T-CELL COSTIMULATORY BLOCKADE IN EXPERIMENTAL CHRONIC CARDIAC ALLOGRAFT-REJECTION - EFFECTS OF CYCLOSPORINE AND DONOR ANTIGEN

Chronic rejection is a T cell-dependent process and blockade of the CD 28-B7 T-cell costimulatory activation pathway by the fusion protein CT LA4Ig has been shown to prevent the development of accelerated graft a rteriosclerosis in a rat model of chronic cardiac allograft rejection. The effectiveness of T-cell costimulatory blockade at preventing chro nic allograft rejection in a clinically relevant model in combination with cyclosporine therapy has not been investigated. Using the web-est ablished LEW into F334 heterotopic cardiac allograft model, we show th at when cyclosporine is administered in combination with CTLA4Ig, it a brogates the previously demonstrated protective effect of CTLA4Ig in p reventing chronic allograft rejection, Long-term surviving allografts from animals treated with a combination of cyclosporine and CTLA4Ig ha d a mean vascular luminal occlusion of 42.2%, affecting more than 90% of graft vessels due to accelerated arteriosclerosis. This was associa ted with up-regulation of intragraft expression of mRNA for CD4, the c ostimulatory molecule B7, the T-cell cytokine interferon-gamma, monocy te chemoattractant protein-1, and the fibrogenic growth factor transfo rming growth factor-beta; all have been previously shown to be associa ted with development of chronic rejection in this model. In comparison , the addition of donor splenocytes to the combination of CTLA4Ig and cyclosporine therapy protocol significantly reduced the amount of arte riosclerosis; mean vascular luminal occlusion was 11.3%, affecting app roximately 50% of vessels. This was associated with decreased intragra ft expression of CD4, B7, interferon-gamma, monocyte chemoattractant p rotein-1, and transforming growth factor-beta, These data indicate tha t the mechanism of action of CTLA4Ig in attenuating chronic rejection is cyclosporine sensitive, and that strategies implying combination of CTLA4Ig and cyclosporine may not be clinically desirable. Administrat ion of donor antigen may be necessary if CTLA4Ig and cyclosporine are to be combined, to prevent the process of chronic rejection.