Donor Fas is not necessary for T-cell-mediated rejection of mouse kidney allografts.
It is important to resolve whether T-cell-mediated rejection (TCMR) is mediated by contact-dependent cytotoxicity or by contact-independent inflammatory mechanisms. We recently showed that the cytotoxic molecules perforin and granzymes A and B are not required for TCMR of mouse kidney transplants. Nevertheless, TCMR could still be mediated by cytotoxicity via Fas on donor cells engaging Fas ligand on host T cells. We examined whether the diagnostic TCMR lesions would be abrogated if donor Fas was absent, particularly in hosts deficient in perforin or granzymes A and B. Kidneys from Fas-deficient donors transplanted into major histocompatibility complex (MHC)- mismatched hosts developed tubulitis and diffuse interstitial infiltration indistinguishable from wild-type (WT) allografts, even in hosts deficient in perforin and granzymes A and B. Gene expression analysis revealed similar molecular disturbances in Fas-deficient and WT allografts at day 21 transplanted into WT, perforin and granzyme A/B-deficient hosts, indicating epithelial injury and dedifferentiation. Thus, donor Fas is not necessary for TCMR diagnostic lesions or molecular changes, even in the absence of perforin-granzyme mechanisms. We propose that in TCMR, interstitial effector T cells mediate parenchymal injury by inflammatory mechanisms that require neither the perforin-granzyme nor the Fas-Fas ligand cytotoxic mechanisms.
Kayser
D
D
Department of Medicine, Division of Nephrology, Alberta Transplant Applied Genomics Centre, Edmonton, Canada.
Einecke
G
G
Famulski
K S
KS
Mengel
M
M
Sis
B
B
Zhu
L-F
LF
Halloran
P F
PF
D000818:Animals; D053222:Fas Ligand Protein / Q000378:metabolism*; D020869:Gene Expression Profiling; D006084:Graft Rejection; D053804:Granzymes / Q000378:metabolism*; D016030:Kidney Transplantation / Q000379:methods*; D008285:Major Histocompatibility Complex; D008297:Male; D051379:Mice; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D054353:Perforin / Q000378:metabolism*; D013601:T-Lymphocytes / Q000378:metabolism*; D019014:fas Receptor / Q000378:metabolism*
D053222:Fas Ligand Protein; D019014:fas Receptor; D054353:Perforin; D053804:Granzymes