Metastable tolerance to rhesus monkey renal transplants is correlated with allograft TGF-beta 1+CD4+ T regulatory cell infiltrates.
Approaches that prevent acute rejection of renal transplants in a rhesus monkey model were studied to determine a common mechanism of acceptance. After withdrawal of immunosuppression, all 14 monkeys retained normal allograft function for >6 mo. Of these, nine rejected their renal allograft during the study, and five maintained normal function throughout the study period. The appearance of TGF-beta 1(+) interstitial mononuclear cells in the graft coincided with a nonrejection histology, whereas the absence/disappearance of these cells was observed with the onset of rejection. Analysis with a variety of TGF-beta 1-reactive Abs indicated that the tolerance-associated infiltrates expressed the large latent complex form of TGF-beta 1. Peripheral leukocytes from rejecting monkeys lacking TGF-beta 1(+) allograft infiltrates responded strongly to donor Ags in delayed-type hypersensitivity trans-vivo assays. In contrast, allograft acceptors with TGF-beta 1(+) infiltrates demonstrated a much weaker peripheral delayed-type hypersensitivity response to donor alloantigens (p < 0.01 vs rejectors), which could be restored by Abs that either neutralized active TGF-beta 1 or blocked its conversion from latent to active form. Anti-IL-10 Abs had no restorative effect. Accepted allografts had CD8(+) and CD4(+) interstitial T cell infiltrates, but only the CD4(+) subset included cells costaining for TGF-beta 1. Our data support the hypothesis that the recruitment of CD4(+) T regulatory cells to the allograft interstitium is a final common pathway for metastable renal transplant tolerance in a non-human primate model.
Torrealba
Jose R
JR
Department of Pathology, University of Wisconsin and Veterans Affairs Hospital, Madison, WI 53792, USA.
Katayama
Masaaki
M
Fechner
John H
JH
Jankowska-Gan
Ewa
E
Kusaka
Satoshi
S
Xu
Qingyong
Q
Schultz
Jacqueline M
JM
Oberley
Terry D
TD
Hu
Huaizhong
H
Hamawy
Majed M
MM
Jonker
Margreet
M
Wubben
Jacqueline
J
Doxiadis
Gaby
G
Bontrop
Ronald
R
Burlingham
William J
WJ
Knechtle
Stuart J
SJ
D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D002465:Cell Movement / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology; D006085:Graft Survival / Q000276:immunology; D006968:Hypersensitivity, Delayed / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology* / Q000473:pathology; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D008253:Macaca mulatta; D051379:Mice; D016513:Mice, SCID; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000096:biosynthesis* / Q000378:metabolism / Q000502:physiology; D053773:Transforming Growth Factor beta1; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous / Q000276:immunology* / Q000473:pathology
C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1