Blockade of Signal

There has been much attention directed recently to apoptosis of alloresponsive T-cells as a prerequisite for the induction of peripheral tolerance (180,181). Addition of a rapamycin treatment for 14 d to a costimulatory blocking induction regimen of anti-CD154 MAb and CTLA4-Ig resulted in indefinite survival of heart and skin grafts in mice, whereas the addition of CSA antagonized the effects of costimulatory blockade. The explanation for these seemingly contradictory effects of immunosuppressive agents lies in the fact that both cyclosporin A and rapamycin inhibit the proliferative component of IL-2 signaling, but only rapamycin allows the antigen-driven, IL-2-dependent, activation-induced cell death (AICD) phenomenon to occur. Enhanced skin graft tolerance in rapamycin-treated animals correlated with massive apoptosis of alloreactive T-cells (182). Administration of the same regimen to mice transgenic for Bcl-xL, an antiapoptotic gene, sharply reduced tolerance induction (180).

T-Cell growth factor deprivation is another form of T-cell apoptosis, distinct from AICD. Targeting T-cell growth factors during clonal expansion of activated T-cells is seen as an efficient way of inducing alloreactive T-cell apoptosis and, thus, peripheral tolerance. Anti-IL-2 receptor a-chain (CD25) MAbs, such as daclizumab and basilix-

imab, have been efficient in preventing acute rejection episodes in clinical trials, but are unable to block other growth factors (183). The fact that all receptors for T-cell growth factor (IL-2, IL-4, IL-7, IL-9, and IL-15) share a common yc-chain was exploited in a murine model, in which anti-yc-chain MAbs were administered to islet transplant recipients. This led to induction of T-cell apoptosis and indefinite allogeneic islet graft survival (184). T-cell apoptosis and stable tolerance are linked by the activation of immunoregulatory mechanisms. Apoptotic lymphocytes release anti-inflammatory and inhibitory cytokines (IL-10 and transforming growth factor-P [TGF-P]) as they die. Further, phagocytosis by macrophages of apoptotic T-cells carrying their specific antigen leads to presentation of the antigen in a tolerogenic form. Thus, tolerance induced by T-cell apoptosis is stable, because deletion is followed by active regulatory pathways induced by the inhibitory properties of the apoptotic cell (181). These observations present some seemingly extraordinary opportunities to exploit in tolerance-inducing protocols for clinical trials.

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