Although the survival of kidney and pancreas vascularized allografts has reached a remarkable 80-90 percent one year and 70-80 percent five year survival rate, the success of neovascularized islet allografts has been less than 10 percent in Type I diabetic recipients. One of the reasons for this poor success may be that existing immunosuppression is toxic to islets and does not prevent islet rejection. We believe that for islet transplantation to become clinically successful, new forms of immunosuppressive agents must be developed. One possible class of new immunosuppressive agents is those that block the non-antigen specific interactions of alloreactive T cells. VLA-4 and its interactions with its two ligands, VCAM-1 and fibronectin (FN), increasingly is being shown to be an important non-antigen specific interaction critical to the activation, homing and effector function of alloreactive T cells. Our preliminary data show that blocking either VLA-4/VCAM-1 interactions with a monoclonal anti-VCAM-1 antibody or VLA-4/FN interactions with a synthetic peptide inhibitor, CS1-P, both prevent islet allograft rejection. The focus of this grant is to determine the mechanism of action of these two potentially important immunosuppressive agents and thereby determine the role of VLA-4/VCAM-1 and VLA-4/FN interactions in allograft rejection. Our global hypothesis is that non-antigen specific interactions such as those between VLA-4 and its ligands, VCAM-1 and FN, are critical to the continuum of allograft rejection including CTL activation, homing to the allograft, and subsequent effector function. Our two major specific hypotheses are that 1) VLA-4/FN interactions in vivo are primarily involved in the homing of alloreactive CTL to the allograft, but are not involved in CTL activation, while 2) VLA-4/VCAM-1 interactions in vivo are primarily involved in CTL activation, but have little role in CTL homing. The approach may lead to novel forms of immune suppression that may benefit not only islet transplantation, but also other types of organ allografts.
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