title: Combined therapy with GABA and proinsulin/alum acts synergistically to restore long-term normoglycemia by modulating T-cell autoimmunity and promoting β-cell replication in newly diabetic NOD mice.
abstract: Antigen-based therapies (ABTs) fail to restore normoglycemia in newly diabetic NOD mice, perhaps because too few β-cells remain by the time that ABT-induced regulatory responses arise and spread. We hypothesized that combining a fast-acting anti-inflammatory agent with an ABT could limit pathogenic responses while ABT-induced regulatory responses arose and spread. γ-Aminobutyric acid (GABA) administration can inhibit inflammation, enhance regulatory T-cell (Treg) responses, and promote β-cell replication in mice. We examined the effect of combining a prototypic ABT, proinsulin/alum, with GABA treatment in newly diabetic NOD mice. Proinsulin/alum monotherapy failed to correct hyperglycemia, while GABA monotherapy restored normoglycemia for a short period. Combined treatment restored normoglycemia in the long term with apparent permanent remission in some mice. Proinsulin/alum monotherapy induced interleukin (IL)-4- and IL-10-secreting T-cell responses that spread to other β-cell autoantigens. GABA monotherapy induced moderate IL-10 (but not IL-4) responses to β-cell autoantigens. Combined treatment synergistically reduced spontaneous type 1 T-helper cell responses to autoantigens, ABT-induced IL-4 and humoral responses, and insulitis, but enhanced IL-10 and Treg responses and promoted β-cell replication in the islets. Thus, combining ABT with GABA can inhibit pathogenic T-cell responses, induce Treg responses, promote β-cell replication, and effectively restore normoglycemia in newly diabetic NOD mice. Since these treatments appear safe for humans, they hold promise for type 1 diabetes intervention.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA dkaufman@mednet.ucla.edu jtian@mednet.ucla.edu.
authors.forename: Jide
authors.initials: J
authors.lastname: Tian
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Hoa
authors.initials: H
authors.lastname: Dang
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA.
authors.forename: An Viet
authors.initials: AV
authors.lastname: Nguyen
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA.
authors.forename: Zheying
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, Los Angeles, CA dkaufman@mednet.ucla.edu jtian@mednet.ucla.edu.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Kaufman
mesh_terms: D000534:Alum Compounds / Q000008:administration & dosage*; D000818:Animals; D015551:Autoimmunity / Q000187:drug effects* / Q000276:immunology; D001786:Blood Glucose / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000276:immunology; D004359:Drug Therapy, Combination; D005260:Female; D016753:Interleukin-10 / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D051379:Mice; D016688:Mice, Inbred NOD; D011384:Proinsulin / Q000008:administration & dosage*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology*
chemical_list: D000534:Alum Compounds; D001786:Blood Glucose; D016753:Interleukin-10; D015847:Interleukin-4; C041524:aluminum sulfate; D011384:Proinsulin