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

Authors: Thiel, Michael A; Steiger, Jurg U¹; O'Connell, Philip J²; Lehnert, Anne M²; Coster, Douglas J³; Williams, Keryn A³

Source: Clinical & Experimental Ophthalmology, Volume 33, Number 2, April 2005 , pp. 176-180(5)

Publisher: Wiley-Blackwell

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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 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.

Keywords: CD28 antigen; corneal transplantation; CTLA4-Ig; rats

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1442-9071.2005.00974.x

Affiliations: 1: Department of Transplantation Immunology and Nephrology, University of Basel, Basel, Switzerland 2: National Pancreas Transplantation Unit, Westmead Hospital, Sydney, New South Wales, Australia 3: Department of Ophthalmology, Flinders University of South Australia, Adelaide, South Australia

Publication date: 2005-04-01

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

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