Background: To determine the role of tumor necrosis factor-alpha (TNF-alpha) receptor (TNFR) function in corneal allograft immunology.
Methods: Animals with gene-targeted deficiency in TNFR-I (p55-/-), TNFR-II (p75-/-), or combined TNFR-I/TNFR-II deficiency (p55-/-p75-/-) and their wild-type 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 recipients were followed biomicroscopically for signs of rejection, and survival data were analyzed by the Kaplan-Meier method.
Results: There was no discernible difference in survival of fully-mismatched BALB/c corneal grafts in p55-/- (n=12; P=0.76) or in double-knockout p55-/-p75-/- (n=13; P=0.41) as compared with wild-type C57BL/6.129 hosts. However, the survival of BALB/c allografts was lower in p75-/- (n=10; median survival 20 days) as compared with control C57BL/6 (n=30; median survival 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 compared with C57BL/6 (n=9) and C57BL/6.129 (n=10) wild-type controls, respectively. However, there was a profound enhancement in the survival of BALB.b allografts 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 grafts, and its selective suppression leads to enhancement of allograft survival. In contrast, TNFR-II (p75) function appears to be associated with enhanced 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 alloantigen-disparate grafts.