title: Blockade of CD28/B7-2 costimulation inhibits experimental obliterative bronchiolitis in rat tracheal allografts: suppression of helper T cell type1-dominated immune response.
abstract: T cell activation is a proximal event in the initiation of chronic rejection that may ultimately lead to obliterative bronchiolitis (OB) after lung transplantation. In addition to primary signals generated by the T cell receptor, T cell activation relies on costimulatory signals, of which the most important are mediated via interaction between CD28 and its ligands B7-1 and B7-2. In nontreated rat tracheal allografts, B7-2, but not B7-1, expression peaked 10 d after transplantation, unlike in syngeneic grafts, where no B7-2 upregulation was observed. Selective blockade of the CD28/B7-1 T cell costimulatory pathway by a mutant form of CTLA4Ig (cytotoxic T lymphocyte antigen 4 immunoglobulin), CTLA4IgY100F, did not affect epithelial injury or degree of luminal occlusion in rat tracheal allografts. Treatment with CTLA4Ig fusion protein, which blocks both CD28/B7-1 and CD28/B7-2 interaction, significantly delayed the development of epithelial injury and airway occlusion. Immunohistochemical analyses of allografts showed that selective inhibition of the CD28/B7-1 pathway did not affect cytokine expression. In contrast, treatment with CTLA4Ig was associated with a significant decrease in the intragraft production of tumor necrosis factor alpha, interleukin 2, and interferon gamma, as well as slightly increased intragraft expression of interleukin 10. In conclusion, CTLA4Ig-mediated costimulatory blockade delays epithelial injury and attenuates obliterative changes and is associated with marked suppression of helper T cell type 1 (Th1)-dominated cytokine response. These observations emphasize the role of the CD28/B7-2 costimulatory pathway in regulating proinflammatory and Th1 cytokine responses and thereby in the development of epithelial and graft injury gradually leading to obliteration of the airway lumen.
authors.affiliation: Cardiopulmonary Research Group, Transplantation Laboratory, University of Helsinki, Haartmaninkatu 3, 00029 Helsinki, Finland. jussi.tikkanen@helsinki.fi
authors.forename: Jussi M
authors.initials: JM
authors.lastname: Tikkanen
authors.forename: Karl B
authors.initials: KB
authors.lastname: Lemström
authors.forename: Petri K
authors.initials: PK
authors.lastname: Koskinen
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology*; D051940:B7-2 Antigen; D001989:Bronchiolitis Obliterans / Q000276:immunology* / Q000473:pathology; D018106:CD28 Antigens / Q000378:metabolism*; D060908:CTLA-4 Antigen; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors*; D051381:Rats; D011919:Rats, Inbred Strains; D011920:Rats, Inbred WF; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects*; D014132:Trachea / Q000276:immunology / Q000473:pathology / Q000637:transplantation*; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D051940:B7-2 Antigen; D018106:CD28 Antigens; D060908:CTLA-4 Antigen; C497966:Cd86 protein, rat; C556708:Ctla4 protein, rat; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D008562:Membrane Glycoproteins; D000069594:Abatacept