title: Recombinant HLA-G as Tolerogenic Immunomodulant in Experimental Small Bowel Transplantation.
abstract: The non-classical MHC I paralogue HLA-G is expressed by cytotrophoblast cells and implicated with fetomaternal tolerance by downregulating the maternal adaptive and innate immune response against the fetus. HLA-G expression correlates with favorable graft outcome in humans and recently promising immunosuppressive effects of therapeutic HLA-G in experimental transplantation (skin allograft acceptance) were shown. Consequently, we examined this novel therapeutic approach in solid organ transplantation. In this study, therapeutic recombinant HLA-G5 was evaluated for the first time in a solid organ model of acute rejection (ACR) after orthotopic intestinal transplantation (ITX). Allogenic ITX was performed in rats (Brown Norway to Lewis) with and without HLA-G treatment. It was found that HLA-G treatment significantly reduced histologically proven ACR at both an early and late postoperative timepoint (POD 4/7), concomitant to a functionally preserved graft contractility at POD 7. Interestingly, graft infiltration by myeloperoxidase+ cells was significantly reduced at POD7 by HLA-G treatment. Moreover, HLA-G treatment showed an effect on the allogenic T-cell immune response as assessed by flow cytometry: The influx of recipient-derived CD8+ T-cells into the graft mesenteric lymphnodes at POD7 was significantly reduced while CD4+ populations were not affected. As a potential mechanism of action, an induction of T-reg populations in the mesenteric lymphnodes was postulated, but flow cytometric analysis of classical CD4+/CD25+/FoxP3+Treg-cells showed no significant alteration by HLA-G treatment. The novel therapeutic approach using recombinant HLA-G5 reported herein demonstrates a significant immunosuppressive effect in this model of allogenic experimental intestinal transplantation. This effect may be mediated via inhibition of recipient-derived CD8+ T-cell populations either directly or by induction of non-classical Treg populations.
authors.affiliation: Department of Surgery, University Hospital of Bonn, Bonn, Germany.
authors.forename: Martin W
authors.initials: MW
authors.lastname: von Websky
authors.affiliation: Department of Surgery, University Hospital of Bonn, Bonn, Germany.|Department of Hepatobiliary Pancreatic Surgery and Transplantation, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Koji
authors.initials: K
authors.lastname: Kitamura
authors.affiliation: Institute for Experimental Immunology, University of Bonn, Germany.
authors.forename: Isis
authors.initials: I
authors.lastname: Ludwig-Portugall
authors.affiliation: Institute for Experimental Immunology, University of Bonn, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Kurts
authors.affiliation: Charité Berlin, Institute of Pathology, Berlin, Germany.
authors.forename: Maximilian
authors.initials: M
authors.lastname: von Laffert
authors.affiliation: CEA, iMETI, Research Division in Hematology and Immunology, Saint-Louis Hospital, Paris, France.
authors.forename: Joel
authors.initials: J
authors.lastname: LeMaoult
authors.affiliation: CEA, iMETI, Research Division in Hematology and Immunology, Saint-Louis Hospital, Paris, France.
authors.forename: Edgardo D
authors.initials: ED
authors.lastname: Carosella
authors.affiliation: Transplant Center, Cleveland Clinic, Cleveland, Ohio, United States of America.
authors.forename: Kareem
authors.initials: K
authors.lastname: Abu-Elmagd
authors.affiliation: Department of Surgery, University Hospital of Bonn, Bonn, Germany.
authors.forename: Joerg C
authors.initials: JC
authors.lastname: Kalff
authors.affiliation: Department of Surgery, University Hospital of Bonn, Bonn, Germany.
authors.forename: Nico
authors.initials: N
authors.lastname: Schäfer
mesh_terms: D000818:Animals; D006084:Graft Rejection / Q000276:immunology*; D059951:HLA-G Antigens / Q000494:pharmacology*; D007155:Immunologic Factors / Q000494:pharmacology*; D007422:Intestines / Q000187:drug effects / Q000276:immunology* / Q000637:transplantation*; D008297:Male; D051381:Rats; D011994:Recombinant Proteins / Q000494:pharmacology*; D014184:Transplantation, Homologous
chemical_list: D059951:HLA-G Antigens; D007155:Immunologic Factors; D011994:Recombinant Proteins