CONTROL OF ESTABLISHED EXPERIMENTAL ALLERGIC ENCEPHALOMYELITIS BY INHIBITION OF TUMOR-NECROSIS-FACTOR (TNF) ACTIVITY WITHIN THE CENTRAL-NERVOUS-SYSTEM USING MONOCLONAL-ANTIBODIES AND TNF RECEPTOR IMMUNOGLOBULIN FUSION PROTEINS

Tumor necrosis factor (TNF) activity was inhibited during the developm ent of actively-induced, chronic relapsing experimental allergic encep halomyelitis (CREAE) in Biozzi AB/H mice, using a mouse TNF-specific ( TN3.19.12) antibody and bivalent human p55 and p75 TNF receptor-immuno globulin (TNFR-Ig) fusion proteins. The development of disease could b e inhibited when repeated doses of antibody were administered prior to the anticipated onset. It has now also been shown that a therapeutic effect is evident even when antibody is administered after the onset o f clinical signs, further indicating an important role for TNF in path ogenic effector mechanisms in CREAE. Although biologically-active TNF was not detected in the circulation, TNF-alpha was detected in lesions within the central nervous system (CNS). This suggested that the CNS may be the main site for TNF-specific immunomodulation and was support ed by the observation that intracranial injection was significantly mo re potent than that administered systemically, for both antibody and T NFR-Ig fusion proteins. The fusion proteins were as effective as antib ody at doses 10-100-fold lower than that used for antibody, reflecting their higher neutralizing capacity in vitro. Although treatment was n ot curative and relapse inevitably occurred in this model if treatment was not sustained, the data indicate that anti-TNF immunotherapy, esp ecially within the CNS, can inhibit CREAE and may, therefore, be usefu l in the control of human neuroimmunological diseases.