(Taken directly from the application) Despite the significance of MHC disparity in causing transplant rejection, the significance of MHC molecules expressed by the donor graft in rejection has been much debated. Studies of skin grafts isolated from gene knockout (GKO) mice lacking both class I and II MHC show that the absence of MHC on the donor graft did not prevent transplant rejection. In contrast to skin grafts, the presence of MHC on solid organ grafts can greatly influence graft survival. This is true of both renal and cardiac grafts. In the first two Aims of this proposal, we plan to explore the involvement of class II MHC on donor organs in more depth. The strategy is to use three strains of GKO mice either as donors for heart and kidney allografts. The strains include: (1) IAb beta-/-GKO, the class II MHC null mice; (2) H-2Ma-/- GKO mice, that are defective in the presentation of alloantigens, and (3) class II transactivator (CIITA-/-) GKO mice, which lack the master transcription factor, CIITA, required for the transcription of all class II MHC genes. In the last Aim, we will explore a pharmacologic approach to reduce class II MHC expression that may affect graft survival. We will explore the significance of prostaglandin (PG)-mediated suppression of class II MHC gene expression in transplant rejection. The suppression of class II MHC by PGE2 is well documented and prostaglandins are known to prolong graft acceptance. We have in vitro data which address the molecular mechanism by which PGE2 suppresses class II MHC expression. The data show that PGE2 suppresses the functional activity of CIITA by a cAMP-mediated phosphorylation process. Understanding the mechanism by which PGE2 decreases class II MHC expression in vivo, and assessing its relevance to transplant rejection is the focus of Aim 3. With the production of the CIITA-/- GKO mice by our laboratory and four different prostaglandin receptor GKO mice by Dr. Bev Koller, we are in a unique position to explore the mechanism by which PGE2 may be modifying class II MHC expression and transplant acceptance.
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