LATE BLOCKADE OF T-CELL COSTIMULATION INTERRUPTS PROGRESSION OF EXPERIMENTAL CHRONIC ALLOGRAFT-REJECTION

Early blockade of T cell-costimulatory activation pathways prevents de velopment of experimental chronic allograft rejection. Ongoing T cell recognition of alloantigen and activation may also play an important r ole in progression of chronic rejection, but definitive evidence is la cking. We used the fusion protein CTLA4Ig to block CD28-B7 T cell cost imulation late after the onset of initial graft injury, Using the F334 into LEW rat model of chronic renal allograft rejection, transplant r ecipients were treated with a 10-d course of cyclosporine, and a subgr oup received a single injection of CTLA4Ig at 8 wk after transplant. F unctionally, CTLA4Ig administration prevented development of progressi ve proteinuria (14.3+/-4.1 mg/24 h versus 41.0+/-12.0 mg/24 h at 24 wk after transplant, P < 0.05), Histologically, graft mononuclear cell i nfiltration, glomerular hypertrophy, focal and segmental glomeruloscle rosis, and intimal vascular hyperplasia were all attenuated in CTLA4Ig -treated animals. Lastly, reverse transcriptase-PCR and immunohistolog ic studies showed a significant reduction in the intragraft expression of key products of T cell and macrophage activation, and upregulation of what have recently been termed as ''protective'' genes, including the bcl family members, Bcl-2 and Bcl-xL, and hemoxygenase, Our data a re the first to demonstrate that blocking T cell-costimulatory activat ion late after transplantation, after initial graft injury, prevents p rogression of chronic allograft rejection supporting the hypothesis th at ongoing T cell recognition of alloantigen and activation are key me diators of ongoing chronic allograft rejection.