Immune sensing of ischemic injury and complement-dependent modulation of alloimmunity in cardiac transplantation

Medical University Of South Carolina, Charleston SC

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Abstract

? DESCRIPTION (provided by applicant): Ischemia reperfusion injury is an unavoidable event in organ transplantation, and it is a major clinical problem that is thought to play an important role in both short-term and long-term graft survival. The mechanisms responsible for induction of post-surgical inflammation and ischemia reperfusion injury are not well defined, although complement, and more recently natural self-reactive IgM, have been shown to play key roles in the process. We have identified neoepitopes that become expressed in cardiac grafts, and which bind natural IgM. We have prepared constructs that target complement inhibitors to a particular neoepitope, and we propose to use these constructs to study the role of IgM in immune sensing of cardiac injury and the subsequent activation of complement. Using mouse models of cardiac transplantation, as well as a series of in vitro model systems, we will investigate how various complement activation products modulate an alloimmune response and acute rejection. We will also investigate how different neoepitopes and their recognition in cardiac grafts relate to each other, and how the length of ischemia and extent of ischemia reperfusion injury relates to neoepitope expression and the priming of an alloimmune response.