CD40-GP39 INTERACTIONS PLAY A CRITICAL ROLE DURING ALLOGRAFT-REJECTION - SUPPRESSION OF ALLOGRAFT-REJECTION BY BLOCKADE OF THE CD40-GP39 PATHWAY

Studies in vivo have documented the importance of CD40-gp39 interactio ns in the development of T-dependent antibody responses to foreign and auto-antigens. In this report, we demonstrate that allograft rejectio n is also associated with strong induction of CD40 and gp39 transcript s, When treatment was initiated at the time of transplant, MR1, a mAb specific for gp39, induced markedly prolonged survival of fully dispar ate murine cardiac allografts in both naive and sensitized hosts, Howe ver, when therapy was delayed until postoperative day 5, anti-gp39 fai led to prolong graft survival, Allografts from recipients treated with MR1 from the time of transplantation showed decreased expression of t ranscripts for the macrophage effector molecule, inducible nitric oxid e synthase, but essentially unaltered expression of B7 molecules and T cell cytokine transcripts (interleukin [IL]-2, interferon-gamma, IL-1 0, and IL-4) relative to control allografts. In addition, alloantibody responses in the MR1-treated mice were profoundly inhibited, However, our studies using B cell-deficient mice indicated that the ability of MR1 to prolong allograft survival was not dependent on B cells, These data suggest that blockade of CD40-gp39 interactions may inhibit allo graft rejection primarily by interfering with T cell help for effector functions, rather than by interference with T cell activation.