Induction of allograft tolerance in the absence of Fas-mediated apoptosis.
Using certain immunosuppressive regimens, IL-2 knockout (KO) mice, in contrast to wild-type (wt) controls, are resistant to the induction of allograft tolerance. The mechanism by which IL-2 regulates allograft tolerance is uncertain. As IL-2 KO mice have a profound defect in Fas-mediated apoptosis, we hypothesized that Fas-mediated apoptosis of alloreactive T cells may be critical in the acquisition of allograft tolerance. To definitively study the role of Fas in the induction of transplantation tolerance, we used Fas mutant B6.MRL-lpr mice as allograft recipients of islet and vascularized cardiac transplants. Alloantigen-stimulated proliferation and apoptosis of Fas-deficient cells were also studied in vivo. Fas mutant B6.MRL-lpr (H-2b) mice rapidly rejected fully MHC-mismatched DBA/2 (H-2d) islet allografts and vascularized cardiac allografts with a tempo that is comparable to wt control mice. Both wt and B6.MRL-lpr mice transplanted with fully MHC-mismatched islet allografts or cardiac allografts can be readily tolerized by either rapamycin or combined costimulation blockade (CTLA-4Ig plus anti-CD40L mAb). Despite the profound defect of Fas-mediated apoptosis, Fas-deficient T cells can still undergo apoptotic cell death in vivo in response to alloantigen stimulation. Our study suggests that: 1) Fas is not necessarily essential for allograft tolerance, and 2) Fas-mediated apoptosis is not central to the IL-2-dependent mechanism governing the acquisition of allograft tolerance.
Li
X C
XC
Department of Medicine, Harvard Medical School, Division of Immunology, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.
Li
Y
Y
Dodge
I
I
Wells
A D
AD
Zheng
X X
XX
Turka
L A
LA
Strom
T B
TB
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology / Q000473:pathology; D007108:Immune Tolerance / Q000276:immunology*; D007376:Interleukin-2 / Q000502:physiology; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D019463:Mice, Inbred MRL lpr; D008817:Mice, Mutant Strains; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism; D016042:Transplantation, Heterotopic / Q000276:immunology / Q000473:pathology; D014184:Transplantation, Homologous; D019014:fas Receptor / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*
D007376:Interleukin-2; D019014:fas Receptor