Systemic administration of AdrCTLA4–Ig prolongs experimental corneal allograft survival

Abstract

Abstract: : Purpose: To investigate the effect and mechanisms of blocking co–stimulatory signals on experimental corneal transplant survival by CTLA4–Ig gene therapy. Methods: A total of 18 female Lewis rats received 3.5 mm corneal grafts of DA donors. Recipients were randomly assigned to receive either (1) no therapy, (2) a single i.p. injection (1x109 pfu/animal) of AdCTL4–Ig or (3) a single Adß–Gal (control) i.p. injection one day before transplantation. The immunoregulatory effect of this treatment was examined by intracorneal cytokine expression using quantitative RT–PCR (day 12 post transplant) and standard MLR technique. Results: Treatment with i.p. injection of AdCTL4–Ig was effective (p<0.05) in prolonging the mean survival time of corneal grafts (26.3+/–6.7 days) compared to Adß–Gal application (13.6+/–1.1 days). Quantitative RT–PCR analysis of cornea explants (day 12 post transplant) revealed diminished expression of proinflammatory cytokines (IL–2, TNF–alpha) in the AdCTLA4–Ig group compared to Adß–Gal treated animals. Conclusions: Gene–based administration of CTLA4–Ig prolongs allograft survival by systemic application before grafting and is sufficient to down–regulate the systemic allo–specific immune response as well as the intra–corneal pro–inflammatory cytokine expression.

Keywords: adenovirus • cytokines/chemokines • gene/expression