GABA<sub>B</sub>-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice

Jide Tian; Blake Middleton; Victoria Seunghee Lee; Hye Won Park; Zhixuan Zhang; Bokyoung Kim; Catherine Lowe; Nancy Nguyen; Haoyuan Liu; Ryan S. Beyer; Hannah W. Chao; Ryan Chen; Davis Mai; Karen Anne O’Laco; Min Song; Daniel L. Kaufman

doi:10.3390/biomedicines9010043

Biomedicines (Jan 2021)

GABA<sub>B</sub>-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice

Jide Tian,
Blake Middleton,
Victoria Seunghee Lee,
Hye Won Park,
Zhixuan Zhang,
Bokyoung Kim,
Catherine Lowe,
Nancy Nguyen,
Haoyuan Liu,
Ryan S. Beyer,
Hannah W. Chao,
Ryan Chen,
Davis Mai,
Karen Anne O’Laco,
Min Song,
Daniel L. Kaufman

Affiliations

Jide Tian: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Blake Middleton: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Victoria Seunghee Lee: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Hye Won Park: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Zhixuan Zhang: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Bokyoung Kim: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Catherine Lowe: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Nancy Nguyen: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Haoyuan Liu: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Ryan S. Beyer: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Hannah W. Chao: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Ryan Chen: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Davis Mai: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Karen Anne O’Laco: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Min Song: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA
Daniel L. Kaufman: Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA 90095-1735, USA

DOI: https://doi.org/10.3390/biomedicines9010043
Journal volume & issue: Vol. 9, no. 1
p. 43

Abstract

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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 β-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.

Published in Biomedicines

ISSN: 2227-9059 (Online)
Publisher: MDPI AG
Country of publisher: Switzerland
LCC subjects: Science: Biology (General)
Website: http://www.mdpi.com/journal/biomedicines

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