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GABAB-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice.
Tian, Jide; Middleton, Blake; Lee, Victoria Seunghee; Park, Hye Won; Zhang, Zhixuan; Kim, Bokyoung; Lowe, Catherine; Nguyen, Nancy; Liu, Haoyuan; Beyer, Ryan S; Chao, Hannah W; Chen, Ryan; Mai, Davis; O'Laco, Karen Anne; Song, Min; Kaufman, Daniel L.
Afiliação
  • Tian J; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Middleton B; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Lee VS; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Park HW; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Zhang Z; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Kim B; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Lowe C; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Nguyen N; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Liu H; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Beyer RS; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Chao HW; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Chen R; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Mai D; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • O'Laco KA; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Song M; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
  • Kaufman DL; Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA.
Biomedicines ; 9(1)2021 Jan 06.
Article em En | MEDLINE | ID: mdl-33418884
ABSTRACT
Some immune system cells express type A and/or type B γ-aminobutyric acid receptors (GABAA-Rs and/or GABAB-Rs). Treatment with GABA, which activates both GABAA-Rs and GABAB-Rs), and/or a GABAA-R-specific agonist inhibits disease progression in mouse models of type 1 diabetes (T1D), multiple sclerosis, rheumatoid arthritis, and COVID-19. Little is known about the clinical potential of specifically modulating GABAB-Rs. Here, we tested lesogaberan, a peripherally restricted GABAB-R agonist, as an interventive therapy in diabetic NOD mice. Lesogaberan treatment temporarily restored normoglycemia in most newly diabetic NOD mice. Combined treatment with a suboptimal dose of lesogaberan and proinsulin/alum immunization in newly diabetic NOD mice or a low-dose anti-CD3 in severely hyperglycemic NOD mice greatly increased T1D remission rates relative to each monotherapy. Mice receiving combined lesogaberan and anti-CD3 displayed improved glucose tolerance and, unlike mice that received anti-CD3 alone, had some islets with many insulin+ cells, suggesting that lesogaberan helped to rapidly inhibit ß-cell destruction. Hence, GABAB-R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABAB-Rs and GABAA-Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Biomedicines Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Idioma: En Revista: Biomedicines Ano de publicação: 2021 Tipo de documento: Article País de afiliação: Estados Unidos