Immune cells express g-aminobutyric acid receptors (GABA-R), and GABA administration can inhibit effector T cell responses in models of autoimmune disease. The pharmacokinetic properties of GABA, however, may be suboptimal for clinical applications. The amino acid homotaurine is a type A GABA-R (GABA A-R) agonist with good pharmacokinetics and appears safe for human consumption. In this study, we show that homotaurine inhibits in vitro T cell proliferation to a similar degree as GABA but at lower concentrations. In vivo, oral homotaurine treatment had a modest ability to reverse hyperglycemia in newly hyperglycemic NOD mice but was ineffective after the onset of severe hyperglycemia. In severely diabetic NOD mice, the combination of homotaurine and low-dose anti-CD3 treatment significantly increased 1) disease remission, 2) the percentages of splenic CD4 + and CD8 + regulatory T cells compared with anti-CD3 alone, and 3) the frequencies of CD4 + and CD8 + regulatory T cells in the pancreatic lymph nodes compared with homotaurine monotherapy. Histological examination of their pancreata provided no evidence of the largescale GABA A-R agonist-mediated replenishment of islet b-cells that has been reported by others. However, we did observe a few functional islets in mice that received combined therapy. Thus, GABA A-R activation enhanced CD4 + and CD8 + regulatory T cell responses following the depletion of effector T cells, which was associated with the preservation of some functional islets. Finally, we observed that homotaurine treatment enhanced b-cell replication and survival in a human islet xenograft model. Hence, GABA A-R agonists, such as homotaurine, are attractive candidates for testing in combination with other therapeutic agents in type 1 diabetes clinical trials. ImmunoHorizons, 2019, 3: 498-510.

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.

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