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GABA B -Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice.

Authors :: Tian J
Middleton B
Lee VS
Park HW
Zhang Z
Kim B
Lowe C
Nguyen N
Liu H
Beyer RS
Chao HW
Chen R
Mai D
O'Laco KA
Song M
Kaufman DL
Source :: Biomedicines [Biomedicines] 2021 Jan 06; Vol. 9 (1). Date of Electronic Publication: 2021 Jan 06.
Publication Year :: 2021
Abstract: Some immune system cells express type A and/or type B γ-aminobutyric acid receptors (GABA <subscript>A</subscript> -Rs and/or GABA <subscript>B</subscript> -Rs). Treatment with GABA, which activates both GABA <subscript>A</subscript> -Rs and GABA <subscript>B</subscript> -Rs), and/or a GABA <subscript>A</subscript> -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 GABA <subscript>B</subscript> -Rs. Here, we tested lesogaberan, a peripherally restricted GABA <subscript>B</subscript> -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 <superscript>+</superscript> cells, suggesting that lesogaberan helped to rapidly inhibit β-cell destruction. Hence, GABA <subscript>B</subscript> -R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABA <subscript>B</subscript> -Rs and GABA <subscript>A</subscript> -Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.