title: Alloantigen gene transfer to hepatocytes promotes tolerance to pancreatic islet graft by inducing CD8+regulatory T cells.
abstract: Induction of donor-specific immune tolerance is a good alternative to chronic life-long immunosuppression for transplant patients. Donor major histocompatibility complex (MHC) molecules represent the main targets of the allogeneic immune response of transplant recipients. Liver targeted gene transfer with viral vectors induces tolerance toward the encoded antigen. The aim of this work was to determine whether alloantigen gene transfer to hepatocytes induces tolerance and promotes graft acceptance.
  
  
  
  C57BL/6 (H-2b) mice were treated with adeno-associated viral (AAV) vector targeting the expression of the MHC class I molecule H-2Kdto hepatocytes, before transplantation with fully allogeneic pancreatic islet from BALB/c mice (H-2d).
  
  
  
  AAV H-2Kdtreated mice were tolerant to the alloantigen, as demonstrated by its long-term expression by the hepatocytes, even after a highly immunogenic challenge with an adenoviral vector. After chemical induction of diabetes, the AAV treated mice had significantly delayed rejection of fully allogeneic pancreatic islet grafts, with more than 40% of recipients tolerant (>100days). AAV-mediated expression of H-2Kdin the liver induced the local expansion of CD8+T lymphocytes with allo-specific suppressive properties. The adoptive transfer of these liver-generated CD8+Tregs into naive diabetic mice promoted the long-term survival of allogeneic pancreatic islet grafts.
  
  
  
  AAV-mediated long-term expression of a single MHC class I molecule in the liver induces the generation of a subset of allo-specific CD8+Treg cells, which promote tolerance toward fully allogeneic graft. Liver gene transfer represents a promising strategy for in vivo induction of donor-specific tolerance.
  
  
  
  The liver has a special immune system, biased toward tolerance. In this study, we investigated the possibility of harnessing this property of the liver to induce tolerance to an allogeneic transplantation. We demonstrate for the first time that the in vivo gene transfer of an allogeneic antigen with an adeno-associated viral vector to mouse hepatocytes induces the expansion of a population of CD8+regulatory T lymphocytes. These Tregs are then instrumental in preventing the rejection of allogeneic pancreatic islets transplanted in these animals. Allogeneic transplantation is the main treatment for the end-stage diseases of a number of organs. Life-long immunosuppressive treatments are still required to limit graft rejection, and these treatments exhibit serious side effects. Our present findings open a new avenue for promoting allo-specific tolerance via in vivo induction of CD8+Treg expansion.
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Valentin
authors.initials: V
authors.lastname: Le Guen
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Judor
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Françoise
authors.initials: F
authors.lastname: Boeffard
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Vanessa
authors.initials: V
authors.lastname: Gauttier
authors.affiliation: Département de Thérapie Cellulaire, CHU Saint Louis, Paris, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Ferry
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Jean-Paul
authors.initials: JP
authors.lastname: Soulillou
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France.
authors.forename: Sophie
authors.initials: S
authors.lastname: Brouard
authors.affiliation: Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université de Nantes, Nantes, France; Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France. Electronic address: sophie.conchon@univ-nantes.fr.
authors.forename: Sophie
authors.initials: S
authors.lastname: Conchon
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000229:Dependovirus; D003921:Diabetes Mellitus, Experimental / Q000276:immunology / Q000628:therapy; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006085:Graft Survival / Q000276:immunology; D006183:H-2 Antigens / Q000235:genetics; D022781:Hepatocytes / Q000276:immunology*; D007165:Immunosuppression Therapy / Q000379:methods*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007519:Isoantigens / Q000235:genetics; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D019219:Parvovirinae / Q000235:genetics; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*; D014019:Tissue Donors; D014184:Transplantation, Homologous
chemical_list: D006183:H-2 Antigens; C024755:H-2K(K) antigen; D007519:Isoantigens
keywords: Allogeneic transplantation; Gene transfer; Liver immunology; Tolerance induction