title: Inhibition of corneal allograft reaction by CTLA4-Ig.
abstract: BACKGROUND
  Activation of T cells requires both the interaction of T-cell receptor with major histocompatibility complex on the antigen-presenting cell and costimulatory signals, for instance the B7 antigens expressed on antigen-presenting cells and the CD28 molecule expressed on T cells. A recombinant fusion protein, CTLA4-Ig, has been produced that contains the extracellular domain of human CTLA4 fused to IgG1 constant region and that binds the B7 molecule with high affinity. Blocking the CD28/B7 interaction with CTLA4-Ig inhibits T cell activation in vitro and in vivo.
  
  
  METHODS
  We used CTLA4-Ig in a fully MHC-mismatched mouse keratoplasty model. The animals were divided into four groups: (1) no treatment, (2) intraperitoneal treatment with 130 micrograms CTLA4-Ig, (3) intraperitoneal treatment with 300 micrograms CTLA4-Ig, (4) subconjunctival treatment with 290 micrograms CTLA4-Ig.
  
  
  RESULTS
  The allograft reaction occurred in untreated animals between days 12 and 16 (mean 13.5). While topical application of CTLA4-Ig seemed to shorten the graft survival (mean 11.6 days) and systemic application of 130 micrograms had no influence (mean 14.0), only intraperitoneal injection of 300 micrograms of CTLA4-Ig prolonged the survival of allografts (mean > 20 days) (P < 0.01).
  
  
  CONCLUSIONS
  CTLA4-Ig prolonged significantly the survival of corneal allografts in a fully MHC-mismatched mouse keratoplasty model, but the small antigen load of the corneal transplant and the anterior chamber-associated immune deviation (ACAID) may have a disadvantage to induce tolerance in this model of CTLA4-Ig therapy.
authors.affiliation: Department of Ophthalmology, Benjamin Franklin Medical Center, Free University of Berlin, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Hoffmann
authors.forename: E P
authors.initials: EP
authors.lastname: Zhang
authors.forename: T
authors.initials: T
authors.lastname: Pohl
authors.forename: U
authors.initials: U
authors.lastname: Kunzendorf
authors.forename: J
authors.initials: J
authors.lastname: Wachtlin
authors.forename: S
authors.initials: S
authors.lastname: Bulfone-Paus
mesh_terms: D000069594:Abatacept; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000008:administration & dosage / Q000494:pharmacology*; D060908:CTLA-4 Antigen; D016039:Corneal Transplantation; D004333:Drug Administration Routes; D005260:Female; D005500:Follow-Up Studies; D006084:Graft Rejection / Q000517:prevention & control*; D006085:Graft Survival; D006801:Humans; D018796:Immunoconjugates; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000494:pharmacology*; D008285:Major Histocompatibility Complex / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000494:pharmacology; D014184:Transplantation, Homologous
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C556707:Ctla4 protein, mouse; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D011993:Recombinant Fusion Proteins; D000069594:Abatacept