Homotaurine Treatment Enhances CD4+ and CD8+ Regulatory T Cell Responses and Synergizes with Low-Dose Anti-CD3 to Enhance Diabetes Remission in Type 1 Diabetic Mice

Abstract

Immune cells express γ-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 (GABAA-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 large-scale GABAA-R agonist–mediated replenishment of islet β-cells that has been reported by others. However, we did observe a few functional islets in mice that received combined therapy. Thus, GABAA-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 β-cell replication and survival in a human islet xenograft model. Hence, GABAA-R agonists, such as homotaurine, are attractive candidates for testing in combination with other therapeutic agents in type 1 diabetes clinical trials.