The class II transactivator (CIITA) is a master transcriptional regulator of all class II MHC genes. It is not a DNAbinding transcription factor, but functions through interactions with DNAbinding transcription factors which recognize the class II MHC promoter. During the last granting period, we showed that CIIT A null (CIIT A-/-) mice ack class II MHC expression in virtually all cells. The elimination of CIITA caused donor cardiac grafts to survive twice as long as grafts lacking the class II MHC gene, A-beta. These experiments suggest that CIITA may provide an intervening point for prolonging graft survival. In the last granting period, we also found that the control of CIITA expression and regulation is extremely complex. The composite results from the field indicate that CIITA expression is governed by at least three promoters, resulting in the production of three isoforms. These promoters as well as isoforms have tissue- and cell- specific expression pathways. Based on these previous findings, this proposal plans to address three seminal issues: (1) What are the in vivo functions and expression profiles of each of these isoforms, and how does each contribute to graft rejection? This is being addressed by producing transgenic mice bearing various CIITA isoforms. (2) What are the molecular targets of each of these isoforms? Do they have different effects on global gene expression? This is being addressed by Affymetrix gene array analysis. (3) What are the biochemical and biophysical natures of these three isoforms? Can this information assist us in the design of small peptides that may block the function of CIITA, and therefore enhance the survival of allogeneic grafts?
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