Peripheral Mechanisms of Immunologic Tolerance

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DESCRIPTION (provided by applicant): The induction of tolerance in transplantation and autoimmunity remains an elusive clinical goal. A more thorough understanding of the fundamental mechanisms of immunologic tolerance is therefore necessary. We propose here a multidisciplinary approach to investigate peripheral mechanisms of immunologic tolerance by studying murine models of solid organ transplantation, bone marrow transplantation, and autoimmunity. A multidisciplinary approach is proposed because the mechanisms responsible for tolerance to self and foreign antigens overlap, and because significant cross-talk among the three clinical disciplines exists: bone marrow transplantation is increasingly employed to induce tolerance to solid organ allografts, and therapeutic agents used in transplantation are applicable to patients with autoimmunity (and vice versa). The PPG consists of three integrated projects and a core: histopathology. Integration among the projects is based on commonality of immunologic concepts, ongoing and future collaborations between the investigators, and the sharing of methods and resources. Project 1 will explore the mechanisms of dendritic cell maturation that lead to graft-versus-host disease (GVHD) following bone marrow transplantation. Project 2 will investigate tolerance induction via the generation of regulatory T cells (Treg) in a mouse model of inflammatory bowel disease. Project 3 will explore the phenomenon of immunologic ignorance by studying the innate and adaptive mechanisms that are responsible for continued recognition of a transplanted organ by the host's immune system. The Histopathology Core (Core B) will provide tissue processing, staining, immunohistochemistry, in situ hybridization, imaging, and interpretation services to all three projects. The Administrative Core (Core A) will provide logistical, communications and data sharing support.