Soluble HLA-G as tolerogenic immunomodulant in experimental small bowel transplantation
Martin von Websky1, Koji Kitamura1, Thomas Pech1, Isis Ludwig-Portugall2, Joel LeMaoult3, Kareem Abu-Elmagd4, Joerg Kalff1, Nico Schaefer1
1Visceral Surgery, University Hospital of Bonn, Bonn, Germany; 2experimental Immunology, University of Bonn, Bonn, Germany; 3Service de recherches en hÃ©mato-immunologie, Hopital Saint-Louis, Paris, France; 4Transplant Institute, Cleveland Clinic, Cleveland, OH, United States
HLA-G is a non-classical member of the HLA family and has been implicated with a central role in fetomaternal tolerance. It partakes in the protection of the fetus (a semi-allogenic allograft) from the mother’s immune system via downregulating adaptive (T cell) and innate (NK cell) immunity. Promising studies have shown immunosuppressive effects of HLA-G in transplantation and allogenic skin allografts were accepted in mice using HLA-G as tolerogenic immunomodulant. In this study, soluble HLA-G dimers are evaluated in experimental intestinal transplantation – a solid organ especially prone to acute and chronic rejection.
Allogenic intestinal transplantation (ITX) was performed in rats (BN ->Lew). HLA-G was coated on polystyrene beads and administered intraperitoneally 24h prior to and upon completion of the transplant. Animals were harvested at 4 and 7 days posttransplant and acute rejection (ACR), as well as effects on T-cell adaptive immune responses were assessed by flow cytometry, histology, graft contractility and qPCR.
HLA-G treatment was observed to significantly protect grafts from histologically proven ACR as assessed by two independent reviewers using the Wu rejection score. While no difference was observed in CD4+ T-cells isolated from graft draining lymphnodes, effector CD8+ cells were found to be significantly reduced after HLA-G treatment at 7 days post allogenic ITX. Furthermore, CD4+/CD25+/FoxP3+ Treg cells appeared to be induced by HLA-G treatment. Graft infiltration with myeloperoxidase positive cells was significantly reduced after HLA treatment at 7 days post ITX concomitantly to ameliorated graft contractility. qPCR showed a significant reduction in ACR-related cytokine expression (TNF α, IL 10, IFN γ) after HLA-G treatment at 4 and 7 days post ITX.
Soluble HLA-G dimers exhibit tolerogenic properties in this model of experimental intestinal transplantation. The protective effect may be mediated via inhibition of the effector CD8+ population either directly or by induction of specific Treg populations. Further studies examining the efficacy and mechanism of HLA-G as tolerogenic immunomodulant in intestinal transplantation are warranted.