title: Adoptive transfer with in vitro expanded human regulatory T cells protects against porcine islet xenograft rejection via interleukin-10 in humanized mice.
abstract: T cell-mediated rejection remains a barrier to the clinical application of islet xenotransplantation. Regulatory T cells (Treg) regulate immune responses by suppressing effector T cells. This study aimed to determine the ability of human Treg to prevent islet xenograft rejection and the mechanism(s) involved. Neonatal porcine islet transplanted NOD-SCID IL2rγ(-/-) mice received human peripheral blood mononuclear cells (PBMC) with in vitro expanded autologous Treg in the absence or presence of anti-human interleukin-10 (IL-10) monoclonal antibody. In addition, human PBMC-reconstituted recipient mice received recombinant human IL-10 (rhIL-10). Adoptive transfer with expanded autologous Treg prevented islet xenograft rejection in human PBMC-reconstituted mice by inhibiting graft infiltration of effector cells and their function. Neutralization of human IL-10 shortened xenograft survival in mice receiving human PBMC and Treg. In addition, rhIL-10 treatment led to prolonged xenograft survival in human PBMC-reconstituted mice. This study demonstrates the ability of human Treg to prevent T-cell effector function and the importance of IL-10 in this response. In vitro Treg expansion was a simple and effective strategy for generating autologous Treg and highlighted a potential adoptive Treg cell therapy to suppress antigraft T-cell responses and reduce the requirement for immunosuppression in islet xenotransplantation.
authors.affiliation: Centre for Transplant and Renal Research, Westmead Millennium Institute, Westmead Hospital, Westmead, New South Wales, Australia. shounan_yi@wsahs.nsw.gov.au
authors.forename: Shounan
authors.initials: S
authors.lastname: Yi
authors.forename: Ming
authors.initials: M
authors.lastname: Ji
authors.forename: Jingjing
authors.initials: J
authors.lastname: Wu
authors.forename: Xiaoqian
authors.initials: X
authors.lastname: Ma
authors.forename: Peta
authors.initials: P
authors.lastname: Phillips
authors.forename: Wayne J
authors.initials: WJ
authors.lastname: Hawthorne
authors.forename: Philip J
authors.initials: PJ
authors.lastname: O'Connell
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D000906:Antibodies; D002478:Cells, Cultured; D005786:Gene Expression Regulation; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism*; D053645:Interleukin-2 Receptor alpha Subunit; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007963:Leukocytes, Mononuclear / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D013552:Swine; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*
chemical_list: D000906:Antibodies; C508017:IL2RA protein, human; D053631:Interleukin Receptor Common gamma Subunit; D053645:Interleukin-2 Receptor alpha Subunit; D016753:Interleukin-10