Immunomodulation after keratoplasty by CTLA4-Ig and anti-CD154 antibodies

Background. The immunoreaction after corneal transplantation is caused by the T cell receptor interacting with the major histocompatibility complex (MHC) receptor of the antigen-presenting cell. The signal is amplified by the CD4 receptor and the costimulatory signal interactions of CD28-B7 and CD40-CD154. We investigated the influence of costimulatory signal blocking on corneal transplant survival in mice. Methods. Seven groups of 6 BALB/c mice received an orthotopic corneal transplant from C3H mice differing in minor and major MHC and were postoperatively treated as follows: (1) 80 mug of CTLA4 fusion protein intra peritoneally (i.p.) for 6 days; (2) 50 mul of PBS i.p.for 6 days; (3) 1 mg of Solu-Decortin H i.p.for 5 days+dexamethasone AT 0.1% for 35 days; (4) therapy (3)+50 mug of CTLA4 fusion protein i.p.for 6 days; (5) CTLA4-Ig as in (1)+15 mug of anti-CD154 subconjunctivally (s.c.) on days 0, 2,4,6, and 8; (6) CTLA4-Ig as in (1)+25 mug of anti-CD154 s.c. for 9 days; and (7) 25 mul of PBS s.c. for 9 days. Results. All animals had an immunoreaction on the following days: (1) day 18+/-3.1; (2) day 13.6+/-1.6; (3) day 48+/-6.6; (4) day 65+/-41; (5) day 23.5+/-8.5; (6) day 16.2+/-3.6; (7) day 13.8+/-2.7. Conclusion. The significant prolongation of transplant survival achieved by corticosteroids alone (P<0.001) is again significantly increased by combining them with CTLA4-Ig (P<0.001). Specific immunotherapy combined with nonspecific steroid therapy may also improve clinical corneal transplantation results. Compared to the two control groups, CTLA4-Ig and anti-CDI 54 only influenced transplant survival at a low dosage (P<0.001).