BLOCKADE OF T-CELL COSTIMULATION PREVENTS DEVELOPMENT OF EXPERIMENTALCHRONIC RENAL-ALLOGRAFT REJECTION

Blocking CD28-B7 T-cell costimulation by systemic administration of CT LA4Ig, a fusion protein which binds B7 molecules on the surface of ant igen-presenting cells, prevents rejection and induces tolerance in exp erimental acute allograft rejection models. We tested the effect of CT LA4Ig therapy on the process of chronic renal allograft rejection usin g an established experimental transplantation model, F344 kidneys were transplanted orthotopically into bilaterally nephrectomized LEW recip ients, Control animals received low dose cyclosporine for 10 days post transplantation, Administration of a single injection of CTLA4Ig on da y 2 posttransplant alone or in addition to the low dose cyclosporine p rotocol resulted in improvement of long-term graft survival as compare d with controls, More importantly, control recipients which received c yclosporine only developed progressive proteinuria by 8-12 weeks, and morphological evidence of chronic rejection by 16-24 weeks, including widespread transplant arteriosclerosis and focal and segmental glomeru losclerosis, while animals treated with CTLA4Ig alone or in addition t o cyclosporine did not, Competitive reverse transcriptase-PCR and immu nohistological analysis of allografts at 8, 16, and 24 weeks showed at tenuation of lymphocyte and macrophage infiltration and activation in the CTLA4Ig-treated animals, as compared with cyclosporine-alone treat ed controls. These data confirm that early blockade of the CD28-B7 T-c ell costimulatory pathway prevents later development and evolution of chronic renal allograft rejection, Our results indicate that T-cell re cognition of alloantigen is a central event in initiating the process of chronic rejection, and that strategies targeted at blocking T-cell costimulation may prove to be a valuable clinical approach to preventi ng development of the process.