Blocking both signal 1 and signal 2 of T-cell activation prevents apoptosis of alloreactive T cells and induction of peripheral allograft tolerance

Y Li, XC Li, XX Zheng, AD Wells, LA Turka, TB Strom - Nature medicine, 1999 - nature.com
Y Li, XC Li, XX Zheng, AD Wells, LA Turka, TB Strom
Nature medicine, 1999nature.com
The alloimmune response against fully MHC-mismatched allografts, compared with immune
responses to nominal antigens, entails an unusually large clonal size of alloreactive T cells
1. Thus, induction of peripheral allograft tolerance established in the absence of immune
system ablation and reconstitution is a challenging task in transplantation. Here, we
determined whether a reduction in the mass of alloreactive T cells due to apoptosis is an
essential initial step for induction of stable allograft tolerance with non-lymphoablative …
Abstract
The alloimmune response against fully MHC-mismatched allografts, compared with immune responses to nominal antigens, entails an unusually large clonal size of alloreactive T cells 1. Thus, induction of peripheral allograft tolerance established in the absence of immune system ablation and reconstitution is a challenging task in transplantation. Here, we determined whether a reduction in the mass of alloreactive T cells due to apoptosis is an essential initial step for induction of stable allograft tolerance with non-lymphoablative therapy. Blocking both CD28–B7 and CD40–CD40 ligand interactions (co-stimulation blockade) inhibited proliferation of alloreactive T cells in vivo while allowing cell cycle-dependent T-cell apoptosis of proliferating T cells, with permanent engraftment of cardiac allografts but not skin allografts. Treatment with rapamycin plus co-stimulation blockade resulted in massive apoptosis of alloreactive T cells and produced stable skin allograft tolerance, a very stringent test of allograft tolerance. In contrast, treatment with cyclosporine A and co-stimulation blockade abolished T-cell proliferation and apoptosis, as well as the induction of stable allograft tolerance. Our data indicate that induction of T-cell apoptosis and peripheral allograft tolerance is prevented by blocking both signal 1 and signal 2 of T-cell activation.
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