Blocking CD28-B7 T-cell costimulation by systemic administration of CTLA4Ig, a fusion
protein which binds
B7 molecules on the surface of antigen-presenting cells, prevents rejection and induces tolerance in experimental acute allograft rejection models. We tested the effect of CTLA4Ig
therapy on the process of chronic renal allograft rejection using an established experimental
transplantation model. F344 kidneys were transplanted orthotopically into bilaterally nephrectomized LEW recipients. Control animals received low dose
cyclosporine for 10 days posttransplantation. Administration of a single injection of CTLA4Ig on day 2 posttransplant alone or in addition to the low dose
cyclosporine protocol resulted in improvement of long-term graft survival as compared with controls. More importantly, control recipients which received
cyclosporine 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 glomerulosclerosis, while animals treated with CTLA4Ig alone or in addition to
cyclosporine did not. Competitive
reverse transcriptase-PCR and immunohistological analysis of allografts at 8, 16, and 24 weeks showed attenuation of lymphocyte and macrophage infiltration and activation in the CTLA4Ig-treated animals, as compared with
cyclosporine-alone treated controls. These data confirm that early blockade of the CD28-B7 T-cell costimulatory pathway prevents later development and evolution of chronic renal allograft rejection. Our results indicate that T-cell recognition 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 preventing development of the process.