, and Jupiter, Florida — has become internationally recognized for its research into immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune diseases, cardiovascular diseases, virology, and synthetic vaccine development. Particularly significant is the institute’s study of the basic structure and design of biological molecules; in this arena TSRI is among a handful of the world’s leading centers.

    The institute’s educational programs are also first rate. TSRI’s Graduate Program is consistently ranked among the best in the nation in its fields of biology and chemistry.

     
  • richardmitnick 10:31 am on December 21, 2015 Permalink | Reply
    Tags: , Immunology, ,   

    From U Washington: “Compound found to trigger innate immunity against viruses” 

    U Washington

    University of Washington

    12.16.2015
    Bobbi Nodell

    1
    A scientist’s illustration of immunology research at UW Medicine’s South Lake Union campus. Dennis Wise

    Research from UW Medicine and collaborators indicates that a drug-like molecule can activate innate immunity and induce genes to control infection in a range of RNA viruses, including West Nile, dengue, hepatitis C, influenza A, respiratory syncytial, Nipah, Lassa and Ebola.

    The findings, published today in the Journal of Virology, show promising evidence for creating a broad-spectrum antiviral.

    “Our compound has an antiviral effect against all these viruses,” said Michael Gale Jr., University of Washington professor of immunology and director of the UW Center for Innate Immunity and Immune Disease. The finding emerged from research by his lab in concert with scientists at Kineta Inc. and the University of Texas at Galveston.

    2
    Dr. Michael Gale, left, talks with immunology researchers. Dennis Wise

    Gale said he thinks the findings are the first to show that innate immunity can be triggered therapeutically through a molecule present in all our cells, known as RIG-I.

    RIG-I is a cellular protein known as a pathogen recognition receptor. These receptors detect viral RNA and signal an innate immune response inside the cell that is essential for limiting and controlling viral infections. The signal induces the expression of many innate immune and antiviral genes and the production of antiviral gene products, pro-inflammatory cytokines, chemokines and interferons.

    “These products act in concert to suppress and control virus infection,” the researchers wrote.

    Such activation of the innate immune response to control viral infection has been tested successfully in cells and in mice. Next steps would be to test dosing and stability in animal models and then in humans, a process that could take two to five years, Gale said.

    Currently, there are no known broad-spectrum antiviral drugs and few therapeutic options against infection by RNA viruses. RNA viruses pose a significant public health problem worldwide because their high mutation rate allows them to escape the immune response. They are a frequent cause of emerging and re-emerging viral infections. West Nile virus infections, for example, started in the United States in 2000 and remerged in 2012. The World Health Organization reports 50 million to 100 million new cases of dengue fever yearly and 22,000 deaths caused by the related dengue virus. Dengue is now present in the southern U.S.

    3
    Cells under a microscope in a UW Medicine immunity lab. Dennis Wise

    Hepatitis C, which is transmitted through the blood, infects upward of 4 million people each year; 150 million people are chronically infected and at risk for developing cirrhosis or liver cancer, according to the paper. Direct-acting antivirals can control hepatitis C and show promise of long-term cure, but viral mutation to drug resistance is a concern with prolonged use of these drugs. Also the drugs’ exorbitant costs make them unaffordable to many or most patients.

    “There is tremendous interest in triggering innate immunity,” said Shawn Iadonato, chief scientific officer at Seattle biotech Kineta. Some viral infections, he pointed out, cannot be treated by traditional antivirals. Activating innate immunity also will make the viruses less likely to resist the drug actions because the therapy targets the cell, via gene action, rather than the virus itself.

    “It’s routine for us to think of broad-spectrum antibiotics, but the equivalent for virology doesn’t exist,” Iadonato said.

    See the full article here .

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    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.

    So what defines us — the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 12:23 pm on November 25, 2015 Permalink | Reply
    Tags: , Immunology, , ,   

    From U Washington: “New center seeks therapies to boost body’s immune system” 

    U Washington

    University of Washington

    11.23.2015
    Bobbi Nodell

    1
    Research on immune responses underway at a UW Department of Immunology lab. Dennis Wise

    A new Center for Innate Immunity and Immune Disease at UW Medicine seeks to become a world leader in finding therapies to regulate the body’s defense system and fend off a wide variety of diseases. Among these are infectious illnesses like Ebola, influenza and dengue fever, autoimmune disorders like rheumatoid arthritis, multiple sclerosis and lupus, and common, complex conditions, like cancer, diabetes and cardiovascular disease.

    The research center, which was formed over the past two years, will officially open for business in January. A seminar and reception to introduce the center will be held at 3:30 p.m., Monday, Nov. 30, at UW Medicine South Lake Union, Building E, 750 Republican St., Seattle.

    Michael Gale Jr., University of Washington professor of immunology and director of the new center, will provide an overview at the event; his talk will stream live.

    Dr. Gale sat down to answer a few question about the center’s goal to “harness the immune system,” the second most complex system in the body next to the brain:

    Q. What does it mean to harness the immune system?

    A. Our bodies have an inborn ability to respond to infections. It doesn’t require pre-exposure. This response is called the innate immune response. Depending on how the innate response plays out, the rest of the immune response will follow – whether it’s going to activate a T-cell to attack a cancer cell or to turn against our own body, for example. The innate immune response shapes the overall immune response. Scientists didn’t know that five to eight years ago. We are studying innate immunity to the point we can harness these processes to enhance or control the immune response.

    Q. Why Seattle?

    A. Seattle is a hotbed for this kind of research. We now have a critical mass of expertise to support a center like this. UW Medicine has one of the highest-ranking immunology departments in the world. Great research institutions, such as Benaroya Research Institute, Fred Hutchinson Cancer Research Center, Institute for Systems Biology, Center for Infectious Disease Research, and Seattle Children’s Research Institute are all in walking distance.

    These institutions, as well as several local biotech companies, have people working on being able to trigger an immune system response for various diseases, but there isn’t one center coordinating all the activity and providing the infrastructure.

    Q. What will the Center for Innate Immunity and Immune Disease offer?

    A. We will be the place coordinating different research efforts in innate immunity to push discoveries into human therapies.

    2
    Researchers working in an immunology lab at UW Medicine South Lake Union.

    With local biotech partners, scientists can quickly test and develop these new advances toward clinical applications.

    We have already discovered drug targets and drug-like compounds of innate immune regulation. These research findings offer the promise to treat Ebola virus, influenza, and West Nile virus infections. The center will help bring forward similar discoveries in autoimmune disease, inflammatory disease and cancer.

    Q. Who will be involved in the center?

    A. The center will have scientists from different fields of expertise, such as infectious disease, rheumatology, computational biology, protein biology, pharmaceutics, vaccinology, genetics, and pathology, microbiology, immunology, and medicine, as well as industry partners. They will work with clinicians to bring understanding from diverse perspectives and with our biotech partners and others to evaluate whether a therapy is ready for preclinical and clinical development.

    Q. What is one of the leading edge technologies used by the center?

    A. The center will be designed around four service cores – cell signaling, transgenic mouse models, immunoinformatics, and translational research. It will also have an educational outreach core. All the cores are innovative, but probably the most cutting edge is the immunoinformatics core. It brings together a group of computational biologists who can process high throughput data sets and build computational models to help steer the research direction. [High throughput is the running of several experimental test simultaneously.]

    Q. What kind of outreach does the center do?

    A. The education outreach core is looking at the next generation by bringing basic immunology teaching and lab exercises in immunology to local public school students. This core also runs a summer research internship in its members’ labs for high school students.

    See the full article here .

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    The University of Washington is one of the world’s preeminent public universities. Our impact on individuals, on our region, and on the world is profound — whether we are launching young people into a boundless future or confronting the grand challenges of our time through undaunted research and scholarship. Ranked number 10 in the world in Shanghai Jiao Tong University rankings and educating more than 54,000 students annually, our students and faculty work together to turn ideas into impact and in the process transform lives and our world. For more about our impact on the world, every day.

    So what defines us — the students, faculty and community members at the University of Washington? Above all, it’s our belief in possibility and our unshakable optimism. It’s a connection to others, both near and far. It’s a hunger that pushes us to tackle challenges and pursue progress. It’s the conviction that together we can create a world of good. Join us on the journey.

     
  • richardmitnick 3:47 pm on August 19, 2015 Permalink | Reply
    Tags: , , Immunology,   

    From UC Davis- “Investigating Immunotherapy: Cancer Breakthrough Leads to Startup 

    UC Davis bloc

    UC Davis

    August 18. 2015
    Jocelyn Anderson

    1
    Chiao-Jung Kao

    UC Davis researchers are exploring novel immunotherapy strategies with the goal of developing targeted treatment for cancer patients.

    Cancer immunotherapy — harnessing the innate powers of the patient’s own immune system to fight the disease — dates back to as early as the 1890s, when one doctor discovered that bacterial infections could stimulate an immune system response that could also trigger cancer remission. More recently, the field has expanded, with new research supporting treatments that either stimulate or restore the immune system. For example, cancer vaccines are designed to make the person’s immune system more effectively attack cancer cells. Advantages include high specificity and relatively low toxicity.

    Results from a new study, published in July in Cancer Immunology Research, suggest that monitoring immune status may be necessary to optimize treatment regimens combining immunotherapy with chemo-radiotherapy.

    “Immunotherapy is poised to become the standard of care for many cancers,” said Chiao-Jung Kao, assistant adjunct professor in the Department of Obstetrics and Gynecology and lead author of the paper. “In the past, cancer immunotherapies such as cancer vaccines have been combined with chemotherapy with limited success.”

    Kao is part of a research team led by Michael DeGregorio, professor of medicine, in the Division of Hematology and Oncology Research within the Department of Internal Medicine at UC Davis.

    The team describes key differences in the effects of chemo-radiotherapy on biomarkers of immune response following two commonly employed treatment regimens in a lung cancer mouse model. While the paper focuses on lung cancer, the findings may be applied to other cancer types.

    “To our knowledge, this is the first clear demonstration in a preclinical mouse model that serial monitoring of a patient’s immune status can be critical when using cancer immunotherapy,” said Kao.

    Additionally, the researchers are testing several small molecule drug candidates for their ability to boost the immune system. Such drug modulators could potentially enhance the effectiveness of cancer immunotherapy. The lead proprietary compound, with the code name IMT-325, has shown promising activity in both in vitro and in vivo preclinical studies.

    “Our approach is to monitor immune status of cancer patients and fortify the immune system with an immune modulator for the purpose of optimizing personalized cancer immunotherapies,” said DeGregorio.

    A modulator would help regulate the immune system. Though the precise mechanism of action is still not widely understood, immune modulators currently are used to control some ailments like Crohn’s disease. Researchers also are investigating a connection to cancer.

    The same team made news a year ago with a potential lung cancer vaccine that shows promise for boosting immune response and reducing the number of tumors in mice with lung cancer. They now believe a drug modulator they are developing could improve the vaccine’s effect.

    Both projects have been supported by Germany-based pharmaceutical company Merck KGaA.

    With the discovery of this new therapeutic approach, DeGregorio and his team formed a startup focused on commercializing the therapy. (DeGregorio and Kao are scientific advisors to the new venture.) The company, called ImmunoTess, was founded in May and has already raised more than $1 million and filed two provisional patent applications.

    The UC Davis Office of Research helps university scientists like DeGregorio and Kao, turn their breakthroughs into commercial products, either through established corporate partners or the formation of startup companies. Such new ventures are facilitated by the Office of Corporate Relations and InnovationAccess, units within the Technology Management & Corporate Relations division. University startup formation is facilitated by Venture Catalyst, also within TMCR. Venture Catalyst and InnovationAccess worked closely with the founders of ImmunoTess throughout the entire process, from offering expertise on forming the new venture to filing provisional patents and licensing the technology to the company. Venture Catalyst’s START program also provided a suite of services designed specifically to help grow technology startups. UC Davis has an equity stake in ImmunoTess.

    “InnovationAccess and Venture Catalyst are immensely helpful resources for faculty members like myself who are motivated to move our research beyond the laboratory into clinical benefit for patients,” said DeGregorio. “The success of ImmunoTess in delivering treatments to patients suffering from cancer will benefit from this continued collaboration.”

    DeGregorio has more than 30 years of experience in drug development research, and is one of the inventors of two drugs approved by the U.S. Food and Drug Administration. Most notably, he developed Osphena, which was approved for women by the FDA in 2013 to treat dyspareunia, pain during sexual intercourse most often associated with menopause. It was approved by the European Medicines Agency in 2015 for the treatment of vulvar and vaginal atrophy in postmenopausal women. The drug also has potential use in breast cancer for preventing bone loss and treating quality-of-life issues in breast cancer survivors.

    With this newest venture, DeGregorio plans to assemble a regulatory and clinical research team and potentially partner with one or more pharmaceutical companies to allow for further development of immunotherapies.

    “As a serial innovator, Dr. DeGregorio has a strong track record of transforming his research into positive quality of life impact through its commercialization,” said Dushyant Pathak, associate vice chancellor for Technology Management and Corporate Relations. “Partnering with him in the success of ImmunoTess is an example of how UC Davis supports the formation of companies and facilitates their success in commercializing university technologies for societal benefit and economic impact.”

    See the full article here.

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    The University of California, Davis, is a major public research university located in Davis, California, just west of Sacramento. It encompasses 5,300 acres of land, making it the second largest UC campus in terms of land ownership, after UC Merced.

     
  • richardmitnick 7:45 am on August 10, 2015 Permalink | Reply
    Tags: , , , , Immunology   

    From Cosmos: “Modifying human immune cells to fight cancer” 

    Cosmos Magazine bloc

    COSMOS

    10 Aug 2015
    Viviane Richter and Elizabeth Finkel

    1
    Coloured scanning electron micrograph of T cells (pink) attacking a cancer cell. Editing T cells’ genes could soon enhance their cancer-attacking abilities.Credit: Science Photo Library / Getty Images

    Immune cells known as T cells are formidable fighters against cancer and HIV.

    2
    Scanning electron micrograph of a human T cell

    But they can be outsmarted by these foes. Now researchers at the University of California, San Francisco have figured out how to help T cells fight back using the latest gene editing technique called CRISPR. The method was published in Proceedings of the National Academy of Sciences in July. “This technique opens a lot of doors for the field,” says lead author Alexander Marson.

    Scientists have been tinkering with genes since the early 1970s to create faster growing pigs or herbicide-resistant crops. But the techniques had poor precision. Tens of thousands of individuals had to be tinkered with to achieve the required edits and usually those edits would be inserted on the wrong pages of the DNA text.

    To reliably manipulate specific genes to fight human disease, pinpoint precision is required.

    2
    The CRISPR-CAS9 gene editing machinery from the Streptococcus pyogenes bacterium. RNA strands (blue) guide CRISPR to a targeted stretch of DNA, where it can snip out a specific gene. Credit: MOLEKUUL / SCIENCE PHOTO LIBRARY / Getty Images

    Which is exactly what the CRISPR gene editing technique offers. It’s no surprise that since scientists first discovered CRISPR in bacteria three years ago, it has taken the world by storm. Microbes evolved CRISPR to edit viruses out of their DNA. Now it’s been used to precisely edit everything from the DNA of crops to editing the HIV virus out of human DNA. Last April, Chinese researchers used it to edit the DNA of a human embryo – a move that created a storm of controversy. Till now tampering with the DNA of an embryo was considered out of bounds.

    But tampering with T cells is not likely to attract bad press. In particular, blood borne T cells form the major defence against viruses and cancer. Or when they misbehave, they cause auto-immune diseases such as Type 1 Diabetes. Controlling these cells by rewriting their DNA could mean a cure for incurable diseases. It’s all very doable: simply filter T cells from a person’s blood, edit their DNA and return them to the individual to do their job.

    The challenge is delivering the CRISPR machinery into T cells. Usually it’s done by packaging CRISPR into a harmless virus that ferries it into cells. CRISPR itself then acts like a guided missile, homing in on a precise stretch of the DNA code. (The guide that targets the DNA is a small piece of RNA. The missile is a shredding protein called Cas 9.) But so far, getting this guided missile inside the cells has been at the very low end of precision and efficiency. If only a tiny percentage of T cells can be engineered to resist HIV or fight cancer, it might hardly be worth the effort.

    So Marson’s team tried brute force. They zapped T cells from healthy donors with an electric current. This made temporary holes in the cells’ membrane, big enough for the intact CRISPR machinery to pop through. They managed to edit the DNA in 20 percent of T cells, a “huge” leap in efficiency according to Marco Herold, molecular biologist at Melbourne’s Walter and Eliza Hall Institute of Medical Research.

    Yet in contrast to their brute force entry, they were able to achieve very fine editing, changing individual letters of the cell’s DNA for the first time, as opposed to inserting or deleting large chunks. For instance they altered a doorway used by HIV known as CXCR4, so the deadly virus would not be able to enter and infect these T cells.

    They were also able to edit a gene called PD-1. Its role is to tell T cells to lay down their weapons so they don’t for instance attack normal cells of the body. But crafty cancer cells have learned how to give this same command to PD-1, so the T-cells lay down their arms in the vicinity of cancer cells. By editing the PD-1 gene of the T cells, the researchers should be able to turn T cells back into a fighting force against cancer. Simular approaches are successfully being trialled in cancer therapy employing antibodies to turn off the PD-1 signal.

    However the editing approach raises some concerns since T cells are long-term residents – sometimes remaining in the body for years. And if they are unleashed against cancer, one has to be sure they will not then go on to attack normal cells. “The danger is to create something you can’t control,” says Herold.

    “We have to work ahead to figure out how to ensure safety” of T cells, Marson agrees. “But it’s an exciting time for cell-based therapies.

    See the full article here.

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  • richardmitnick 3:42 pm on January 29, 2015 Permalink | Reply
    Tags: , Bill and Melinda Gates Foundation, , Immunology, ,   

    From Stanford: “Stanford launches major effort to expedite vaccine discovery with $50 million grant” 

    Stanford University Name
    Stanford University

    January 29, 2015
    Anneke Cole, Office of Development, Stanford University: (650) 724-3298, annekec@stanford.edu

    Stanford University today announced that it has received a grant from the Bill & Melinda Gates Foundation to accelerate efforts in vaccine development. The $50 million grant over 10 years will build on existing technology developed at Stanford and housed in the Human Immune Monitoring Core, and will establish the Stanford Human Systems Immunology Center. The center aims to better understand how the immune system can be harnessed to develop vaccines for the world’s most deadly infectious diseases.

    While illnesses like polio and measles are now readily preventable, scientists have been stymied in their efforts to fight diseases such as HIV and malaria. In part, this is because large-scale clinical trials can cost hundreds of millions of dollars and can take up to 10 years to determine the success – or often failure – of a vaccine candidate.

    The work funded through the new center will enable researchers in diverse fields of study at Stanford and other institutions to use advanced immunological tools to understand how vaccines protect and to help prioritize the most promising vaccines for clinical trials. The center will be led by Mark Davis of Stanford’s School of Medicine and will also involve faculty in the School of Engineering. Their effort furthers the university’s commitment to addressing global problems through novel, interdisciplinary collaborations.

    1
    Professor Mark Davis of the Stanford School of Medicine will lead the new Stanford Human Systems Immunology Center, established with a grant from the Bill & Melinda Gates Foundation to aid vaccine research.

    “Effective vaccines are urgently needed to prevent disease and save lives,” said John L. Hennessy, president of Stanford University. “This grant will allow Stanford to leverage advances in technology and accelerate progress in this important area.”

    The Stanford Human Systems Immunology Center will draw upon a repertoire of technologies, many of which have been pioneered at Stanford, to provide a detailed profile of the human immune response. Seed grants will be made available to Stanford faculty, as well as investigators from other institutions, in order to fuel innovations in immunology and vaccine-related efforts.

    Davis, the center’s principal investigator, said animal models of vaccines have not been successful in most cases, as multiple vaccine candidates shown to work in mice and non-human primates have failed in human trials.

    “What we need is a new generation of vaccines and new approaches to vaccination,” said Davis, who is the Burt and Marion Avery Family Professor of Immunology and director of the Stanford Institute for Immunity, Transplantation, and Infection. “This will require a better understanding of the human immune response and clearer predictions about vaccine efficacy for particular diseases.”

    Davis will be joined in the effort by Holden Maecker, associate professor in the Department of Microbiology and Immunology and director of the Human Immune Monitoring Center; Garry Nolan, the Rachford and Carlota A. Harris Professor, also in the Department of Microbiology and Immunology; Atul Butte, associate professor of pediatrics and genetics and, by courtesy, computer science; Yvonne Maldonado, professor of pediatrics and of health policy and research; Karla Kirkegaard, the Violetta L. Horton Research Professor and professor of genetics; Peter Kim, the Virginia and D. K. Ludwig Professor in Biochemistry; Thomas Baer, executive director of the Stanford Photonics Research Center; and other faculty.

    The researchers also plan to analyze why some people are able to effectively fight off pathogens, while others remain vulnerable. For instance, many millions of people are carriers of the tuberculosis bacteria, yet fewer than 10 percent develop active disease.

    “This grant will provide crucial support to Stanford’s world-class scientists as they collaborate with investigators around the globe to assess vaccines against some of the most formidable diseases of our time,” said Lloyd Minor, dean of the School of Medicine. “The Stanford Human Systems Immunology Center will help the most promising vaccine candidates to move quickly and efficiently from the lab to the front lines of treatment, impacting countless lives.”

    “We are pleased to make this grant, which is all about enabling collaboration,” said Chris Wilson, director of the Discovery and Translational Sciences program at the Bill & Melinda Gates Foundation. “It will enable vaccinologists to take advantage of the state-of-the-art technologies that Stanford has developed to monitor the human immune response and allow Stanford investigators to collaborate to help solve the real-world problems we face when trying to harness the power of the immune system to provide protection for those in the developing world.”

    Stanford has a long track record in immunology. In 1970, the late Professor Len Herzenberg invented the fluorescence-activated cell sorter (FACS), a revolutionary technique that is now a mainstay in labs around the world. In the last decade, Stanford scientists have developed or refined a host of other sophisticated tools that are transforming the ability to understand immune responses in humans at a deep level. These include technologies that can rapidly analyze individual cells and tools that can provide a detailed portrait of the human immune system, with all of its many components.

    “We hope our work will have a profound effect on our ability to combat diseases of the developing world,” said Davis, who is also an investigator at the Howard Hughes Medical Institute.

    See the full article here.

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  • richardmitnick 2:29 pm on June 12, 2014 Permalink | Reply
    Tags: , , , Immunology,   

    From Brown University: “Proliferation cues ‘natural killer’ cells for job change” 

    Brown University
    Brown University

    June 12, 2014
    David Orenstein

    June 12, 2014 | Media Contact: David Orenstein | 401-863-1862

    woman

    Purposeful proliferation Working with colleagues including Professor Christine Biron, graduate student Margarite Tarrio helped discover that when ‘natural killer’ cells proliferate after infection, their role changes from marshaling the immune response to regulating it. Credit: David Orenstein/Brown University

    Why would already abundant ‘natural killer’ cells proliferate even further after subduing an infection? It’s been a biological mystery for 30 years. But now Brown University scientists have an answer: After proliferation, the cells switch from marshaling the immune response to calming it down. The findings illuminate the functions of a critical immune system cell important for early defense against disease induced by viral infection.

    The immune system maintains a rich abundance of “natural killer” cells to confront microbial invaders, but as the body gains the upper hand in various infections it sometimes starts to produce even more of the cells. For three decades, scientists haven’t understood what purpose that serves. In a new paper, Brown University researchers show one: proliferation helps change the NK cells’ function from stimulating the immune response to calming it down, lest it get out of hand.

    In a series of experiments now published online in the Journal of Immunology, the researchers show that the process of proliferation unlocks expression of the gene in NK cells for producing Interleukin-10(IL-10), a protein that moderates other immune system cells.

    “It’s really important for regulating potentially dangerous CD8 T cell responses,” said Margarite Tarrio, co-lead author of the paper and a graduate student in the lab of Brown immunology Professor Christine Biron. “If you get CD8 T cells that are hyperactivated they can cause a tremendous amount of damage.”

    Ever since Biron and colleagues published the first observations of NK cell proliferation in 1982, she has sought to figure out why it happens. Knowing the answer is important both as a matter of basic immunology and because NK cells, as crucial members of the body’s first line of infection defense, are often the subjects of efforts to harness the immune system in protection against infections and cancer.

    “The work provides another important role for lymphocyte proliferation, to set up the conditions needed for changing function,” Biron said. “It is likely to be part of the mechanism for changing the functions of other immune cells, and the insight may help in designing vaccines.”

    Shown down to the gene

    An association between NK cells and IL-10 production doesn’t necessarily emerge in all infections, but it does come up in some pretty important ones. Scientists have observed it in human cases of hepatitis C, for example.

    In the new study, the researchers used a different virus, known as MCMV in mice, as part of their investigation of NK proliferation. The human version, CMV, can cause birth defects (http://www.cdc.gov/CMV/index.html) if it’s active in a woman who is pregnant.

    The first step was to confirm that in mice infected with MCMV, NK cells were indeed pumping out the IL-10. The researchers noticed that in highly infected mice, NK cells produced IL-10 about 3.5 days into the infection – days later than when they’d produce IFN-gamma, a protein that helps to mount, rather than defuse, the immune system response.

    In lab cultures, they found that only cells that were about 3.5 days post infection would produce IL-10. A subsequent experiment showed that exposure to a virus wasn’t necessary, per se, but several rounds of replication and proliferation (over about 3 days) enabled the IL-10 production.

    “Taken together, these studies show that the NK cell IL-10 response is associated with extensive proliferation, either under in vitro conditions independent of infection, or in vivo during infection,” wrote the authors, including co-lead author and former Brown postdoctoral researcher Seung-Hwan Lee, who is now at the University of Ottawa.

    Having shown that IL-10 production was associated with NK cell proliferation, Tarrio, Biron and colleagues sought even more evidence: The mechanism in the NK cells that triggers the switch to IL-10 production.

    They found it by comparing the genome-wide conformation of DNA in NK cells before and after proliferation in infected mice. They found that in NK cells that hadn’t undergone the proliferation process, the gene for IL-10 was tightly wrapped up and inaccessible for expression. Post-proliferation cells had IL-10 genes that were more open and accessible for expression.

    “When we got those results everybody was really excited about it, because pulling out epigenetic changes from a cell population during an infection in vivo is really pretty remarkable,” Tarrio said.

    New investigations

    Because the epigenetic study looked at the broader genome of NK cell DNA, not just at the IL-10 gene, Tarrio added, the researchers can now go back to the data to look for other proliferation-induced changes. That could tell them whether proliferation perhaps alters other important functions in NK cells.

    “It’s entirely likely there are other changes going on and it could be for other purposes,” Tarrio said. “This is one answer to why NK cells proliferate.”

    With her first grad school paper now published, Tarrio is continuing the research with Biron. The next question in her thesis work will be how long post-infection proliferation and any associated functional changes persist in the NK cells.

    In addition to Tarrio, Biron and Lee, other authors are Maria Fragoso of Brown and Hong-Wei Sun, Yuka Kanno and John J. O’Shea of the National Institutes of Health.

    The U.S. National Institutes of Health and the Department of Education funded the study.

    See the full article here.

    Welcome to Brown

    Rhode Island Hall: Rhode Island Hall’s classical exterior was recently renovated with a modern interiorRhode Island Hall: Rhode Island Hall’s classical exterior was recently renovated with a modern interior

    Located in historic Providence, Rhode Island and founded in 1764, Brown University is the seventh-oldest college in the United States. Brown is an independent, coeducational Ivy League institution comprising undergraduate and graduate programs, plus the Alpert Medical School, School of Public Health, School of Engineering, and the School of Professional Studies.

    With its talented and motivated student body and accomplished faculty, Brown is a leading research university that maintains a particular commitment to exceptional undergraduate instruction.

    Brown’s vibrant, diverse community consists of 6,000 undergraduates, 2,000 graduate students, 400 medical school students, more than 5,000 summer, visiting and online students, and nearly 700 faculty members. Brown students come from all 50 states and more than 100 countries.

    Undergraduates pursue bachelor’s degrees in more than 70 concentrations, ranging from Egyptology to cognitive neuroscience. Anything’s possible at Brown—the university’s commitment to undergraduate freedom means students must take responsibility as architects of their courses of study.


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