A recombinant fusion protein derived from dog hookworm inhibits autoantibody-induced dermal-epidermal separation ex vivo
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A recombinant fusion protein derived from dog hookworm inhibits autoantibody-induced dermal-epidermal separation ex vivo. / Kemmer, Annette; Bieber, Katja; Abadpour, Aida; Yu, Xinhua; Mitschker, Nina; Roth, Sara; Kauderer, Claudia; Ludwig, Ralf J; Seeger, Karsten; Köhl, Jörg; Zillikens, Detlef; Recke, Andreas.
in: EXP DERMATOL, Jahrgang 24, Nr. 11, 11.2015, S. 872-8.Publikationen: SCORING: Beitrag in Fachzeitschrift/Zeitung › SCORING: Zeitschriftenaufsatz › Forschung › Begutachtung
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TY - JOUR
T1 - A recombinant fusion protein derived from dog hookworm inhibits autoantibody-induced dermal-epidermal separation ex vivo
AU - Kemmer, Annette
AU - Bieber, Katja
AU - Abadpour, Aida
AU - Yu, Xinhua
AU - Mitschker, Nina
AU - Roth, Sara
AU - Kauderer, Claudia
AU - Ludwig, Ralf J
AU - Seeger, Karsten
AU - Köhl, Jörg
AU - Zillikens, Detlef
AU - Recke, Andreas
N1 - © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.
PY - 2015/11
Y1 - 2015/11
N2 - The proteins secreted by parasitic nematodes are evolutionarily optimized molecules with unique capabilities of suppressing the immune response of the host organism. Neutrophil inhibitory factor (NIF), which is secreted by the dog hookworm Ancylostoma caninum, binds to the β2 integrin CD11b/CD18, which is expressed on human neutrophils, eosinophils, monocytes and macrophages and inhibits neutrophil-dependent lung injury and neutrophil invasion of ischaemic brain tissue. Neutrophils are key players in the pathogenesis of subepidermal autoimmune blistering diseases (sAIBDs), and their pathogenic activities are crucially dependent on β2 integrin functionality. Based on the template of single-stranded, dimerizing antibody derivatives, which are already used in cancer treatment, we designed a novel biologic, NIF-IGHE-CH4, comprising NIF and the dimerizing but otherwise inert constant heavy subdomain 4 (CH4) of human IgE (IGHE). This molecule was evaluated in a variety of in vitro assays, demonstrating its ability to inhibit pathogenically relevant neutrophil functions such as migration, adhesion and spreading, and release of reactive oxygen species. Finally, we confirmed that NIF-IGHE-CH4 inhibits blister formation in an ex vivo assay of sAIBD. These results suggest that NIF-IGHE-CH4 is a novel potential anti-inflammatory drug for the treatment of neutrophil-mediated diseases such as sAIBDs. This study promotes the drugs from bugs concept and encourages further research and development focused on turning parasite proteins into useful anti-inflammatory biologics.
AB - The proteins secreted by parasitic nematodes are evolutionarily optimized molecules with unique capabilities of suppressing the immune response of the host organism. Neutrophil inhibitory factor (NIF), which is secreted by the dog hookworm Ancylostoma caninum, binds to the β2 integrin CD11b/CD18, which is expressed on human neutrophils, eosinophils, monocytes and macrophages and inhibits neutrophil-dependent lung injury and neutrophil invasion of ischaemic brain tissue. Neutrophils are key players in the pathogenesis of subepidermal autoimmune blistering diseases (sAIBDs), and their pathogenic activities are crucially dependent on β2 integrin functionality. Based on the template of single-stranded, dimerizing antibody derivatives, which are already used in cancer treatment, we designed a novel biologic, NIF-IGHE-CH4, comprising NIF and the dimerizing but otherwise inert constant heavy subdomain 4 (CH4) of human IgE (IGHE). This molecule was evaluated in a variety of in vitro assays, demonstrating its ability to inhibit pathogenically relevant neutrophil functions such as migration, adhesion and spreading, and release of reactive oxygen species. Finally, we confirmed that NIF-IGHE-CH4 inhibits blister formation in an ex vivo assay of sAIBD. These results suggest that NIF-IGHE-CH4 is a novel potential anti-inflammatory drug for the treatment of neutrophil-mediated diseases such as sAIBDs. This study promotes the drugs from bugs concept and encourages further research and development focused on turning parasite proteins into useful anti-inflammatory biologics.
KW - Animals
KW - Cell Adhesion
KW - Drug Evaluation, Preclinical
KW - Glycoproteins
KW - Helminth Proteins
KW - Humans
KW - Membrane Proteins
KW - Neutrophils
KW - Reactive Oxygen Species
KW - Recombinant Fusion Proteins
KW - Skin Diseases, Vesiculobullous
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1111/exd.12804
DO - 10.1111/exd.12804
M3 - SCORING: Journal article
C2 - 26174039
VL - 24
SP - 872
EP - 878
JO - EXP DERMATOL
JF - EXP DERMATOL
SN - 0906-6705
IS - 11
ER -
