Death of alloreactive T cells sets the stage for immunoregulation to act

Abstract

WHILE MANY tolerizing treatment protocols use broadly reactive lymphocyte-depleting antibodies or achieve clone-specific depletion via the clonal depletive effect of the mixed chimeric state, nondepleting agents such as nondepleting anti-CD4 or anti-CD3mAb, costimulation blockade, rapamycin, or combined costimulation blockade plus rapamycin therapy can also induce tolerance. We have determined that induction of allograft tolerance achieved through use of nondepleting lymphocyte agents requires activation-induced cell death (AICD) and passive cell death (PCD) of alloreactive T-cell clones. If AICD, a process that is IL-2-dependent, is blocked by the potent immunosuppressive combination of calcineurin inhibitors plus costimulation blockade, a combination that blocks both signal 1 and 2 of T-cell activation, peripheral tolerance is not achieved. IL-2 KO mice that accumulate activated T cells in peripheral lymphoid tissues as a result of a failure to mount IL-2-dependent AICD are refractory to tolerance induction by rapamycin or by agents that block costimulation. If PCD is blocked via overexpression of antiapoptotic genes in T-cells, peripheral tolerance is not achieved. Thus, at least some nondepleting treatments require T-cell depletion via AICD and PCD for tolerance induction. A minimal requirement for tolerance is the depletion of alloaggressive T-cell (trim the pool size) clones. Regulatory T cells can readily be detected in many tolerized allograft recipients. In essence, we believe that the outcome of the allograft response, be it rejection or tolerance, depends upon the speed with which the pool of donor-specific alloaggressive or counteracting pool of T-reg cells expand posttransplantation. In the absence of effective treatment, the pool of alloaggressive clones expands more rapidly than the pool of T-reg cells; rejection is the result.