The overall purpose of this application is to examine the role of apoptotic cells in the induction of donor-specific tolerance observed following the pre-transplantation administration of DST. While a role for apoptotic antigen in the development of autoimmunity has been increasingly recognized, the potential contribution of apoptotic antigen to the development and/or maintenance of tolerance has been less well studied. It is a central tenet of this application that apoptotic cells and antigen play a critical role in the maintenance of tolerance, and that lessons derived from studies of the role of apoptotic antigen in autoimmunity can be translated to the arena of transplantation. In its simplest form, this model predicts that the immune system will interpret antigen encountered within the context of apoptotic cells as self-antigen, whereas the immune system will interpret antigen encountered within the context of necrotic cells (or generalized inflammation) as foreign. This hypothesis leads to the following very testable prediction. The degree of cell injury plus the mechanism of cell death of the various cellular components of DST contribute critically to the balance between tolerization and sensitization. Apoptotic components shift the balance towards tolerization, whereas necrotic components shift the balance towards sensitization.
The aims of this application are to use a murine model of allogeneic heart transplantation to: 1. Determine the differential response on tolerization (allograft survival) and sensitization (several indices of humoral and cellular immune activity) after infusion of donor specific splenocytes exposed to graded toxic stimuli leading to a spectrum of cell death ranging from apoptosis to necrosis. 2. Determine definitively the role of apoptotic death in inducing tolerization by using donor splenocytes from caspase-l-deficient mice and Bcl2-transgenic mice, both genetically incapable of undergoing apoptosis in response to certain optimal stimuli identified in Specific Aim 1. 3. Determine the importance to tolerance induction of apoptotic cell uptake via phagocytic receptors specific for apoptotic cells by diverting uptake of apoptotic cells away from phagocytic receptors for apoptotic cells to a different receptor system of uptake.
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