Induction of long-term rat renal allograft survival by pretransplant T cell receptor-α/β-targeted therapy

The success of organ transplantation is hampered by the present need for chronic immunosuppression to prevent allograft rejection. Thus, multiple modalities are under investigation employing new immunosuppressive drugs to achieve the ultimate goal of tolerance induction with concomitant withdrawal of immunosuppressive medication. Among these strategies is the application of monoclonal antibodies (mAb) with specificities for T cells, their subsets, and other structures involved in lymphocyte adhesion or signal transduction. CD3, CD4, and CD25-targeted therapies have been successfully used in humans to combat and prevent rejection, while in rodents graft acceptance could be achieved with a wide variety of antibodies specific for CD3, CD4, ICAM-1/LFA-1, etc. There is substantial evidence that T cells are the mediators of acute graft rejection. Consequently, TCR-directed antibody therapy was successfully employed in preventing acute rejection of heterotopic cardiac allografts as well as allosensitization following skin grafting in the rat. TCR-targeted mAb therapy using R73 mAb has been shown to initially deplete T cells from the peripheral blood and subsequently modulate TCR. Furthermore, abrogation of accelerated cardiac allograft rejection and prevention of sensitization by pretransplant therapy with anti-TCR mAbs was associated with an intragraft upregulation of Th2 cytokines. In this study, the capacity of a R73 mAb to prolong renal allograft survival was investigated in nephrectomized recipients. Two therapeutic modalities, posttransplant ("classically immunosuppressive") and pretransplant ("immunomodulatory") short-term mAb applications, were evaluated in a life-sustaining model of kidney transplantation and correlated with graft prolongation and intragraft cytokine production.