title: Modulation of costimulation by CD28 and CD154 alters the kinetics and cellular characteristics of corneal allograft rejection.
abstract: OBJECTIVE
  To examine the effect of modulating the lymphocyte costimulation pathways through CD28 and CD154 (CD40 ligand) in a model of corneal allograft rejection, with particular interest in changes in the observed features of rejection.
  
  
  METHODS
  CD28 knock-out (CD28KO) and wild-type BALB/c control mice received corneal grafts from fully major histocompatibility complex (MHC)-mismatched C3H donors and were treated with CTLA4-Ig and/or anti-CD154 Ab on days 0, 2, and 4 after transplantation. Proliferation of BALB/c and CD28KO T cells in response to C3H stimulators was examined in a mixed lymphocyte reaction (MLR) in the presence of CTLA4-Ig or anti-CD154 Ab.
  
  
  RESULTS
  Corneal allograft survival in wild-type BALB/c mice (median survival time [MST] 14 days) was significantly prolonged by blockade of the costimulatory pathways with CTLA4-Ig or anti-CD154 Ab (MST 21 days and 25 days respectively). MST in recipients treated with CTLA4-Ig and anti-CD154 Ab in combination was 29 days, not significantly longer than graft survival in single-treatment groups. MST in CD28KO recipients was 46 days and was not prolonged after treatment with anti-CD154 Ab (MST, 43 days). A similar result was found in the MLR, in which anti-CD154 Ab had no effect on proliferation of CD28KO compared with wild-type T cells. In CTLA4-Ig-treated CD28KO, grafts were rejected at an accelerated tempo, similar to that in wild-type BALB/c recipients (MST 16 days). More severe graft injury after the onset of rejection in untreated allograft recipients was accompanied by a higher number of graft-infiltrating CD45(+) cells, but similar proportions of CD4(+) and CD8(+) cells.
  
  
  CONCLUSIONS
  CD28- and CD154-mediated costimulation have significant functional roles in corneal allograft rejection. Agents that modulate CD28 and CD154 pathways delay onset and reduce the severity of observed allograft rejection. However, their use in combination did not have an additive effect, MLR data indicating that the CD40-CD154 system depends on a functioning CD28 costimulatory pathway.
authors.affiliation: Department of Immunology, Division of Medicine, Faculty of Medicine, Imperial College of Science, Technology and Medicine, Hammersmith Hospital, London, United Kingdom.
authors.forename: Navid
authors.initials: N
authors.lastname: Ardjomand
authors.forename: James C
authors.initials: JC
authors.lastname: McAlister
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Rogers
authors.forename: Peng H
authors.initials: PH
authors.lastname: Tan
authors.forename: Andrew J T
authors.initials: AJ
authors.lastname: George
authors.forename: Daniel F P
authors.initials: DF
authors.lastname: Larkin
mesh_terms: D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D018106:CD28 Antigens / Q000502:physiology*; D023201:CD40 Ligand / Q000502:physiology*; D016466:CHO Cells; D003315:Cornea / Q000276:immunology / Q000473:pathology; D016039:Corneal Transplantation / Q000276:immunology* / Q000473:pathology; D006224:Cricetinae; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006084:Graft Rejection / Q000276:immunology* / Q000473:pathology; D006085:Graft Survival / Q000502:physiology; D018796:Immunoconjugates / Q000008:administration & dosage; D007700:Kinetics; D007959:Lymphocyte Culture Test, Mixed; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D018345:Mice, Knockout; D013601:T-Lymphocytes / Q000276:immunology; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D018796:Immunoconjugates; D023201:CD40 Ligand; D000069594:Abatacept