title: Abrogation of antibody-mediated allograft rejection by regulatory CD4 T cells with indirect allospecificity.
abstract: Alloantibody is an important effector mechanism for allograft rejection. In this study, we tested the hypothesis that regulatory T cells with indirect allospecificity can prevent humoral rejection by using a rat transplant model in which acute rejection of MHC class I-disparate PVG.R8 heart grafts by PVG.RT1(u) recipients is mediated by alloantibody and is dependent upon help from CD4 T cells that can recognize the disparate MHC alloantigen only via the indirect pathway. Pretransplant treatment of PVG.RT1(u) recipients with anti-CD4 mAb plus donor-specific transfusion abrogated alloantibody production and prolonged PVG.R8 graft survival indefinitely. Naive syngeneic splenocytes injected into tolerant animals did not effect heart graft rejection, suggesting the presence of regulatory mechanisms. Adoptive transfer experiments into CD4 T cell-reconstituted, congenitally athymic recipients confirmed that regulation was mediated by CD4 T cells and was alloantigen-specific. CD4 T cell regulation could be broken in tolerant animals either by immunizing with an immunodominant linear allopeptide or by depleting tolerant CD4 T cells, but surprisingly this resulted in neither alloantibody generation nor graft rejection. These findings demonstrate that anti-CD4 plus donor-specific transfusion treatment results in the development of CD4 regulatory T cells that recognize alloantigens via the indirect pathway and act in an Ag-specific manner to prevent alloantibody-mediated rejection. Their development is associated with intrinsic tolerance within the alloantigen-specific B cell compartment that persists after T cell help is made available.
authors.affiliation: University Department of Surgery, Addenbrooke's Hospital, Cambridge, United Kingdom.
authors.forename: Chris J
authors.initials: CJ
authors.lastname: Callaghan
authors.forename: Foad J
authors.initials: FJ
authors.lastname: Rouhani
authors.forename: Margaret C
authors.initials: MC
authors.lastname: Negus
authors.forename: Allison J
authors.initials: AJ
authors.lastname: Curry
authors.forename: Eleanor M
authors.initials: EM
authors.lastname: Bolton
authors.forename: J Andrew
authors.initials: JA
authors.lastname: Bradley
authors.forename: Gavin J
authors.initials: GJ
authors.lastname: Pettigrew
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D000917:Antibody Formation / Q000187:drug effects / Q000276:immunology; D000918:Antibody Specificity / Q000187:drug effects / Q000276:immunology*; D017951:Antigen Presentation / Q000187:drug effects / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology; D015704:CD4 Antigens / Q000276:immunology; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology; D007518:Isoantibodies / Q000276:immunology*; D007519:Isoantigens / Q000276:immunology / Q000494:pharmacology; D008212:Lymphocyte Depletion; D010455:Peptides / Q000276:immunology / Q000494:pharmacology; D051381:Rats; D011917:Rats, Inbred Lew; D050378:T-Lymphocytes, Regulatory / Q000276:immunology* / Q000637:transplantation; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D015704:CD4 Antigens; D007518:Isoantibodies; D007519:Isoantigens; D010455:Peptides