Induction of allograft tolerance in the absence of Fas-mediated apoptosis

Using certain immunosuppressive regimens, IL-2 knockout (KO) mice, in contr ast to wild-type (wt) controls, are resistant to the induction of allograft tolerance. The mechanism by which IL-2 regulates allograft tolerance is un certain. As IL-2 KO mice have a profound defect in Pas-mediated apoptosis, we hypothesized that Fas-mediated apoptosis of alloreactive T cells may be critical in the acquisition of allograft tolerance, To definitively study t he role of Fas in the induction of transplantation tolerance, we used Fas m utant B6.MRL-lpr mice as allograft recipients of islet and vascularized car diac transplants, Alloantigen-stimulated proliferation and apoptosis of Fas -deficient cells were also studied in vivo. Fas mutant B6.MRL-lpr (H-2(b)) mice rapidly rejected fully MRC-mismatched DBA/2 (H-2(d)) islet allografts and vascularized cardiac allografts with a tempo that is comparable to wt c ontrol mice, Both wt and B6,MRL-lpr mice transplanted with fully MBC-mismat ched islet allografts or cardiac allograRs can be readily tolerized by eith er rapamycin or combined costimulation blockade (CTLA-4Ig plus anti-CD40L m Ab), Despite the profound defect of Fas-mediated apoptosis, Fas-deficient T cells can still undergo apoptotic cell death in vivo in response to alloan tigen stimulation. Our study suggests that: 1) Fas is not necessarily essen tial for allograft tolerance, and 2) Fas-mediated apoptosis is not central to the LC-2-dependent mechanism governing the acquisition of allograft tole rance.