GABA(B)-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.

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.