title: Local or short-term systemic costimulatory molecule blockade prolongs rat corneal allograft survival.
abstract: BACKGROUND
  Costimulatory molecule blockade with antibody-based immunosuppressive agents has been shown to prolong the survival of many types of allograft. The effects were evaluated of local costimulatory molecule blockade with different CTLA4-Ig constructs and of systemic, short-term treatment with an anti-CD28 monoclonal antibody on orthotopic corneal allograft survival in the rat.
  
  
  METHODS
  Adult Fischer-344 rats underwent Wistar-Furth orthotopic corneal grafts. The rats were treated with two different CTLA4-fusion proteins administered intraocularly in the perioperative period, or systemically with anti-CD28 monoclonal antibody JJ319. Corneal graft survival was determined by daily slit-lamp examination. The day of rejection was defined as the first postoperative day on which the iris margin was no longer clearly visible through the corneal graft.
  
  
  RESULTS
  Local administration of CTLA4-fusion protein with mutated immunoglobulin constant region domains via a single perioperative intraocular injection prolonged corneal graft survival modestly but significantly (P < 0.05), in contrast to a CTLA4-fusion protein with wild-type immunoglobulin domains, which had no effect on graft survival (P > 0.5). Systemic short-term administration of 400 microg total of an anti-CD28 monoclonal antibody also prolonged corneal graft survival significantly (P < 0.05) and was more effective than systemic administration of 2 mg total of CTLA4-fusion protein (P < 0.05).
  
  
  CONCLUSIONS
  Local administration of CTLA4-fusion protein with mutated (non-functional) immunoglobulin domains or systemic administration of anti-CD28 monoclonal antibody can prolong corneal allograft survival in the rat.
authors.affiliation: Department of Ophthalmology, Flinders University of South Australia, Adelaide, South Australia, Australia.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Thiel
authors.forename: Jurg U
authors.initials: JU
authors.lastname: Steiger
authors.forename: Philip J
authors.initials: PJ
authors.lastname: O'Connell
authors.forename: Anne M
authors.initials: AM
authors.lastname: Lehnert
authors.forename: Douglas J
authors.initials: DJ
authors.lastname: Coster
authors.forename: Keryn A
authors.initials: KA
authors.lastname: Williams
mesh_terms: D000069594:Abatacept; D000287:Administration, Topical; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D018106:CD28 Antigens / Q000276:immunology*; D016039:Corneal Transplantation; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D006085:Graft Survival / Q000187:drug effects*; D018796:Immunoconjugates / Q000627:therapeutic use*; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011920:Rats, Inbred WF; D014184:Transplantation, Homologous
chemical_list: D000911:Antibodies, Monoclonal; D018106:CD28 Antigens; D018796:Immunoconjugates; D000069594:Abatacept