title: Xenograft tolerance and immune function of human T cells developing in pig thymus xenografts.
abstract: Transplantation of xenogeneic thymus tissue allows xenograft tolerance induction in the highly disparate pig-to-mouse model. Fetal swine thymus (SW THY) can support the generation of a diverse human T cell repertoire that is tolerant of the pig in vitro. We demonstrate that SW THY generates all human T cell subsets, including regulatory T cells (Tregs), in similar numbers as fetal human thymus (HU THY) grafts in immunodeficient mice receiving the same human CD34(+) cells. Peripheral T cells are specifically tolerant to the mouse and to the human and porcine donors, with robust responses to nondonor human and pig Ags. Specific tolerance is observed to pig skin grafts sharing the THY donor MHC. SW THY-generated peripheral Tregs show similar function, but include lower percentages of naive-type Tregs compared with HU THY-generated Tregs. Tregs contribute to donor-pig specific tolerance. Peripheral human T cells generated in SW THY exhibit reduced proportions of CD8(+) T cells and reduced lymphopenia-driven proliferation and memory-type conversion, accelerated decay of memory-type cells, and reduced responses to protein Ags. Thus, SW thymus transplantation is a powerful xenotolerance approach for human T cells. However, immune function may be further enhanced by strategies to permit positive selection by autologous HLA molecules.
authors.affiliation: Transplantation Biology Research Center, Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114.
authors.forename: Hannes
authors.initials: H
authors.lastname: Kalscheuer
authors.forename: Takashi
authors.initials: T
authors.lastname: Onoe
authors.forename: Alexander
authors.initials: A
authors.lastname: Dahmani
authors.forename: Hao-Wei
authors.initials: HW
authors.lastname: Li
authors.forename: Markus
authors.initials: M
authors.lastname: Hölzl
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamada
authors.forename: Megan
authors.initials: M
authors.lastname: Sykes
mesh_terms: D000328:Adult; D000818:Animals; D000941:Antigens / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D049109:Cell Proliferation; D016332:Fetal Tissue Transplantation / Q000379:methods*; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016130:Immunophenotyping; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D013552:Swine; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000276:immunology / Q000378:metabolism; D013745:Tetanus Toxoid / Q000276:immunology; D060168:Thymocytes / Q000276:immunology / Q000378:metabolism; D013950:Thymus Gland / Q000196:embryology / Q000276:immunology / Q000637:transplantation*; D013997:Time Factors; D014183:Transplantation, Heterologous
chemical_list: D000941:Antigens; D013745:Tetanus Toxoid