title: Reversal of New-Onset Type 1 Diabetes With an Agonistic TLR4/MD-2 Monoclonal Antibody.
abstract: Type 1 diabetes (T1D) is currently an incurable disease, characterized by a silent prodromal phase followed by an acute clinical phase, reflecting progressive autoimmune destruction of insulin-producing pancreatic β-cells. Autoreactive T cells play a major role in β-cell destruction, but innate immune cell cytokines and costimulatory molecules critically affect T-cell functional status. We show that an agonistic monoclonal antibody to TLR4/MD-2 (TLR4-Ab) reverses new-onset diabetes in a high percentage of NOD mice. TLR4-Ab induces antigen-presenting cell (APC) tolerance in vitro and in vivo, resulting in an altered cytokine profile, decreased costimulatory molecule expression, and decreased T-cell proliferation in APC:T-cell assays. TLR4-Ab treatment increases T-regulatory cell (Treg) numbers in both the periphery and the pancreatic islet, predominantly expanding the Helios(+)Nrp-1(+)Foxp3(+) Treg subset. TLR4-Ab treatment in the absence of B cells in NOD.scid mice prevents subsequent T cell-mediated disease, further suggesting a major role for APC tolerization in disease protection. Specific stimulation of the innate immune system through TLR4/MD-2, therefore, can restore tolerance in the aberrant adaptive immune system and reverse new-onset T1D, suggesting a novel immunological approach to treatment of T1D in humans.
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Kyle J
authors.initials: KJ
authors.lastname: Bednar
authors.affiliation: Laboratory of Oncology, Pharmacy Practice and Sciences, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Japan.
authors.forename: Hiroki
authors.initials: H
authors.lastname: Tsukamoto
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Kritika
authors.initials: K
authors.lastname: Kachapati
authors.affiliation: Department of Laboratory Medicine, Saga Medical School, Saga, Japan.
authors.forename: Shoichiro
authors.initials: S
authors.lastname: Ohta
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH.
authors.forename: Yuehong
authors.initials: Y
authors.lastname: Wu
authors.affiliation: Division of Immunobiology, Cincinnati Children's Research Foundation, Cincinnati, OH.
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Katz
authors.affiliation: Division of Rheumatology, Miller School of Medicine, University of Miami, Miami, FL.
authors.forename: Dana P
authors.initials: DP
authors.lastname: Ascherman
authors.affiliation: Division of Immunology, Allergy and Rheumatology, University of Cincinnati College of Medicine, Cincinnati, OH ridgwawm@ucmail.uc.edu.
authors.forename: William M
authors.initials: WM
authors.lastname: Ridgway
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000938:Antigen-Presenting Cells / Q000502:physiology*; D015415:Biomarkers / Q000378:metabolism; D001786:Blood Glucose; D016207:Cytokines / Q000235:genetics / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000628:therapy*; D005260:Female; D005786:Gene Expression Regulation; D007167:Immunotherapy / Q000379:methods; D007515:Islets of Langerhans / Q000276:immunology / Q000503:physiopathology; D051218:Lymphocyte Antigen 96 / Q000819:agonists* / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D051197:Toll-Like Receptor 4 / Q000819:agonists* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D015415:Biomarkers; D001786:Blood Glucose; D016207:Cytokines; C411728:Ly96 protein, mouse; D051218:Lymphocyte Antigen 96; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4