title: Metastable tolerance to rhesus monkey renal transplants is correlated with allograft TGF-beta 1+CD4+ T regulatory cell infiltrates.
abstract: 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.
authors.affiliation: Department of Pathology, University of Wisconsin and Veterans Affairs Hospital, Madison, WI 53792, USA.
authors.forename: Jose R
authors.initials: JR
authors.lastname: Torrealba
authors.forename: Masaaki
authors.initials: M
authors.lastname: Katayama
authors.forename: John H
authors.initials: JH
authors.lastname: Fechner
authors.forename: Ewa
authors.initials: E
authors.lastname: Jankowska-Gan
authors.forename: Satoshi
authors.initials: S
authors.lastname: Kusaka
authors.forename: Qingyong
authors.initials: Q
authors.lastname: Xu
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Schultz
authors.forename: Terry D
authors.initials: TD
authors.lastname: Oberley
authors.forename: Huaizhong
authors.initials: H
authors.lastname: Hu
authors.forename: Majed M
authors.initials: MM
authors.lastname: Hamawy
authors.forename: Margreet
authors.initials: M
authors.lastname: Jonker
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Wubben
authors.forename: Gaby
authors.initials: G
authors.lastname: Doxiadis
authors.forename: Ronald
authors.initials: R
authors.lastname: Bontrop
authors.forename: William J
authors.initials: WJ
authors.lastname: Burlingham
authors.forename: Stuart J
authors.initials: SJ
authors.lastname: Knechtle
mesh_terms: 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
chemical_list: C508960:TGFB1 protein, human; C508961:Tgfb1 protein, mouse; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1