title: IL-17 deficiency attenuates allograft injury and prolongs survival in a murine model of fully MHC-mismatched renal allograft transplantation.
abstract: IL-17 is a pro-inflammatory cytokine implicated in the pathogenesis of inflammatory and autoimmune diseases. However the role of IL-17 in renal allograft rejection has not been fully explored. Here, we investigate the impact of IL-17 in a fully MHC-mismatched, life-sustaining, murine model of kidney allograft rejection using IL-17 deficient donors and recipients (IL-17(-/-) allografts). IL-17(-/-) allografts exhibited prolonged survival which was associated with reduced expression of the Th1 cytokine IFN-γ and histological attenuation of acute and chronic allograft rejection, as compared to wild-type allograft recipients. Results were confirmed in WT allograft recipients treated with an IL-17 blocking antibody. Subsequent experiments using either donors or recipients deficient in IL-17 showed a trend towards prolongation of survival only when recipients were IL-17(-/-) . Administration of a depleting anti-CD25 antibody to IL-17(-/-) recipients abrogated the survival advantage conferred by IL-17 deficiency, suggesting the involvement of a CD4(+) CD25(+) T cell regulatory mechanism. Therefore, IL-17 deficiency or neutralization was protective against the development of kidney allograft rejection, which may be mediated by impairment of Th1 responses and/or enhanced protection by Tregs.
authors.affiliation: Collaborative Transplant Research Group and Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: T
authors.initials: T
authors.lastname: Kwan
authors.affiliation: Collaborative Transplant Research Group and Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: S J
authors.initials: SJ
authors.lastname: Chadban
authors.affiliation: Collaborative Transplant Research Group and Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: J
authors.initials: J
authors.lastname: Ma
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, Australia.|Discipline of Pathology, School of Medical Sciences.
authors.forename: S
authors.initials: S
authors.lastname: Bao
authors.affiliation: Sydney Medical School, University of Sydney, Sydney, Australia.|The Children Hospital at Westmead, Australia.
authors.forename: S I
authors.initials: SI
authors.lastname: Alexander
authors.affiliation: Collaborative Transplant Research Group and Renal Medicine, Royal Prince Alfred Hospital, Sydney, Australia.|Sydney Medical School, University of Sydney, Sydney, Australia.
authors.forename: H
authors.initials: H
authors.lastname: Wu
mesh_terms: D064591:Allografts; D000818:Animals; D006084:Graft Rejection / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D006648:Histocompatibility / Q000276:immunology* / Q000502:physiology; D007371:Interferon-gamma / Q000502:physiology; D020381:Interleukin-17 / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D015847:Interleukin-4 / Q000502:physiology; D016030:Kidney Transplantation / Q000401:mortality*; D008285:Major Histocompatibility Complex / Q000276:immunology* / Q000502:physiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D015996:Survival Rate; D050378:T-Lymphocytes, Regulatory / Q000502:physiology
chemical_list: D020381:Interleukin-17; D015847:Interleukin-4; D007371:Interferon-gamma
keywords: cytokines/cytokine receptors; innate immunity; tolerance: mechanisms