Tolerance And Cell Death

There are now many examples where evidence is found for alloreactive T-cell death in response to transplanted tissue without the need for purposeful chimer-ism. For example, two interesting recent papers demonstrate that tolerance induction with therapeutic anti-CD40L mAbs requires cell death.39,40 In fact, blockade of activation induced cell death (AICD) either by using transgenic mice resistant to apoptosis,40 or by using Cyclosporin-A (CsA)39 resulted in graft rejection in animals subjected to antibody blockade of CD28 and CD40L.

In spite of the importance of AICD in anti-CD40L transplantation tolerance, regulatory cells also play a role in its maintenance. In fact, tolerance induction with therapeutic anti-CD40L results in linked-suppression28 and in infectious tolerance.25 Thus, regulatory CD4+ T cells emerge, following tolerance induction, and actively enforce a dominant tolerance state.

We can safely speculate that amplification of regulatory cells and induction of AICD are probably general mechanisms exploited in the different tolerance inducing strategies. It is likely, although not yet demonstrated, that anti-CD4 therapeutic mAbs also require some cell death for the induction of transplantation tolerance. Recently it has been shown that anti-CD4 tolerance is independent of the Fas (CD95) pathway.41 Probably in all tolerance inducing strategies some cell clones will remain fully committed towards an aggressive phenotype and their physical (AICD) or functional (anergy) deletion is required if tolerance induction is to be successful.

Information is lacking on whether therapeutic protocols that aim at the deletion of alloreactive clones, such as the ones based on macrochimerism,2 also support the emergence of regulatory cells. Such studies need to be performed.

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