title: CTLA4ig induces long-term graft survival of allogeneic skin grafts and totally inhibits T-cell proliferation in LFA-1-deficient mice.
abstract: BACKGROUND
  It was recently shown that some strains of mice are capable of rejecting transplants independently of B7 and CD40L signaling and that this rejection is mediated by CD8(+) T cells. LFA-1 is known to be important for CD8(+) T cell activation and cytotoxicity. Therefore, blockade of LFA-1 could be important in overcoming costimulation blockade, CD8(+) T-cell-mediated, resistant rejection. The purpose of this study was to define the effect of combined blockade of the LFA-1 and B7 costimulation pathways on the alloimmune response in mice.
  
  
  METHODS
  Allogeneic skin transplantation was performed using BALB/c mice as donors and C57BL/6J wild-type or LFA-1-deficient (CD11a(-/-)) mice as recipients. CTLA4Ig or anti-LFA-1 was administered either as an induction or a prolonged therapy. Mixed lymphocyte reactions were conducted to study the effect of CTLA4Ig on T-cell proliferation in CD11a(-/-) mice.
  
  
  CONCLUSIONS
  Administration of CTLA4Ig completely inhibits CD11a(-/-) T-cell proliferation in response to alloantigens and significantly improved skin allograft survival in CD11a(-/-) mice. Prolonged treatment of wild-type recipient mice with CTLA4Ig and anti-LFA-1 increased median survival time to 45.5 days compared with 16 days after induction therapy, but it was not sufficient to induce indefinite allograft survival in this model.
authors.affiliation: Department of Nephrology and Transplantation, Malmö University Hospital, Lund University, S-205 02 Malmö, Sweden.
authors.forename: Helene
authors.initials: H
authors.lastname: Malm
authors.forename: Matthias
authors.initials: M
authors.lastname: Corbascio
authors.forename: Cecilia
authors.initials: C
authors.lastname: Osterholm
authors.forename: Shannon
authors.initials: S
authors.lastname: Cowan
authors.forename: Christian P
authors.initials: CP
authors.lastname: Larsen
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Pearson
authors.forename: Henrik
authors.initials: H
authors.lastname: Ekberg
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000494:pharmacology*; D060908:CTLA-4 Antigen; D004305:Dose-Response Relationship, Drug; D006084:Graft Rejection; D006085:Graft Survival / Q000187:drug effects*; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008213:Lymphocyte Activation / Q000187:drug effects*; D016169:Lymphocyte Function-Associated Antigen-1 / Q000502:physiology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D012086:Reoperation; D016038:Skin Transplantation / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D016169:Lymphocyte Function-Associated Antigen-1; D000069594:Abatacept