Local or short-term systematic costimulatory molecule blockade prolongs rat corneal allograft survival

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 μg 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.