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-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.
Yamada
J
J
Department of Ophthalmology, Harvard Medical School, Boston, Massachusetts 02114, USA.
Streilein
J W
JW
Dana
M R
MR
D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D016039:Corneal Transplantation / Q000276:immunology*; D006084:Graft Rejection / Q000276:immunology; D006085:Graft Survival / Q000276:immunology; D007519:Isoantigens / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000502:physiology*; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II
D015703:Antigens, CD; D007519:Isoantigens; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II