Area of Research: Basic Immunology/Virology Dr. Robert Mittler’s primary research interests lie in the area of T-cell activation. Broadly described, he seeks to answer why the immune system fails to eradicate tumors from the body. Dr. Mittler also heads the Emory arm of a multi-site study of the existing anthrax vaccine, headed by the Centers for Disease Control and Prevention. Dr. Mittler’s lab is working to establish simian-human correlates of immunity provided by the anthrax vaccine. This will allow monkeys to be used in subsequent studies of vaccine efficacy aimed at determining the level and duration of protection provided by certain vaccine dosages. Dr. Mittler is an Associate Professor in the Department of Surgery of the Emory University School of Medicine. Dr. Mittler received his Ph.D. in immunology from New York University School of Medicine and College of Dentistry. Research Dr. Mittler currently serves as co-director of the Immunology Core Laboratory and as Principal Investigator for the laboratory portion of the Anthrax Vaccine Program contract with the Centers for Disease Control and Prevention (both described elsewhere in this report). The focus of Dr. Mittler's individual research program is the study of mouse and human T-cell costimulation pathways that are essential for productive T-cell responses to foreign antigens. In this context, they hope to learn how to artificially regulate immune responses in humans, either to enhance the response in situations of immunodeficiency and cancer, or to selectively diminish the response to organ transplantation or in autoimmune diseases. In this context, they have focused upon T-cell activation regulated by CTLA-4 and the CD137 (4-1BB) receptor molecules. The CD137 receptor is a member of the Tumor Necrosis Factor Receptor Superfamily (TNFRS) that is rapidly expressed on murine T-lymphocytes and Natural Killer (NK) cells following activation. They found that in the mouse, CD137 receptors are preferentially used to activate CD8+ T-cells despite the fact that both CD4+ and CD8+ T cells express them. Dr Mittler and his colleagues were also the first to show that administration of monoclonal anti-CD137 antibodies into mice receiving skin or cardiac allografts rejected their grafts much more rapidly than mice injected with a control mAb. In a second study, Drs. Mittler and Chen demonstrated that unlike any other form of immunotherapy currently available at the time, anti-CD137 mAbs effectively induced (70-95%) anti-tumor immunity and the complete eradication of established poorly immunogenic tumors in mice. Recent studies conducted in Dr. Mittler’s lab have demonstrated that anti-CD137 monoclonal antibodies are remarkably effective in not only preventing the progression of Systemic Lupus Erythematosus (SLE) disease in mice, but that they reversed the course of disease development and extended the lifespan of these mice from 8-9 months to a normal lifespan of >2 years. SLE is a disabling disease that primarily affects women of childbearing age. The disease can affect cognitive skills and lead to renal failure and death. These studies are the first to demonstrate the blockade and reversal of disease progression without using approaches that rely upon global immunosuppression as a modality of treatment.
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