Dominant-negative inhibitors of soluble TNF attenuate experimental arthritis without suppressing innate immunity to infection

Autor: Paul Michael Steed, Araz Eivazi, James Kung, Stephen K. Doberstein, François Erard, Jonathan Zalevsky, Laure Janot, Sergei A. Ezhevsky, Bernhard Ryffel, Christopher D. O'Brien, David E. Szymkowski, Duc-Hanh T. Nguyen, Thomas Secher
Přispěvatelé: Xencor, Immunologie et Embryologie Moléculaires (IEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS)
Jazyk: angličtina
Rok vydání: 2007
Předmět:
Male
MESH: Arthritis
Experimental
medicine.medical_treatment
Arthritis
MESH: Recombinant Proteins
Mice
0302 clinical medicine
Immunology and Allergy
Listeriosis
MESH: Animals
0303 health sciences
Mice
Inbred BALB C
U937 cell
U937 Cells
Caspase Inhibitors
Recombinant Proteins
3. Good health
Cytokine
Mice
Inbred DBA
Caspases
[SDV.IMM]Life Sciences [q-bio]/Immunology
Tumor necrosis factor alpha
Female
MESH: Membrane Proteins
medicine.symptom
Inflammation Mediators
MESH: Listeria Infections
MESH: Cell Line
Tumor
Immunology
MESH: Inflammation Mediators
MESH: Mice
Inbred BALB C
Inflammation
Biology
MESH: U937 Cells
03 medical and health sciences
Immune system
Immunity
Cell Line
Tumor
Paracrine Communication
medicine
Animals
Humans
MESH: Paracrine Communication
MESH: Mice
030304 developmental biology
MESH: Immunity
Natural
Innate immune system
MESH: Caspases
MESH: Humans
MESH: Mice
Inbred DBA
Tumor Necrosis Factor-alpha
Interleukin-8
Membrane Proteins
medicine.disease
Arthritis
Experimental
Immunity
Innate
MESH: Male
MESH: Interleukin-8
MESH: Solubility
Solubility
MESH: Tumor Necrosis Factor-alpha
MESH: Female
030217 neurology & neurosurgery
Zdroj: Journal of Immunology
Journal of Immunology, Publisher : Baltimore : Williams & Wilkins, c1950-. Latest Publisher : Bethesda, MD : American Association of Immunologists, 2007, 179 (3), pp.1872-83
Europe PubMed Central
Scopus-Elsevier
ISSN: 0022-1767
1550-6606
Popis: TNF is a pleiotropic cytokine required for normal development and function of the immune system; however, TNF overexpression also induces inflammation and is associated with autoimmune diseases. TNF exists as both a soluble and a transmembrane protein. Genetic studies in mice have suggested that inflammation in disease models involves soluble TNF (solTNF) and that maintenance of innate immune function involves transmembrane TNF (tmTNF). These findings imply that selective pharmacologic inhibition of solTNF may be anti-inflammatory and yet preserve innate immunity to infection. To address this hypothesis, we now describe dominant-negative inhibitors of TNF (DN-TNFs) as a new class of biologics that selectively inhibits solTNF. DN-TNFs blocked solTNF activity in human and mouse cells, a human blood cytokine release assay, and two mouse arthritis models. In contrast, DN-TNFs neither inhibited the activity of human or mouse tmTNF nor suppressed innate immunity to Listeria infection in mice. These results establish DN-TNFs as the first selective inhibitors of solTNF, demonstrate that inflammation in mouse arthritis models is primarily driven by solTNF, and suggest that the maintenance of tmTNF activity may improve the therapeutic index of future anti-inflammatory agents.
Databáze: OpenAIRE
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