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 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.
Baker
D
D
Department of Pathology, Royal College of Surgeons of England, London.
Butler
D
D
Scallon
B J
BJ
O'Neill
J K
JK
Turk
J L
JL
Feldmann
M
M
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002455:Cell Division / Q000502:physiology; D002490:Central Nervous System / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000628:therapy; D005455:Fluorescent Antibody Technique; D007136:Immunoglobulins / Q000276:immunology; D007167:Immunotherapy; D051379:Mice; D008815:Mice, Inbred Strains; D010081:Oxazolone / Q000494:pharmacology; D018124:Receptors, Tumor Necrosis Factor / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000502:physiology*
D000911:Antibodies, Monoclonal; D007136:Immunoglobulins; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D010081:Oxazolone