Heads of Laboratories
Dr. Ravetch dissects the cellular and molecular mechanisms that govern the generation of antibody specificity and the translation of that specificity into cellular responses. By identifying the genetic components that cause immune system cells to respond to specific antibodies, Dr. Ravetch hopes to gain a better understanding of how a functioning immune system protects organisms from invaders, and how a dysfunctional immune system attacks the body’s own tissues.
The Ravetch laboratory analyzes systemic autoimmunity in mouse models of certain diseases by investigating the genesis and fate of the pathological antigen-antibody complexes that form and trigger tissue damage. They simplify this complex problem by examining the mechanisms through which immune complexes influence both the afferent and efferent immune responses by interacting with a family of low-affinity surface receptors, the Fc receptors. These receptors are expressed as pairs of activation and inhibitory molecules, providing a mechanism for establishing thresholds for cellular triggering and for terminating the activation response. Disruptions of these pathways have revealed the central role these receptors play in appropriate immune responses.
Dr. Ravetch has shown that inhibitory Fc receptors for immunoglobulin G (IgG) are responsible for maintaining peripheral tolerance; animals without inhibitory Fc receptors develop spontaneous autoimmunity and autoimmune disease. Conversely, a deficiency of activation Fc receptors results in a protective effect, in which mice susceptible to autoimmune disease fail to develop it. But loss of activation receptors does not alter the development of autoantibody and immune complex deposition. Rather, Dr. Ravetch has found that these potentially pathogenic complexes are unable to trigger effector cell responses and are therefore benign. His lab is now investigating the precise cellular pathways engaged by activation receptors via autoantibodies by generating cell type-specific targeted gene disruptions of relevant activation receptors and by identifying the downstream effector molecules responsible. Recent work from the Ravetch lab showed that a sugar attached to IgG antibodies confers their protective ability; they are now working on a synthetic therapy rich in these sugar-linked antibodies.
Another focus in the Ravetch lab is the circuits involved in coordinating the regulation of activation and inhibitory receptors, in order to determine the signals that shift the balance from inhibition to activation. He has demonstrated that removing the inhibitory pathway in vivo, for example, can dramatically increase the potency of a cytotoxic antitumor antibody. This was the first demonstration of antibody-dependent cell cytotoxicity in vivo. Current studies are now aimed at manipulating the inhibitory response to enhance or limit the cytotoxicity of antibodies in vivo to better understand the role these pathways play in protective immunity and their therapeutic potential.
The lab is also working to determine the pathways through which the coupling of innate and adaptive mechanisms are coordinated to initiate an immune response. Two such pathways are currently under investigation: the feedback by immune complexes on antigen presentation and the targeting of selected antigens to restricted follicular locations to initiate T cell independent responses. Using a series of mice deficient in specific Fc receptors and immune complexes designed to selectively engage these pathways, they are determining the role of each in activating or tolerizing presenting cells in vivo.
Work by Dr. Ravetch led to the cloning and mapping of the first malarial parasite chromosome and more recently to the cloning of the first Fc receptor genes. He discovered how immunoglobulin receptors mediate antibody-triggered inflammation and determined the mechanism by which intravenous immunoglobulin causes immunosuppression. He also played a key role in establishing Fc receptor pathways as an essential part of the immune response and in describing the mechanisms of antibody-mediated effector responses.
Dr. Ravetch graduated from Yale University in 1973 and received his Ph.D. in 1978 from The Rockefeller University, where he studied under Norton Zinder and Peter Model. He received his M.D. from Cornell University Medical College in 1979 and completed his postdoctoral research at the National Institutes of Health with Philip Leder. In 1982 Dr. Ravetch joined the faculty of Memorial Sloan-Kettering Cancer Center and in 1984 also became a guest investigator in Rockefeller’s Laboratory of Cellular Physiology and Immunology. He was appointed professor at Rockefeller in 1996 and named Theresa and Eugene M. Lang Professor in 1997.
Dr. Ravetch received the Canada Gairdner International Award and the Sanofi-Pasteur Award in 2012, the Coley Award from the Cancer Research Institute in 2007, the American Association of Immunologists-Huang Foundation Meritorious Career Award in 2005, the Lee C. Howley Sr. Prize for Arthritis Research in 2004 and the Burroughs Wellcome Fund Award in Molecular Parasitology in 1986. He is a fellow of the American Academy of Arts and Sciences and the American Association for the Advancement of Science and a member of the National Academy of Sciences and the Institute of Medicine.
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