Single Dose of Ibalizumab Boosts Immunity in Resistant HIV

MedicalResearch.com Interview with:

Brinda Emu, MD Assistant Professor of Medicine (Infectious Diseases) Yale School of Medicine

Dr. Emu

Brinda Emu, MD
Assistant Professor of Medicine (Infectious Diseases)
Yale School of Medicine

MedicalResearch.com: What is the background for this study?

Response: This was a Phase 3 study of a new antiretroviral agent, ibalizumab, for the treatment of HIV-1 infection.  Ibalizumab is a monoclonal antibody that targets the CD4 receptor on host cells.  CD4 is the receptor that HIV uses to infect CD4+ T cells.  By binding to the CD4 receptor, ibalizumab prevents viral entry.  This study recruited patients that harbor multi-drug resistant HIV and were failing their current regimen of antiretroviral agents, and thus had limited options for treatment of their HIV-1 infection using approved medications.

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Wistar Scientists Delineate Critical Steps in Antibody Formation

MedicalResearch.com Interview with:

Chih-Chi Andrew Hu, Ph.D. Associate professor in Microenvironment & Metastasis Program Wistar Institute

Dr. Chih-Chi Andrew Hu

Chih-Chi Andrew Hu, Ph.D.
Associate professor in Microenvironment & Metastasis Program
Wistar Institute 

MedicalResearch.com: What is the background for this study? What are the main findings? 

Response: To help our body fight infections, B cells need to differentiate into plasma cells so that they can produce abundant antibodies against pathogens. Antibodies are folded and assembled in the endoplasmic reticulum (ER). Only those perfectly manufactured antibodies are allowed to be released from the ER and delivered to the outside of B cells to fight against the pathogens. IRE1 is a sensor protein that sits on the membrane of the ER, and can respond to B cell differentiation by activating the transcription factor called XBP1s. Activation of XBP1s allows B cells to expand the size of the ER and produce necessary chaperone proteins to help B cells manufacture perfect antibodies. By studying B cells that lack XBP1s, we discovered that these B cells produced dramatically increased levels of IRE1, and such IRE1 acquired phosphorylation at its serine 729 (S729).  Continue reading

Boy and Girl Fetuses Elicit Different Immune Response in Mother

MedicalResearch.com Interview with:

Amanda Mitchell PhD Postdoctoral researcher Institute for Behavioral Medicine Research The Ohio State University Wexner Medical Center

Dr. Mitchell

Amanda Mitchell PhD
Postdoctoral researcher
Institute for Behavioral Medicine Research
The Ohio State University Wexner Medical Center

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: Our study followed 80 pregnant women across the course of their pregnancy – throughout 1st, 2nd, and 3rd trimesters. We examined whether women exhibited different levels of immune markers called cytokines based on fetal sex. We looked at this in two ways – levels of cytokines in the blood, and levels produced by a sample of immune cells that were exposed to bacteria in the laboratory. While women did not exhibit differences in blood cytokine levels based on fetal sex, we found that the immune cells of women carrying female fetuses produced more proinflammatory cytokines when exposed to bacteria. This means that women carrying female fetuses exhibited a heightened inflammatory response when their immune system was challenged compared to women carrying male fetuses.

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Breast Feeding Educates Baby’s Immune System

MedicalResearch.com Interview with:
Ameae M. Walker
Vice Provost for Academic Personnel
Distinguished Teaching Professor
Biomedical Sciences
School of Medicine
University of California, Riverside

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: There has previously been some evidence that immune cells in breast milk could pass through the wall of the immature gut, but if active they, like antibodies in milk, were considered likely a form of passive immunity. We now show that in addition to some maternal cells being active in the newborn (i.e. that they do contribute to passive cellular immunity), there are, more importantly, others that go to the thymus where they participate in selection of the neonate’s T cells. In this fashion, the neonate develops cells that recognize antigens against which the mother has been vaccinated – a process we have dubbed maternal educational immunity.

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Inflammatory Molecule Links Metabolic Environment and Innate Immunity

MedicalResearch.com Interview with:

David Underhill, PhD Professor of Biomedical Sciences Research scientist, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute Cedars-Sinai

Dr. David Underhill

David Underhill, PhD
Professor of Biomedical Sciences
Research scientist, F. Widjaja Foundation Inflammatory Bowel and Immunobiology Research Institute
Cedars-Sinai
Los Angeles, CA

MedicalResearch.com: What is the background for this study?

Response: “Innate immunity” is the body’s natural resistance to microbial infection and stands in contrast to “adaptive immunity,” which is the body’s learned response to infection (e.g. antibodies and vaccines). In the standard model of innate immunity that has emerged over the last several decades, scientists have come to understand that the human genome encodes many “receptors” that have evolved as sensors for specific common microbial molecules, such as bacterial or viral DNA or components of bacterial or fungal cell walls. The job of these receptors is to survey the environment (skin, blood, etc.) for potentially dangerous microbes and initiate inflammatory responses if they are found. These activities are essential for defense against infection, and people and animals with defects in these sensors or the responses they trigger can be susceptible to infection.

My laboratory has been interested for more than a decade in identifying these innate sensors and the microbial targets that they recognize. In this study, we were looking for the sensor that allows white blood cells (e.g. macrophages and dendritic cells) to detect Gram-positive bacterial cell walls and trigger a specific inflammatory response: secretion of the potent inflammatory mediator interleukin-1β (IL-1β).
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Some Immune Cells Avoid Aging Until 60

MedicalResearch.com Interview with:
Dr. Martin Piskacek
Laboratory of Cancer Biology and Genetics
Department of Pathological Physiology,
Faculty of Medicine, Masaryk University Brno, Czech Republic

MedicalResearch.com: What is the background for this study? What are the main findings?

Response: From genome-wide expression analyses, the B lymphocytes avoid the aging until 60 years of age. We did not found any gene expression differences between young (30-45 years) and early aged healthy donors (50-60 years).

Our results demonstrate the potential of hematopoietic stem cells to generate uncompromised B lymphocytes in early elderly.

These are very encouraging findings for general health, because the immunity maintenance does not seem to need artificial intervention to keep B lymphocytes uncompromised in the early elderly.

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Our Immune Systems Are Wired To Fight Infections At First Contact

Professor Søren Riis Paludan DMSc, PhD Department of Biomedicine Aarhus University Denmark

Prof. Paludan

MedicalResearch.com Interview with:
Professor Søren Riis Paludan DMSc, PhD
Department of Biomedicine
Aarhus University
Denmark

Medical Research: What is the background for this study? What are the main findings?

Prof. Paluden: We were interested in understanding the first immune reactions that occur when an organism meets an infectious agent (virus or bacteria).

The main finding is that we have identified an immune reaction that is activated as the microbe disturbed the mucus layer at mucosal surfaces. This is an immune reaction occuring earlier than what has been thought previously, and may represent a mechanism that enables the organism to fight most microbes that we meet without mounting strong immune responses. This is important, since strong immune reactions – in addition to contributing to elimination of microbes – also have negative effects such as fever, etc.

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Scientists Get Closer To A Vaccine Against Allergies

Dr. Christine McCusker MD Associate Professor, Department Pediatrics Meakins-Christie Laboratories McGill University and the MUHCRI, Montreal Quebec, CanadaMedicalResearch.com Interview with:
Dr. Christine McCusker MD
Associate Professor, Department Pediatrics
Meakins-Christie Laboratories
McGill University and the MUHCRI, Montreal
Quebec, Canada

Medical Research: What is the background for this study? What are the main findings?

Dr. McCusker: When the body is exposed to new substances, the immune system must evaluate the “threat” and choose the type of response that will best protect the host. Allergies and allergic asthma develop after the response to “allergens” follows the TH2-type inflammatory pathway instead of the non-inflammatory tolerant pathway.  Evidence suggests that there is some plasticity in this “choice” and thus it may be possible to influence the immune response to preferentially choose the tolerant pathway when exposed to allergens. We therefore treated very young mice to a molecule designed to inhibit activation of the TH2 pathway.

We showed that this early treatment resulted in long-lasting protection from the development of allergies.  Instead of allergic responses, vaccinated animals developed tolerant responses to allergens and did not show any signs of allergies or asthma.  Importantly, while the influence of the treatment was long-lasting, the molecule itself is rapidly removed from the system. Continue reading

Deficient Calcium Channels Weaken Immune Response To Chronic Infections

Dr. Ludovic Desvignes. PhD. Assistant Professor, Departments of Medicine and Pathology NYU Langone Medical CenterMedicalResearch.com Interview
Dr. Ludovic Desvignes PhD.
Assistant Professor, Departments of Medicine and Pathology
NYU Langone Medical Center

MedicalResearch: What is the background for this study?

Dr. Desvignes: This study is the result of a collaboration at NYU Langone Medical Center, between the laboratories of Dr. Stefan Feske and Dr. Joel Ernst, my mentor. Dr. Feske and colleagues had developed a mouse model of rare, inherited mutations he had identified in infants. These mutations occur in the genes for STIM1 and ORAI1, which are crucial for calcium flux in cells of the immune system. The young patients affected by these mutations suffer from severe, recurrent and chronic infections that often cause death before their first birthday. In particular, some of these patients cannot control infection with BCG, which is a normally innocuous strain of mycobacteria administered to protect against tuberculosis (TB). TB is a chronic infection and one of the leading causes of infection-related death worldwide. Going into this study, Dr. Feske and colleagues knew that without functional calcium channels, immune cells do not function properly. However, they did not fully understand how these channels contribute to immune responses to infectious pathogens in a living organism and in particular, for pathogens that cause chronic infections such as TB. This is why Dr. Ernst and I collaborated with Dr. Feske and provided him with our clinical and research expertise in TB.

MedicalResearch: What are the main findings?

Dr. Desvignes: Dr. Feske’s mice are genetically engineered to lack STIM1 in a certain type of immune cells, known as T cells or T lymphocytes. We infected these mice with Mycobacterium tuberculosis, the bacterium causing TB. Mycobacterium tuberculosis causes chronic infection by manipulating the immune system even in healthy people. The first very surprising result of our study was that mice lacking calcium flux in T cells handled acute TB fairly well. Only during the chronic phase of infection did they become unable to control mycobacterial growth and developed a strong inflammation in their lungs, which was due to an infiltration by different types of immune cells, including T cells. We discovered that the accumulation of STIM1-deficient T cells in the lungs resulted from the cells’ inability to die, which is a normal mechanism to limit an immune response and prevent excessive inflammation.

Another immune control mechanism that failed in the absence of STIM1 is mediated by a subset of T cells called induced regulatory T cells, or iTreg cells. These cells are essential to prevent normal immune responses from going “overboard” by suppressing the functions of other immune cells, including T cells. We found that calcium signals are required for the development of iTreg cells and that their numbers were strongly reduced in the lungs of infected STIM1-deficient mice. We therefore think that the lack of iTreg cells in the absence of STIM1 contributes to the severe lung inflammation in chronic TB.

The third finding that really surprised us was that T cells accumulating in the lungs of STIM1-deficient mice produced large amounts of a protein called interferon gamma. While interferon gamma is required to control Mycobacterium tuberculosis, it is also a very potent promoter of inflammation and too much of it can lead to tissue damage. Dr. Feske and colleagues had previously observed that calcium fluxes promote the production of interferon gamma in T cells cultured in vitro and we expected the STIM1-deficient T cells to be defective in the production of that protein. During chronic TB, however, calcium signaling turned out to be not only dispensable for the production of interferon gamma by T cells but it was actually required to limit its production and thus, to control inflammation.

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Protein Delivered By Gene Vector May Protect Against HIV-Like Viruses

Dr. Michael Farzan PhD Vice Chairman Department of Immunology and Microbial Science Florida Campus The Scripps Research InstituteMedicalResearch.com Interview with:
Dr. Michael Farzan PhD
Vice Chairman
Department of Immunology and Microbial Science
Florida Campus
The Scripps Research Institute

Medical Research: What is the background for this study?

Dr. Farzan: The key points are that HIV-1 needs two receptors – CD4 and CCR5 – to infect cells.  CD4’s primary job is to initially bind the viral entry protein, which upon CD4 binding, uncloaks its CCR5 binding site.   A number of years ago we observed that CCR5 had an unusual modification that was really important to HIV-1.  We later showed that antibodies – protein your body makes to protect from pathogens – mimics CCR5 by incorporating this modification.  We develop a peptide from one of these antibodies that mimics CCR5.

Medical Research: What are the main findings?

Dr. Farzan: By combined a soluble form of CD4 with this CCR5-mimicking peptide, we created a protein that neutralizes all HIV-1 isolates tested, including the hardest-to-stop viruses, as well as distantly related viruses found in monkeys.  It does so better than the best HIV-1 antibodies.  We expressed this protein using a commonly used gene-therapy vector, and showed that after a one-time inoculation we could protect from doses much higher than most humans are likely to see, and we did so 34 weeks after the inoculation.
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Healthy Skin Guards Against Infection By Constant Immune Surveillance

Univ.-Prof. Dr. med. Tilo Biedermann Klinikdirektor Klinik und Poliklinik für Dermatologie und Allergologie der Technischen Universität München Biedersteinerstr. MünchenMedicalResearch.com Interview with:
Univ.-Prof. Dr. med. Tilo Biedermann

Klinikdirektor
Klinik und Poliklinik für Dermatologie und Allergologie
der Technischen Universität München
Biedersteinerstr. München

Medical Research: What is the background for this study? What are the main findings?

Prof. Biedermann: The skin is constantly exposed to microbes and skin developed during evolution under the constant influence of microbes. Tightly regulated communication between microbes and the skin can be expected and levels of regulation still needed to be explored. We found that Gram-positive bacteria when sensed by one certain innate immune receptor (hetero dimer TLR 2-6 suppresses immunity both in animal models and in humans. Following the sensing of lipoproteins by toll like receptor 2-6) skin produces high levels of InterleukinL6 that induce the accumulation of so called myeloid-derived suppressor cells. These cells can be found in the blood but also migrate to the skin suppressing T-cell-immunity allowing infections to spread on the skin.

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