title: Rejection triggers liver transplant tolerance: Involvement of mesenchyme-mediated immune control mechanisms in mice.
abstract: Liver tolerance was initially recognized by the spontaneous acceptance of liver allografts in many species. The underlying mechanisms are not completely understood. However, liver transplant (LT) tolerance absolutely requires interferon (IFN)-γ, a rejection-associated inflammatory cytokine. In this study, we investigated the rejection of liver allografts deficient in the IFN-γ receptor and reveal that the liver graft is equipped with machineries capable of counterattacking the host immune response through a mesenchyme-mediated immune control (MMIC) mechanism. MMIC is triggered by T effector (Tef) cell-derived IFN-γ that drives expression of B7-H1 on graft mesenchymal cells leading to Tef cell apoptosis. We describe the negative feedback loop between graft mesenchymal and Tef cells that ultimately results in LT tolerance. Comparable elevations of T-regulatory cells and myeloid-derived suppressor cells were observed in both rejection and tolerance groups and were not dependent on IFN-γ stimulation, suggesting a critical role of Tef cell elimination in tolerance induction. We identify potent MMIC activity in hepatic stellate cells and liver sinusoidal endothelial cells. MMIC is unlikely exclusive to the liver, given that spontaneous acceptance of kidney allografts has been reported, although less commonly, probably reflecting variance in MMIC activity.
  
  
  CONCLUSIONS
  MMIC may represent an important homeostatic mechanism that supports peripheral tolerance and could be a target for the prevention and treatment of transplant rejection. This study highlights that the graft is an active participant in the equipoise between tolerance and rejection and warrants more attention in the search for tolerance biomarkers.
authors.affiliation: Department of Immunology, Lerner Research InstituteCleveland Clinic, Cleveland, OH.
authors.forename: Miwa
authors.initials: M
authors.lastname: Morita
authors.affiliation: Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Daniel
authors.initials: D
authors.lastname: Joyce
authors.affiliation: Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Charles
authors.initials: C
authors.lastname: Miller
authors.affiliation: Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: John J
authors.initials: JJ
authors.lastname: Fung
authors.affiliation: Department of Immunology, Lerner Research InstituteCleveland Clinic, Cleveland, OH.|Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Lina
authors.initials: L
authors.lastname: Lu
authors.affiliation: Department of Immunology, Lerner Research InstituteCleveland Clinic, Cleveland, OH.|Department of General Surgery, Transplant Center, Digestive Disease Institute, Cleveland Clinic, Cleveland, OH.
authors.forename: Shiguang
authors.initials: S
authors.lastname: Qian
mesh_terms: D000818:Animals; D016207:Cytokines / Q000276:immunology; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D007108:Immune Tolerance / Q000276:immunology*; D007155:Immunologic Factors / Q000378:metabolism; D016031:Liver Transplantation / Q000009:adverse effects; D008297:Male; D008648:Mesoderm / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D017471:Receptors, Interferon / Q000276:immunology* / Q000378:metabolism; D012680:Sensitivity and Specificity; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D014181:Transplantation Immunology / Q000502:physiology*; D014184:Transplantation, Homologous; D000096743:Interferon gamma Receptor
chemical_list: D016207:Cytokines; D007155:Immunologic Factors; D017471:Receptors, Interferon; D000096743:Interferon gamma Receptor