title: Cutting Edge: Nanogel-Based Delivery of an Inhibitor of CaMK4 to CD4+ T Cells Suppresses Experimental Autoimmune Encephalomyelitis and Lupus-like Disease in Mice.
abstract: Treatment of autoimmune diseases is still largely based on the use of systemically acting immunosuppressive drugs, which invariably cause severe side effects. Calcium/calmodulin-dependent protein kinase IV is involved in the suppression of IL-2 and the production of IL-17. Its pharmacologic or genetic inhibition limits autoimmune disease in mice. In this study, we demonstrate that KN93, a small-molecule inhibitor of calcium/calmodulin-dependent protein kinase IV, targeted to CD4(+) T cells via a nanolipogel delivery system, markedly reduced experimental autoimmune encephalomyelitis and was 10-fold more potent than the free systemically delivered drug in the lupus mouse models. The targeted delivery of KN93 did not deplete T cells but effectively blocked Th17 cell differentiation and expansion as measured in the spinal cords and kidneys of mice developing experimental autoimmune encephalomyelitis or lupus, respectively. These results highlight the promise of cell-targeted inhibition of molecules involved in the pathogenesis of autoimmunity as a means of advancing the treatment of autoimmune diseases.
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Kotaro
authors.identifier: http://orcid.org/0000-0002-9726-412X
authors.initials: K
authors.lastname: Otomo
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Tomohiro
authors.initials: T
authors.lastname: Koga
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Masayuki
authors.identifier: http://orcid.org/0000-0003-2543-8108
authors.initials: M
authors.lastname: Mizui
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215;
authors.forename: Nobuya
authors.initials: N
authors.lastname: Yoshida
authors.affiliation: Department of Biomedical Engineering, Yale University and Yale University School of Medicine, New Haven, CT 06511;
authors.forename: Christina
authors.initials: C
authors.lastname: Kriegel
authors.affiliation: Department of Biomedical Engineering, Yale University and Yale University School of Medicine, New Haven, CT 06511;
authors.forename: Sean
authors.initials: S
authors.lastname: Bickerton
authors.affiliation: Department of Biomedical Engineering, Yale University and Yale University School of Medicine, New Haven, CT 06511; Department of Chemical and Environmental Engineering, Yale University and Yale University School of Medicine, New Haven, CT 06511; and Department of Immunobiology, Yale University and Yale University School of Medicine, New Haven, CT 06511.
authors.forename: Tarek M
authors.initials: TM
authors.lastname: Fahmy
authors.affiliation: Division of Rheumatology, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215; gtsokos@bidmc.harvard.edu.
authors.forename: George C
authors.initials: GC
authors.lastname: Tsokos
mesh_terms: D000818:Animals; D001596:Benzylamines / Q000008:administration & dosage* / Q000494:pharmacology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4 / Q000037:antagonists & inhibitors; D002454:Cell Differentiation / Q000187:drug effects; D002478:Cells, Cultured; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy* / Q000276:immunology; D006801:Humans; D007165:Immunosuppression Therapy; D008180:Lupus Erythematosus, Systemic / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D000080385:Nanogels; D011092:Polyethylene Glycols / Q000008:administration & dosage*; D011094:Polyethyleneimine / Q000008:administration & dosage*; D013449:Sulfonamides / Q000008:administration & dosage* / Q000494:pharmacology; D058504:Th17 Cells / Q000187:drug effects* / Q000276:immunology; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D054734:Calcium-Calmodulin-Dependent Protein Kinase Type 4; D000080385:Nanogels; D011092:Polyethylene Glycols; D011094:Polyethyleneimine; D013449:Sulfonamides; C413692:polyethylene glycol polyethyleneimine nanogel; C072105:KN 93; D000096926:Benzenesulfonamides; C517685:Camk4 protein, mouse