title: The cholinergic anti-inflammatory pathway delays TLR-induced skin allograft rejection in mice: cholinergic pathway modulates alloreactivity.
abstract: Activation of innate immunity through Toll-like receptors (TLR) can abrogate transplantation tolerance by revealing hidden T cell alloreactivity. Separately, the cholinergic anti-inflammatory pathway has the capacity to dampen macrophage activation and cytokine release during endotoxemia and ischemia reperfusion injury. However, the relevance of the α7 nicotinic acetylcholine receptor (α7nAChR)-dependent anti-inflammatory pathway in the process of allograft rejection or maintenance of tolerance remains unknown. The aim of our study is to investigate whether the cholinergic pathway could impact T cell alloreactivity and transplant outcome in mice. For this purpose, we performed minor-mismatched skin allografts using donor/recipient combinations genetically deficient for the α7nAChR. Minor-mismatched skin grafts were not rejected unless the mice were housed in an environment with endogenous pathogen exposure or the graft was treated with direct application of imiquimod (a TLR7 ligand). The α7nAChR-deficient recipient mice showed accelerated rejection compared to wild type recipient mice under these conditions of TLR activation. The accelerated rejection was associated with enhanced IL-17 and IFN-γ production by alloreactive T cells. An α7nAChR-deficiency in the donor tissue facilitated allograft rejection but not in recipient mice. In addition, adoptive T cell transfer experiments in skin-grafted lymphopenic animals revealed a direct regulatory role for the α7nAChR on T cells. Taken together, our data demonstrate that the cholinergic pathway regulates alloreactivity and transplantation tolerance at multiple levels. One implication suggested by our work is that, in an organ transplant setting, deliberate α7nAChR stimulation of brain dead donors might be a valuable approach for preventing donor tissue inflammation prior to transplant.
authors.affiliation: Department of Anaesthesiology, Erasme Hospital, Brussels, Belgium ; Institute for Medical Immunology, Gosselies, Belgium.
authors.forename: Claude
authors.initials: C
authors.lastname: Sadis
authors.forename: Sophie
authors.initials: S
authors.lastname: Detienne
authors.forename: Benoît
authors.initials: B
authors.lastname: Vokaer
authors.forename: Louis-Marie
authors.initials: LM
authors.lastname: Charbonnier
authors.forename: Philippe
authors.initials: P
authors.lastname: Lemaître
authors.forename: Chloé
authors.initials: C
authors.lastname: Spilleboudt
authors.forename: Sandrine
authors.initials: S
authors.lastname: Delbauve
authors.forename: Carole
authors.initials: C
authors.lastname: Kubjak
authors.forename: Véronique
authors.initials: V
authors.lastname: Flamand
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Field
authors.forename: Michel
authors.initials: M
authors.lastname: Goldman
authors.forename: Fleur S
authors.initials: FS
authors.lastname: Benghiat
authors.forename: Alain
authors.initials: A
authors.lastname: Le Moine
mesh_terms: D019264:Adoptive Transfer; D064591:Allografts; D000818:Animals; D001483:Base Sequence; D002478:Cells, Cultured; D017931:DNA Primers; D005260:Female; D005434:Flow Cytometry; D006084:Graft Rejection; D007249:Inflammation / Q000378:metabolism / Q000517:prevention & control*; D051379:Mice; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016038:Skin Transplantation; D013601:T-Lymphocytes / Q000637:transplantation; D051193:Toll-Like Receptors / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor / Q000502:physiology*
chemical_list: D017931:DNA Primers; D051193:Toll-Like Receptors; D064569:alpha7 Nicotinic Acetylcholine Receptor