GABA_B-Receptor Agonist-Based Immunotherapy for Type 1 Diabetes in NOD Mice

Some immune system cells express type A and/or type B γ-aminobutyric acid receptors (GABA_A-Rs and/or GABA_B-Rs). Treatment with GABA, which activates both GABA_A-Rs and GABA_B-Rs), and/or a GABA_A-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_B-Rs. Here, we tested lesogaberan, a peripherally restricted GABA_B-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, GABA_B-R-specific agonists may provide adjunct therapies for T1D. Finally, the analysis of microarray and RNA-Seq databases suggested that the expression of GABA_B-Rs and GABA_A-Rs, as well as GABA production/secretion-related genes, may be a more common feature of immune cells than currently recognized.