T-Cell Costimulatory Blockade in Experimental Chronic Cardiac Allograft Rejection

Abstract

Chronic rejection is a T cell-dependent process and blockade of the CD28-B7 T-cell costimulatory activation pathway by the fusion protein CTLA4Ig has been shown to prevent the development of accelerated graft arteriosclerosis in a rat model of chronic cardiac allograft rejection. The effectiveness of T-cell costimulatory blockade at preventing chronic allograft rejection in a clinically relevant model in combination with cyclosporine therapy has not been investigated. Using the well-established LEW into F334 heterotopic cardiac allograft model, we show that when cyclosporine is administered in combination with CTLA4Ig, it abrogates the previously demonstrated protective effect of CTLA4Ig in preventing chronic allograft rejection. Long-term surviving allografts from animals treated with a combination of cyclosporine and CTLA4Ig had a mean vascular luminal occlusion of 42.2%, affecting more than 90% of graft vessels due to accelerated arteriosclerosis. This was associated with up-regulation of intragraft expression of mRNA for CD4, the costimulatory molecule B7, the T-cell cytokine interferon-gamma, monocyte chemoattractant protein-1, and the fibrogenic growth factor transforming growth factor-beta; all have been previously shown to be associated 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 arteriosclerosis; mean vascular luminal occlusion was 11.3%, affecting approximately 50% of vessels. This was associated with decreased intragraft expression of CD4, B7, interferon-gamma, monocyte chemoattractant protein-1, and transforming growth factor-beta. These data indicate that 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. Administration of donor antigen may be necessary if CTLA4Ig and cyclosporine are to be combined, to prevent the process of chronic rejection.

Angiogenesis and Endothelial Cell Repair in Renal Disease and Allograft Rejection

“…They also noted that the increased capillary density was associated with T cell and monocyte infiltrates within the parenchyma of cardiac transplants (113). Using an established Lewis into Fisher rat model of chronic cardiac allograft rejection (8,114,115), we also found that angiogenesis was present in large CAV lesions, again in association with mononuclear infiltrates. Because the neovascular response itself is proinflammatory, we questioned whether it could sustain the growth of the intimal component of the CAV lesion.…”

Late blockade of T cell costimulation interrupts progression of experimental chronic allograft rejection.

“…In particular, blocking T cell-costimulatory activation early after transplantation prevents development of experimental chronic cardiac (9)(10)(11), as well as renal (12), allograft rejection. It has been suggested, however, that continuous T cell recognition of alloantigen, presumably via the indirect pathway (i.e., T cells that recognize donor-derived peptides presented by self antigen-presenting cells [APCs] 1 ), and activation may play an important role in progression of chronic rejection (13), although definitive studies are lacking. Understanding these mechanisms is essential for development of clinical strategies to prevent and interrupt progression of chronic allograft rejection.…”

“…Signal 2, a costimulatory signal, is delivered by interaction of T cell receptors with their specific ligands on APCs. Perhaps the best characterized T cell-costimulatory signal is that delivered by CD28 binding to B7 (13,(17)(18)(19)(20); blockade of this pathway prevents acute graft rejection and induces tolerance in some transplant models (13,(21)(22)(23)(24)(25)(26)(27). More recently, we have shown that early blockade of CD28-B7 by CTLA4Ig prevents development of chronic rejection (9,12).…”

Finally, CTLA4Ig graduates to the clinic

“…We need to explore whether CTLA4Ig may be used safely and effectively with other immunosuppressive agents or agents that block other costimulatory pathways, such as the CD40/CD154 pathway (24)(25)(26). Indeed, there are experimental data in small animals to indicate that calcineurin inhibitors, such as cyclosporine, may abrogate the immunosuppressive or tolerogenic effects of B7 and/or CD154 blockade (24,27,28). Finally, we need to investigate and better understand the exact mechanisms of costimulatory blockade in vivo in humans with different diseases and to develop surrogate markers to monitor disease activity and response to therapy.…”