Lesions of T-cell-mediated kidney allograft rejection in mice do not require perforin or granzymes A and B.
Organ allograft rejection is strongly associated with the presence of alloreactive cytotoxic T cells but the role of cytotoxicity in the pathologic lesions is unclear. Previous studies showed that the principal lesions of kidney rejection - interstitial infiltration, tubulitis, and endothelial arteritis - are T-cell-dependent and antibody-independent. We studied the role of cytotoxic granule components perforin and granzymes A and B in the evolution of the T-cell-mediated lesions of mouse kidney transplant rejection. By real-time RT-PCR, allografts rejecting in wild-type hosts at days 5, 7, 21, and 42 showed massively elevated and persistent expression of perforin and granzymes A and B, but evolution of tubulitis and arteritis did not correlate with increasing granzyme or perforin expression. Allografts transplanted into hosts with disrupted genes for perforin or granzymes A and B showed no change in tubulitis, arteritis, or MHC induction. Thus the development of the histologic lesions diagnostic of T-cell-mediated kidney transplant rejection are associated with but not mediated by perforin or granzyme A or B. Together with previous graft survival studies, these results indicate that the granule-associated cytotoxic mechanisms of T cells are not the effectors of T-cell-mediated allograft rejection.
Halloran
Philip F
PF
Department of Medicine, Division of Nephrology & Transplantation Immunology, University of Alberta, Edmonton, Alberta, Canada. phil.halloran@ualberta.ca
Urmson
Joan
J
Ramassar
Vido
V
Melk
Anette
A
Zhu
Lin-Fu
LF
Halloran
Brendan P
BP
Bleackley
R Chris
RC
D000818:Animals; D000943:Antigens, Differentiation / Q000378:metabolism*; D010450:Endopeptidases / Q000378:metabolism*; D006084:Graft Rejection / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D053804:Granzymes; D007668:Kidney / Q000166:cytology / Q000276:immunology / Q000473:pathology; D016030:Kidney Transplantation; D008233:Lymphotoxin-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008285:Major Histocompatibility Complex / Q000235:genetics / Q000276:immunology; D008297:Male; D008562:Membrane Glycoproteins / Q000378:metabolism*; D051379:Mice; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
D000943:Antigens, Differentiation; D008233:Lymphotoxin-alpha; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; C013094:lymphocyte effector molecules; D054353:Perforin; D010450:Endopeptidases; D053804:Granzymes; C509214:Gzmb protein, mouse; D012697:Serine Endopeptidases