1 Keenan Research Centre of the Li Ka Shing Knowledge Institute, Toronto, Ontario, Canada. 2 Department of Laboratory Medicine, St. Michael's Hospital, Toronto, Ontario, Canada. 3 Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Toronto. 4 Department of Surgery, McGill University Health Centre, Montreal, Quebec, Canada. 5 Division of Endocrinology and Metabolism, Department of Medicine, St. Michael's Hospital, Toronto, Ontario, Canada. 6 Departments of Physiology and Medicine, University of Toronto, Toronto, Ontario, Canada. 7 Address correspondence to: Gérald J. Prud'homme, M.D., St. Michael's Hospital, 30 Bond Street, Room 418-LKSKI, Toronto, Ontario, Canada M5B 1W8.
Transplantation. 2013 Oct 15;96(7):616-23. doi: 10.1097/TP.0b013e31829c24be.
We recently found that γ-aminobutyric acid (GABA) protects mouse islet β cells. It prevented autoimmune type 1 diabetes in mice, induced islet β-cell regeneration, and exerted immunoinhibitory effects. However, it is not known whether GABA would be equally active on human islet and immune cells.
In vitro culture of human islets and immune cells with or without GABA and immunosuppressive drugs. In vitro analysis of apoptosis, proliferation, nuclear factor (NF)-κB activation, calcium signaling, and insulin secretion.
GABA reduced human islet cell apoptosis in culture, such that the yield of live cells was approximately tripled after 1 week, and it stimulated insulin secretion. It protected against the deleterious effects of rapamycin, tacrolimus, and mycophenolate mofetil. In human immune cells, GABA had inhibitory effects similar to mouse cells, such as suppressed anti-CD3-stimulated T-cell proliferation, in a GABA type A receptor-dependent fashion. The immunosuppressive mechanisms have been unclear, but we found that GABA blocked calcium influx, which is a key activation signal. GABA also suppressed NF-κB activation in both human islet cells and immune cells. We found that it could be combined with rapamycin to increase its suppressive effects.
GABA improved human islet cell survival and had suppressive effects on human immune cells. It inhibited canonical NF-κB activation in both islet and immune cells. This is important because activation of this pathway is detrimental to islet cells and likely promotes damaging autoimmunity and alloreactivity against transplanted islets. These findings suggest that GABA might find applications in clinical islet transplantation.
我们最近发现γ-氨基丁酸（GABA）可以保护小鼠胰岛β细胞。它可以预防小鼠自身免疫性 1 型糖尿病，诱导胰岛β细胞再生，并发挥免疫抑制作用。然而，目前尚不清楚 GABA 是否对人类胰岛和免疫细胞同样有效。
用 GABA 和免疫抑制药物对体外培养的人胰岛和免疫细胞进行培养。体外分析细胞凋亡、增殖、核因子（NF）-κB 激活、钙信号和胰岛素分泌。
GABA 减少了人胰岛细胞在培养中的凋亡，使活细胞的产量在 1 周后增加了大约两倍，并且刺激了胰岛素的分泌。它可以抵抗雷帕霉素、他克莫司和霉酚酸酯的有害影响。在人类免疫细胞中，GABA 具有类似于小鼠细胞的抑制作用，如抑制抗-CD3 刺激的 T 细胞增殖，这种作用依赖于 GABA 型 A 受体。其免疫抑制机制尚不清楚，但我们发现 GABA 阻断了钙内流，这是一个关键的激活信号。GABA 还抑制了人胰岛细胞和免疫细胞中 NF-κB 的激活。我们发现它可以与雷帕霉素联合使用，以增加其抑制作用。
GABA 提高了人胰岛细胞的存活率，并对人免疫细胞具有抑制作用。它抑制了胰岛和免疫细胞中经典的 NF-κB 激活。这很重要，因为该途径的激活对胰岛细胞有害，并可能促进对移植胰岛的自身免疫和同种异体反应。这些发现表明 GABA 可能在临床胰岛移植中得到应用。
