Liver Targeted Expression of a Single Allogeneic MHC I Molecule Promotes Tolerance to Pancreatic Islet Allograft by Inducing Specific CD8+ Regulatory T Cells in Mice.
1Centre de Recherche en Transplantation et Immunologie UMR1064, INSERM, Université
de Nantes, Nantes, France
2Institut de Transplantation Urologie Néphrologie (ITUN), CHU Nantes, Nantes, France
3Département de Thérapie Cellulaire, CHU Saint Louis, Paris, France
Meeting: 2017 American Transplant Congress
Abstract number: C289
Keywords: Alloantigens, Gene therapy, Mice, Tolerance
Session Information
Session Name: Poster Session C: Tolerance/Immune Regulation
Session Type: Poster Session
Date: Monday, May 1, 2017
Session Time: 6:00pm-7:00pm
Presentation Time: 6:00pm-7:00pm
Location: Hall D1
A. 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 expression of a therapeutic transgene with viral vectors can result in tolerance induction and long-term expression of the product of the transgene. Our aim was to take advantage of these properties to induce tolerance in an allogeneic transplantation model.
B. C57BL/6 (H-2b) mice were treated with adeno-associated viral (AAV) vector targeting the expression of the MHC class I molecule H-2Kd to hepatocytes. Diabetes was then chemically induced and fully allogeneic pancreatic islets prepared from BALB/c mice (H-2d) were transplanted under their kidney capsule.
C. AAV H-2Kd treated mice were tolerant to the alloantigen, as demonstrated by its long-term expression by the hepatocytes, even after a highly immunogenic challenge. 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 (>100 days).
Mechanistically, we have demonstrated the expansion in the liver of AAV H-2Kd mice of a population of CD8+ regulatory T lymphocytes instrumental to the induction of tolerance. We have confirmed their suppressive function in vitro as well as in vivo, in adoptive transfer experiments in allogeneic pancreatic islet allograft in naïve diabetic mice.
D. In conclusion, AAV-mediated long-term expression of a single MHC class I molecule in the liver induces the generation of a subset of allospecific 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.
CITATION INFORMATION: Le Guen V, Judor J.-P, Gauttier V, Ferry N, Soulillou J.-P, Brouard S, Conchon S. Liver Targeted Expression of a Single Allogeneic MHC I Molecule Promotes Tolerance to Pancreatic Islet Allograft by Inducing Specific CD8+ Regulatory T Cells in Mice. Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Guen VLe, Judor J-P, Gauttier V, Ferry N, Soulillou J-P, Brouard S, Conchon S. Liver Targeted Expression of a Single Allogeneic MHC I Molecule Promotes Tolerance to Pancreatic Islet Allograft by Inducing Specific CD8+ Regulatory T Cells in Mice. [abstract]. Am J Transplant. 2017; 17 (suppl 3). https://atcmeetingabstracts.com/abstract/liver-targeted-expression-of-a-single-allogeneic-mhc-i-molecule-promotes-tolerance-to-pancreatic-islet-allograft-by-inducing-specific-cd8-regulatory-t-cells-in-mice/. Accessed May 12, 2025.« Back to 2017 American Transplant Congress