title: Absence of MyD88 signaling induces donor-specific kidney allograft tolerance.
abstract: Toll-like receptors (TLRs) play a fundamental role in innate immunity and provide a link between innate and adaptive responses to an allograft; however, whether the development of acute and chronic allograft rejection requires TLR signaling is unknown. Here, we studied TLR signaling in a fully MHC-mismatched, life-sustaining murine model of kidney allograft rejection. Mice deficient in the TLR adaptor protein MyD88 developed donor antigen-specific tolerance, which protected them from both acute and chronic allograft rejection and increased their survival after transplantation compared with wild-type controls. Administration of an anti-CD25 antibody to MyD88-deficient recipients depleted CD4(+)CD25(+)FoxP3(+) cells and broke tolerance. In addition, defective development of Th17 immune responses to alloantigen both in vitro and in vivo occurred, resulting in an increased ratio of Tregs to Th17 effectors. Thus, MyD88 deficiency was associated with an altered balance of Tregs over Th17 cells, promoting tolerance instead of rejection. This study provides evidence that targeting innate immunity may be a clinically relevant strategy to facilitate transplantation tolerance.
authors.affiliation: Transplant Research Group, University of Sydney, Sydney, NSW 2006, Australia. huiling.wu@sydney.edu.au
authors.forename: Huiling
authors.initials: H
authors.lastname: Wu
authors.forename: Gerda A
authors.initials: GA
authors.lastname: Noordmans
authors.forename: Maya R
authors.initials: MR
authors.lastname: O'Brien
authors.forename: Jin
authors.initials: J
authors.lastname: Ma
authors.forename: Cathy Y
authors.initials: CY
authors.lastname: Zhao
authors.forename: Geoff Y
authors.initials: GY
authors.lastname: Zhang
authors.forename: Tony K T
authors.initials: TK
authors.lastname: Kwan
authors.forename: Stephen I
authors.initials: SI
authors.lastname: Alexander
authors.forename: Steven J
authors.initials: SJ
authors.lastname: Chadban
mesh_terms: D000818:Animals; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance; D007113:Immunity, Innate; D053645:Interleukin-2 Receptor alpha Subunit / Q000037:antagonists & inhibitors; D007519:Isoantigens; D016030:Kidney Transplantation / Q000276:immunology*; D007959:Lymphocyte Culture Test, Mixed; D008212:Lymphocyte Depletion; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency* / Q000235:genetics / Q000276:immunology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000276:immunology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D016207:Cytokines; D053645:Interleukin-2 Receptor alpha Subunit; D007519:Isoantigens; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D012333:RNA, Messenger