title: Neuroimmune semaphorin 4A as a drug and drug target for asthma.
abstract: Neuroimmune semaphorin 4A (Sema4A) has been shown to play an important costimulatory role in T cell activation and regulation of Th1-mediated diseases such as multiple sclerosis (MS), experimental autoimmune encephalomyelitis (EAE), and experimental autoimmune myocarditis (EAM). Sema4A has three functional receptors, Tim-2 expressed on CD4+ T cells, Th2 cells in particular, and Plexin B1 and D1 predominantly expressed on epithelial and endothelial cells, correspondingly. We recently showed that Sema4A has a complex expression pattern in lung tissue in a mouse model of asthma. We and others have shown that corresponding Plexin expression can be found on immune cells as well. Moreover, we demonstrated that Sema4A-deficient mice displayed significantly higher lung local and systemic allergic responses pointing to its critical regulatory role in the disease. To determine the utility of Sema4A as a novel immunotherapeutic, we introduced recombinant Sema4A protein to the allergen-sensitized WT and Sema4A(-/-) mice before allergen challenge. We observed significant reductions in the allergic inflammatory lung response in Sema4A-treated mice as judged by tissue inflammation including eosinophilia and mucus production. Furthermore, we demonstrated that in vivo administration of anti-Tim2 Ab led to a substantial upregulation of allergic inflammation in WT mouse lungs. These data highlight the potential to develop Sema4A as a new therapeutic for allergic airway disease.
authors.affiliation: Center for Vascular and Inflammatory Diseases, Greenebaum Cancer Center, University of Maryland School of Medicine, Baltimore, MD, USA.
authors.forename: G
authors.initials: G
authors.lastname: Mogie
authors.forename: K
authors.initials: K
authors.lastname: Shanks
authors.forename: E H
authors.initials: EH
authors.lastname: Nkyimbeng-Takwi
authors.forename: E
authors.initials: E
authors.lastname: Smith
authors.forename: E
authors.initials: E
authors.lastname: Davila
authors.forename: M M
authors.initials: MM
authors.lastname: Lipsky
authors.forename: L J
authors.initials: LJ
authors.lastname: DeTolla
authors.forename: A D
authors.initials: AD
authors.lastname: Keegan
authors.forename: S P
authors.initials: SP
authors.lastname: Chapoval
mesh_terms: D000485:Allergens / Q000276:immunology; D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D001249:Asthma / Q000276:immunology*; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D002452:Cell Count; D016207:Cytokines / Q000097:blood; D005260:Female; D006098:Granulocytes / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D010047:Ovalbumin / Q000276:immunology; D011994:Recombinant Proteins / Q000494:pharmacology; D039961:Semaphorins / Q000276:immunology* / Q000494:pharmacology
chemical_list: D000485:Allergens; D000906:Antibodies; D016207:Cytokines; D008565:Membrane Proteins; D011994:Recombinant Proteins; C534721:Sema4A protein, mouse; D039961:Semaphorins; C442242:Timd2 protein, mouse; D010047:Ovalbumin
keywords: Asthma; In vivo; Mouse model; Recombinant protein; Sema4A; Tim-2