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Augmentation of anti-cytokine immunotherapy by combining neutralizing monoclonal antibodies to interferon- and the interferon- receptor: protection in endotoxin shock

Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, USA, Department of Pathology and Oncology, and The Cancer Center, University of Kansas Medical Center, Kansas City, USA

S.W. Russell

Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, USA, Department of Pathology and Oncology, and The Cancer Center, University of Kansas Medical Center, Kansas City, USA

D.C. Morrison

Department of Microbiology, Molecular Genetics and Immunology, University of Kansas Medical Center, Kansas City, USA, Department of Pathology and Oncology, and The Cancer Center, University of Kansas Medical Center, Kansas City, USA

We have employed neutralizing monoclonal antibodies to mouse interferon- (IFN) and to the receptor for mouse IFNy in studies designed to assess the protective efficacy of each of these monoclonals, administered either separately or in combination, in endotoxin-induced lethality. While pretreatment with either antibody alone, at doses of 200 µg per mouse, provided limited protection (70-50% lethality) in comparison to non-neutralizing antibody controls (100% lethality), the two monoclonal antibodies administered together provided a substantially greater level of protection (17% lethality). Although administration of 100 µg per mouse of either monoclonal alone was not protective (more than 65% lethality), a combination of both antibodies at this dose provided significant protection (19% lethality). In addition, administration of both antibodies 30 min post-endotoxin challenge also demonstrated significant protection in comparison to single antibody immunotherapy. In vitro studies using mouse peritoneal macrophages stimulated with LPS and IFNy have established confirmatory data for a synergistic effect of neutralizing antibody to IFNy and the IFN receptor in inhibiting macrophage activation as assessed by production of nitric oxide. These results provide a strong rationale for dual targeting of ligand and receptor in single cytokine immunotherapy.

Journal of Endotoxin Research, Vol. 1, No. 1, 45-51 (1994)
DOI: 10.1177/096805199400100108


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