Although microvascular endothelia are known to regulate regional inflammatory responses; the role of microvascular endothelia in allograft rejection is poorly understood. The proposed studies are based on two experimental observations: 1) that the microvascular endothelia of murine cardiac allografts, but not isografts, display the inflammatory adhesion molecule, VCAM-1, despite the appearance of inflammation in both graft types, and 2) that daily treatment of murine cardiac allograft recipients with the VCAM-1-reactive mAb, M/K-2, for a defined period abrogates rejection and promotes long-term graft acceptance without the need for additional M/K-2 mAb. We hypothesize that VCAM-1 expression reflects a heightened inflammatory response due to local T cell activation. We further hypothesize that VCAM-1 plays a critical role in the rejection process. Finally, we hypothesize that interference with VCAM-1 during an allogeneic response leads to antigen-specific immune tolerance. The experiments in this proposal employ limiting dilution analysis, PCR analysis, immunoperoxidase analysis, flow cytometry, and ELISA to test these hypotheses. Specifically, we will determine 1) what T cells and cytokines promote endothelial VCAM-1 expression in murine cardiac allografts, 2) whether VCAM-1 expression is also characteristic of acute rejection in murine kidney or liver allografts, 3) how effective M/K-2 therapy is at interfering with graft-induced humoral allosensitization or ongoing cardiac allograft rejection, 4) whether M/K-2 therapy can be optimized by pairing with anti-VLA-4 or anti-CD4 mAb, 5) the immune mechanisms by which M/K-2 therapy interferes with acute rejection and initiates 6) independent vs. VCAM-1-associated patterns of inflammation.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
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Surgery, Anesthesiology and Trauma Study Section (SAT)
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Ohio State University
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