Cell-type-restricted anti-cytokine therapy: TNF inhibition from one pathogenic source.

Autor:	Efimov GA; Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; Laboratory of Experimental Immunology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia;, Kruglov AA; Laboratory of Experimental Immunology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia; Research Group Inflammation Biology, German Rheumatism Research Center, a Leibniz Institute, 10117 Berlin, Germany; Department of Immunology, Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 199991, Russia;, Khlopchatnikova ZV; Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia;, Rozov FN; Laboratory of Experimental Immunology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia; Department of Immunology, Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 199991, Russia;, Mokhonov VV; Laboratory of Experimental Immunology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia;, Rose-John S; Institute of Biochemistry, Christian-Albrechts-University, 24118 Kiel, Germany;, Scheller J; Institute of Biochemistry and Molecular Biology II, Medical-Faculty, Heinrich-Heine-University, 40225 Duesseldorf, Germany;, Gordon S; Sir William Dunn School of Pathology, University of Oxford, Oxford OX1 3RF, United Kingdom;, Stacey M; School of Molecular and Cellular Biology, Faculty of Biological Sciences, University of Leeds, Leeds LS2 9JT, United Kingdom;, Drutskaya MS; Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia;, Tillib SV; Department of Immunology, Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 199991, Russia; Laboratory of Molecular Biotechnologies, Institute of Gene Biology, Russian Academy of Sciences, Moscow 119334, Russia., Nedospasov SA; Laboratory of Molecular Mechanisms of Immunity, Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow 119991, Russia; Laboratory of Experimental Immunology, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod 603950, Russia; Research Group Inflammation Biology, German Rheumatism Research Center, a Leibniz Institute, 10117 Berlin, Germany; Department of Immunology, Faculty of Biology and Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, Moscow 199991, Russia; sergei@nedos.net.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2016 Mar 15; Vol. 113 (11), pp. 3006-11. Date of Electronic Publication: 2016 Mar 02.
DOI:	10.1073/pnas.1520175113
Abstrakt:	Overexpression of TNF contributes to pathogenesis of multiple autoimmune diseases, accounting for a remarkable success of anti-TNF therapy. TNF is produced by a variety of cell types, and it can play either a beneficial or a deleterious role. In particular, in autoimmunity pathogenic TNF may be derived from restricted cellular sources. In this study we evaluated the feasibility of cell-type-restricted TNF inhibition in vivo. To this end, we engineered MYSTI (Myeloid-Specific TNF Inhibitor)--a recombinant bispecific antibody that binds to the F4/80 surface molecule on myeloid cells and to human TNF (hTNF). In macrophage cultures derived from TNF humanized mice MYSTI could capture the secreted hTNF, limiting its bioavailability. Additionally, as evaluated in TNF humanized mice, MYSTI was superior to an otherwise analogous systemic TNF inhibitor in protecting mice from lethal LPS/D-Galactosamine-induced hepatotoxicity. Our results suggest a novel and more specific approach to inhibiting TNF in pathologies primarily driven by macrophage-derived TNF.
Databáze:	MEDLINE
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