CRITICAL ROLE OF PERIPHERAL-BLOOD PHAGOCYTES AND THE INVOLVEMENT OF COMPLEMENT IN TUMOR-NECROSIS-FACTOR ENHANCEMENT OF PASSIVE COLLAGEN-ARTHRITIS

Studies have implicated tumour necrosis factor-alpha (TNF-alpha) in ty pe-II collagen (CII)-induced arthritis (CIA), a well established anima l model of human rheumatoid arthritis. Precisely how TNF is involved i n CIA is not yet clear. In this study the effects of TNF on CIA were e xamined, independent of its potential effects on the immune response, by performing peri-articular injection of TNF in combination with pass ive immunization of rats. A sub-arthritic dose (5 mg) of affinity-puri fied anti-CII IgG, which alone was insufficient to induce spontaneous clinical arthritis, was used throughout the study. Obvious clinical ar thritis that persisted for several days was rapidly induced by injecti ons of 100 ng TNF into hindpaws of rats that were passively immunized shortly before the TNF injection. Injections of TNF in non-immunized c ontrol rats did not induce clinical arthritis, nor did buffer-only inj ections in passively immunized controls. The clinical arthritic respon se was a local phenomenon, limited only to the TNF-injected hindpaws. No swelling was observed in the opposite, buffer-injected hindpaws, in dicating the effects of TNF were not systemic. Depletion of peripheral blood phagocytes with anti-rat neutrophil antiserum before passive im munization completely abolished the ability of TNF to induce clinical arthritis, identifying phagocytic cells as the essential target cells in evoking this arthritic response. A role for complement activation w as also demonstrated in this model through the use of a soluble recomb inant version of CD35, the cell surface complement receptor type-1 (sC R1, BRL55730), which significantly reduced TNF-induced arthritis in ph agocyte-replete rats.