Although pretransplant HLA matching of recipients with cadaveric allografts may add modestly to graft survival, most improvements until now and prospects for the future depend on more effective immunosuppression. During the past 6 years cyclosporine and the anti CD-3 mAb OKT3 have increased graft survival by preventing, delaying or diminishing rejection episodes and by reversing them when they occur. Despite their potent immunosuppressive properties both reagents create new clinical problems even as they improve graft survival; cyclosporine compromises renal function via preglomerular arteriolopathy, and the first dose of OKT-3 leads to a range of potentially serious clinical responses attributed in part to activation of T-cells and release of lymphokines and cytokines: IL-2, IFN-gamma and TNFalpha. Clearly more effective and safe immunosuppressive agents are still needed. At present preclinical testing of potentially immunosuppressive mAbs is limited to in vitro assays and trials in primates whose responses may or may not correspond with those of man. We propose to continue our ongoing program of developing clinically relevant anti T-cell mAbs and will also obtain relevant antibodies from Ortho Biotech. After characterizing them in vitro and (when it is developed) in the hu-SCID mouse model described by Thistlethwaite in this proposal, we will proceed directly to clinical pilot studies in renal transplant recipients at The University of Chicago Medical Center after approved by its Investigational Review Board. We will draw on mouse models described by Bluestone and Fitch to determine clinically relevant regimens of mAbs which alone or in combinations might effectively prevent or reverse rejection with minimal side effects from lymphokines or cytokines. We will also seek regimens that minimize induction of human antibody responses to the murine mAbs. As part of our clinical observations in kidney transplant recipients, we will focus on the development of molecular approaches to analyzing the mechanisms involved in transplant rejection and the effect of mAb therapy on the molecular expression lymphokines and rejection episodes. We will look for evidence of these molecules and other cells obtained from lymphoid tissue and the graft itself.
Showing the most recent 10 out of 41 publications
