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Tumor necrosis factor (TNF) activity was inhibited during the development of actively-induced, chronic relapsing experimental allergic encephalomyelitis (CREAE) in Biozzi AB/H mice, using a mouse TNF-specific (TN3.19.12) antibody and bivalent human p55 and p75 TNF receptor-immunoglobulin (TNFR-Ig) fusion proteins. The development of disease could be 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 of clinical signs, further indicating an important role for TNF in pathogenic 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 supported by the observation that intracranial injection was significantly more potent than that administered systemically, for both antibody and TNFR-Ig fusion proteins. The fusion proteins were as effective as antibody at doses 10-100-fold lower than that used for antibody, reflecting their higher neutralizing capacity in vitro. Although treatment was not curative and relapse inevitably occurred in this model if treatment was not sustained, the data indicate that anti-TNF immunotherapy, especially within the CNS, can inhibit CREAE and may, therefore, be useful in the control of human neuroimmunological diseases.

Original publication

DOI

10.1002/eji.1830240916

Type

Journal article

Journal

European journal of immunology

Publication Date

09/1994

Volume

24

Pages

2040 - 2048

Addresses

Department of Pathology, Royal College of Surgeons of England, London.

Keywords

Central Nervous System, Animals, Mice, Inbred Strains, Mice, Encephalomyelitis, Autoimmune, Experimental, Oxazolone, Tumor Necrosis Factor-alpha, Immunoglobulins, Receptors, Tumor Necrosis Factor, Recombinant Fusion Proteins, Antibodies, Monoclonal, Fluorescent Antibody Technique, Immunotherapy, Cell Division