title: TLR engagement prevents transplantation tolerance.
abstract: In many experimental models, heart, pancreas and kidney allografts are accepted long-term following costimulation-targeting therapies, whereas skin, lung and intestine resist the induction of tolerance under the same regimens. We noted that a common feature of the resistant organs is their constant exposure to commensal microbes and hypothesized that these microorganisms may stimulate Toll-like receptors (TLRs), promote alloresponses and prevent tolerance induction. This hypothesis prompts the predictions that TLR engagement at the time of transplantation should avert tolerance to heart allografts in animals treated with costimulation-targeting therapies, whereas inhibition of TLR signaling should promote tolerance to skin allografts under the same conditions. Indeed, engagement of a single TLR was sufficient to prevent anti-CD154-mediated long-term cardiac allograft acceptance and correlated with abolished intragraft recruitment of CD4+/FoxP3+ regulatory T cells and the development of linked-suppression. Conversely, a lack of donor and recipient MyD88-dependent signaling led to successful skin allograft acceptance in anti-CD154-treated animals. Thus, the status of TLR signaling contributes to the resistance versus susceptibility of organs to transplantation tolerance.
authors.affiliation: Department of Medicine, The University of Chicago, Chicago, Illinois, USA.
authors.forename: L
authors.initials: L
authors.lastname: Chen
authors.forename: T
authors.initials: T
authors.lastname: Wang
authors.forename: P
authors.initials: P
authors.lastname: Zhou
authors.forename: L
authors.initials: L
authors.lastname: Ma
authors.forename: D
authors.initials: D
authors.lastname: Yin
authors.forename: J
authors.initials: J
authors.lastname: Shen
authors.forename: L
authors.initials: L
authors.lastname: Molinero
authors.forename: T
authors.initials: T
authors.lastname: Nozaki
authors.forename: T
authors.initials: T
authors.lastname: Phillips
authors.forename: S
authors.initials: S
authors.lastname: Uematsu
authors.forename: S
authors.initials: S
authors.lastname: Akira
authors.forename: C-R
authors.initials: CR
authors.lastname: Wang
authors.forename: R L
authors.initials: RL
authors.lastname: Fairchild
authors.forename: M-L
authors.initials: ML
authors.lastname: Alegre
authors.forename: A
authors.initials: A
authors.lastname: Chong
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D001323:Autoantibodies / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D023201:CD40 Ligand / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D016207:Cytokines / Q000235:genetics; D004195:Disease Models, Animal; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000502:physiology*; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012333:RNA, Messenger / Q000235:genetics; D016038:Skin Transplantation / Q000276:immunology*; D013997:Time Factors; D051193:Toll-Like Receptors / Q000037:antagonists & inhibitors / Q000276:immunology*; D016042:Transplantation, Heterotopic; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D016207:Cytokines; D012333:RNA, Messenger; D051193:Toll-Like Receptors; D023201:CD40 Ligand