Experimental Study On Molecular Mechanisms Of A Small Non-peptidic CD4/MHC-â…¡ Inhibitor In Prevention Of Mouse Corneal Allograft Rejection

Backgroud: keratonosus is the main eye diseases that can lead to blind. Keratoplasty is the important vision restoration operation that can treat the corneal blind. Corneal transplantation is the most common form of solid tissue transplantation in humans and is characterized by an unusually high success in graft survival. Although the cornea is generally considered an immuneprivileged tissue, allograft rejection is still a main cause of graft failure in high-risk conditions.Topical and systemic immunosuppressivedrugs such as steroids, and cyclosporine are not adequate to prevent allograft rejection after penetrating keratoplasty (PKP) and often produce severe local and systemic adverse effects. HLA Class I matching may help where it is available, whereas it is difficult to predict. Current immunosuppressive and immunomodulatory Pharmaceuticals used in the prevention and treatment of corneal allograft rejection have significant limitations from the standpoint of both efficacy and side effects. Despite these measures, the results of corneal transplantation have not shown the improvement seen in solid organ transplantation.To obtain the long term survival of corneal grafts, especially in high risk recipients, it is necessary to search for new and effective immunosuppressive approaches with minimal undesirable side effects. Objective: To determine the differential gene expression of chemokine species of grafts in the early pre-rejection postoperative period after corneal transplantation. To determine the effectiveness of treatment with J2 (a small non-peptidic CD4 inhibitor) after penetrating keratoplasty in model of mouse recipients.Methods: The donor and acceptor corneas of two groups of mice were studied after receiving an allo- (C57BL/10 to BALB/c) or autograft (BALB/c ). Autograft were treated as control group. Half of mice receiving allograft treated as blank group and half were treated with orally J2. The drugs were delivered for 12 days beginning atthe day of transplantation. Graft rejection was observed by biomicroscopy. Grafted eyes were removed at specified times and examined histologically. NF-kB activation was assayed using ELISA-based transactivation TransAM kit. The expression of FasL mRNA, Icos mRNA in cornea and Icos mRNA, Foxp3 mRNA in spleen were analyzed by real-time quantitative polymerase chain reaction(QRT-PCR). Result: Comeal rejection was characterized by opaque corneas with prominent neovasculanzation.The average transplant survival time in the allograft control was (12.57±1.27)d. NF-kB activation and expression of FasL mRNA and Icos mRNA in cornea was significantly increased and Foxp3 mRNA in spleen was decreased compared to autograft following comeal transplantation. The average transplant survival time in the allograft treatment with J2 led to a statistically prolongation of transplant survival to(40.25±8.78)d (P < 0.01). NF-kB activation and expression of FasL mRNA and Icos mRNA in cornea was decreased and Foxp3 mRNA in spleen was increased compared with control (P < 0.01).Conclusion: The results indicated that J2 could prolong comeal graft survival from rejection in mouse and inhibit immune responses.