title: Alloantigen-specific regulatory T cells prevent experimental chronic graft-versus-host disease by simultaneous control of allo- and autoreactivity.
abstract: Chronic graft-versus-host disease (cGVHD) is characterised by a complex etiology of both alloimmune- and autoimmune-mediated disease progression and pathology, and is consequently difficult to control. The therapeutic potential of regulatory T (Treg) cells for cGVHD is currently being investigated; however, the relative ability of Treg cells with defined antigen specificities for auto- and alloantigen to prevent disease has not been previously examined. In this study, we show that donor-derived Treg-cell lines generated with self-MHC H-2(b)  specificity or specificity for BALB/c H-2(d)  alloantigen presented via the direct or indirect pathways are able to mediate an equal protection against cGVHD immune pathology in a disease model associated with recipient B-cell-driven humoral autoimmunity and glomerulonephritis. Mechanistically, autospecific Treg cells prevented disease induction by blocking donor T-cell engraftment whereas allospecific Treg cells permitted long-term engraftment of donor T cells. Donor T cells, while unresponsive to auto- and recipient alloantigens, retained the capacity to respond to third party alloantigens on ex vivo stimulation. These findings indicate that allospecific Treg cells may therefore be more clinically relevant as a cell therapy for cGVHD in the context of haplo-identical hematopoietic transplantation, as they allow persistence of donor T cells capable of responding to foreign antigens whilst preventing cGVHD-mediated autoimmunity.
authors.affiliation: NIHR Biomedical Research Centre, Guy's & St Thomas' NHS Foundation Trust & King's College London, Great Maze Pond, London, UK.
authors.forename: Pervinder
authors.initials: P
authors.lastname: Sagoo
authors.forename: Kulachelvy
authors.initials: K
authors.lastname: Ratnasothy
authors.forename: Yuen
authors.initials: Y
authors.lastname: Tsang
authors.forename: Linda D
authors.initials: LD
authors.lastname: Barber
authors.forename: Alistair
authors.initials: A
authors.lastname: Noble
authors.forename: Robert I
authors.initials: RI
authors.lastname: Lechler
authors.forename: Giovanna
authors.initials: G
authors.lastname: Lombardi
mesh_terms: D000818:Animals; D015551:Autoimmunity; D002908:Chronic Disease; D004195:Disease Models, Animal; D005260:Female; D005921:Glomerulonephritis / Q000276:immunology / Q000517:prevention & control; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology / Q000517:prevention & control*; D006183:H-2 Antigens / Q000276:immunology*; D018380:Hematopoietic Stem Cell Transplantation; D056724:Immunity, Humoral; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D014184:Transplantation, Homologous
chemical_list: D006183:H-2 Antigens; D007519:Isoantigens