title: Mechanisms of tolerance induced by donor-specific transfusion and ICOS-B7h blockade in a model of CD4+ T-cell-mediated allograft rejection.
abstract: The inducible co-stimulatory molecule (ICOS) has been shown to play a critical role in T-cell activation and differentiation, and the regulation of alloimmune responses in vivo. Using an MHC class II mismatched model of CD4(+) T-cell-mediated rejection, we found that treatment of mice with DST and ICOS-B7h blockade induced long-term skin allograft survival and donor-specific transplantation tolerance. ICOS blockade, either during antigen priming or during the effector phase, previously shown to alter the outcome of the immune response, had a similar effect on graft survival. DST and anti-B7h mAb reduced the frequency of IFN-gamma-producing allospecific cells but did not produce deviation to a T(H)2 phenotype. In an adoptive transfer model using ABM TCR transgenic mice directly reactive to I-A(bm12), DST and anti-B7h mAb reduced the number of allospecific CD4(+) T cells and increased CD4(+) T-cell apoptosis. These data demonstrate that DST and anti-B7h mAb induces transplantation tolerance to MHC class II mismatched skin grafts by a reduction of the alloreactive clone size that is, at least in part, dependent on apoptosis of host alloantigen-specific CD4(+) T cells.
authors.affiliation: Transplantation Research Center, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
authors.forename: Sigrid E
authors.initials: SE
authors.lastname: Sandner
authors.forename: Michael R
authors.initials: MR
authors.lastname: Clarkson
authors.forename: Alan D
authors.initials: AD
authors.lastname: Salama
authors.forename: Alberto
authors.initials: A
authors.lastname: Sanchez-Fueyo
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Laurence A
authors.initials: LA
authors.lastname: Turka
authors.forename: Mohamed H
authors.initials: MH
authors.lastname: Sayegh
mesh_terms: D000818:Animals; D000945:Antigens, Differentiation, T-Lymphocyte / Q000737:chemistry* / Q000378:metabolism; D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D002470:Cell Survival; D016207:Cytokines / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D005802:Genes, MHC Class II; D006084:Graft Rejection; D006085:Graft Survival; D007108:Immune Tolerance; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000378:metabolism; D008198:Lymph Nodes / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D010641:Phenotype; D011506:Proteins / Q000378:metabolism*; D016038:Skin Transplantation / Q000379:methods*; D013601:T-Lymphocytes / Q000378:metabolism*; D018418:Th2 Cells; D013997:Time Factors; D023001:Transplantation Tolerance; D014184:Transplantation, Homologous / Q000379:methods*
chemical_list: D000945:Antigens, Differentiation, T-Lymphocyte; D016207:Cytokines; C556694:Icos protein, mouse; C400230:Icosl protein, mouse; D060945:Inducible T-Cell Co-Stimulator Ligand; D060889:Inducible T-Cell Co-Stimulator Protein; D011506:Proteins; D007371:Interferon-gamma