Role of tumor necrosis factor receptors TNFR-I (p55) and TNFR-II (p75) in corneal transplantation

Background To determine the role of tumor necrosis factor-alpha (TNF-LU) re ceptor (TNFR) function in corneal allograft immunology. Methods. Animals with gene-targeted deficiency in TNFR-I (p55(-/-)), TNFR-I I (p75(-/-)), or combined TNFR-I/TNFR-II deficiency (p55(-/-)p75(-/-)) and their wildtype controls were used as recipients of fully-mismatched (BALB/c ; n=88) or multiple minor alloantigen-mismatched (BALB,b; n=62) orthotopic corneal transplants to determine the effect of selective deficiency in one or both TNF-alpha receptors on corneal allograft survival, Grafted recipien ts were followed biomicroscopically for signs of rejection, and survival da ta were analyzed by the Kaplan-Meier method. Results. There was no discernible difference in survival of fully-mismatche d BALB/c corneal grafts in p55(-/-) (n=12; P=0.76) or in double-knockout p5 5(-/-)p75(-/-) (n=13; P=0.41) as compared with wildtype C57BL/6.129 hosts. However, the survival of BALB/c allografts was lower in p75(-/-) (n=10; med ian survival 20 days) as compared with control C57BL/6 (n=30; median surviv al 30 days) hosts (P=0.02). In contrast, there was no discernible effect in survival of minor alloantigen-disparate BALB.b corneal grafts in p75(-/-) (n=13; P=0.95) or in combined p55(-/-)p75(-/-)(n=10; P=0.17) hosts as compa red with C57BL/6 (n=9) and C57BL/6.129 (n=10) wild-type controls, respectiv ely. However, there was a profound enhancement in the survival of BALB.b al lografts in p55(-/-) recipients (n=10; median survival 35 days) as compared to wild-type C57BL/6.129 (n=10; median survival 25 days) controls (P<0.01) . Conclusions. Our data suggest that the two TNF-alpha receptors largely play discrete roles in mediating rejection of murine corneal allografts, TNFR-I (p55) function seems to be integral to the rejection of minor-disparate gr afts, and its selective suppression leads to enhancement of allograft survi val. In contrast, TNFR-II (p75) function appears to be associated with enha nced survival of major histocompatibility complex disparate allografts, The combined deletion of TNFR functionality in p55(-/-)p75(-/-) confers no net advantage or disadvantage to major histocompatibility complex or minor all oantigen-disparate grafts.