IL-1 and TNF receptor-deficient mice show decreased. inflammation in an immune complex model of uveitis

PURPOSE. TO determine the role of interleukin-1 (IL-1) and tumor necrosis f actor-alpha (TNF-alpha) in the induction of uveitis by a reverse passive Ar thus reaction (RP,VI). METHODS. Human serum albumin (HSA) antiserum a-as injected into the vitreou s of "knockout" or "double knockout" mice genetically deficient in IL-1 rec eptor type I (IL-1RI(-/-)), TNF receptors p55 and p75 (TNFR p55(-/-)/p75(-/ -)), IL-1RI and TNFR p55 (IL-1RI(-/-)/TNFR p55(-/-)), and controls. Twenty- four hours later, animals were challenged with intravenous HSA. Eyes were e nucleated 4 hours after antigen challenge, and inflammation was quantitated by counting cells on histologic sections. Interleukin-6 in aqueous humor w as measured with a B9 cell bioassay. The distribution of immune complexes i n eyes was observed by immunohistochemical staining for IgG and complement component C3. RESULTS. Four hours after antigen challenge, immune complexes were localize d at the ciliary body and iris of receptor-deficient mice. A transient uvei tis was most severe at this time. A significant reduction in the median num ber of infiltrating cells was found in TNFR p55(-/-)/p75(-/-) mice (4.8, n = 15), compared with controls (14.2. n = 20, P < 0.05). The median number o f infiltrating cells was significantly reduced in IL-1RI(-/-) mice (knockou t 2.6, n = 11; controls 7.4, n = 8, P < 0.005), Interleukin-1RI(-/-)/TNFR p 55(-/-) mice had a strong reduction in infiltrating cells (knockout 1.6, n = 11; controls 27.3, n = 12, P = 0.002). Interleukin-6 activity in aqueous humor was reduced in IL-1RT(-/-)/TNFR p55(-/-) mice <P = 0.03) but not in T NFR p55(-/-)p75(-/-) (P = 0.40) mice. Most IL-1RI(-/-) mice had no detectab le aqueous humor IL-6, but this group was not statistically different from controls. CONCLUSIONS. In contrast to endotoxin-induced uveitis, both IL-1 and TNF ap pear to have critical roles in RPAR uveitis. When receptors for these cytok ines were deleted, the severity of immune complex-induced uveitis was profo undly reduced.