INDIRECT ALLORECOGNITION AND T CELL COSTIMULATION PATHWAYS IN CHRONIC REJECTION

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T cell recognition of alloantigens is the key initial event which ultimately results in allograft rejection and graft loss. It is now clear that there are two non-mutually exclusive pathways of allorecognition. In the "direct" pathway T cells recognize intact allo-MHC molecules on donor cells, while in the indirect pathway T cell recognize processed alloantigen presented as peptides by responder (self) antigen-presenting cells (APCs). Although it is fairly well established that both pathways are active early after engraftment, the contribution of either pathway of allorecognition to the process of allograft rejection remains unclear. There is some evidence to suggest that early acute allograft rejection is predominantly mediated by the direct pathway, since the graft contains a significant number of donor-derived passenger APCs (particularly dendritic cells) which present a high density of intact donor MHC molecules. Chronic rejection, on the other hand, may be predominantly mediated by indirect allorecognition where CD4+ T cells recognize processed alloantigens and effect delayed type hypersensitivity (DTH) responses and provide help to B cells for production of alloantibodies. From available sequence data for MHC molecules specific polymorphic peptides can be synthesized, and these provide a novel approach to study the role of indirect allorecognition in chronic rejection. It is now accepted that T cells need 2 signals for full activation. The first signal is provided by engagement of the T cell receptor (TCR) with the foreign antigen presented as a peptide by APCs, and thus provides antigen-specificity to the immune response. The second is a "co- stimulatory" signal, the best characterized of which is provided through the T cell accessory molecule CD28 interacting with the B7 family (B7-1 and B7-2) of receptors on APCs, In vitro, blockade of co-stimulatory signals inhibits T cell activation and induces a state of antigen-specific unresponsiveness. In vivo, agents which block CD28-B7 co-stimulation have proven extremely effective in inhibiting the immune response in experimental models of acute transplant rejection; the role of co- stimulatory blockade in chronic rejection has not been investigated. Our hypothesis is that T cell recognition of processed alloantigen in the indirect pathway is a key and ongoing feature of chronic rejection resulting in the continuous recruitment and activation of T cells, and that the CD28-B7 co-stimulatory pathway is necessary for full activation of these T cells which initiate the necessary effector mechanisms for development of chronic rejection. The corollary hypothesis is that strategies targeted at blocking indirect allorecognition and/or CD28-B7 co-stimulation should prevent development, or even interrupt progression, of chronic allograft rejection. We plan to use an established rat model (F344 into LEW of chronic renal allograft rejection to study this role of indirect aIlorecognition in chronic allograft rejection, and specific means to inhibit its development by interrupting this pathway.