Reversal of T1D in NOD mice using a safe combination therapy

使用安全的联合疗法逆转 NOD 小鼠的 T1D

• 批准号: 8464092
• 负责人: DANIEL KAUFMAN
• 金额: $ 32.32万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8464092
• 关键词: Adverse effects; Affect; Aminobutyric Acids; Animals; Antigens; Apoptosis; Autoimmune Diseases; Autoimmune Responses; Biology; Blood - brain barrier anatomy; Cell Cycle; Cell Survival; Cells; Clinical; Clinical Trials; Collaborations; Collagen Arthritis; Combined Modality Therapy; Consumption; DBA/1J Mouse; Data; Development; Diabetic mouse; Disease Progression; Experimental Autoimmune Encephalomyelitis; Failure; Foundations; Future; Generations; Genetic; Human; Hyperglycemia; Immune; Immune Cell Activation; Immune Tolerance; Immune response; Immune system; Immunocompetent; Immunotherapy; In Vitro; Inbred NOD Mice; Individual; Inflammatory; Inflammatory Response; Insulin; Insulin-Dependent Diabetes Mellitus; Intervention Trial; Laboratories; Ligands; Mediating; Modality; Mus; Nervous system structure; Neurons; Newly Diagnosed; Oxidative Stress; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pilot Projects; Population; Production; Recommendation; Regulatory T-Lymphocyte; Residual state; Rheumatoid Arthritis; Risk; SJL Mouse; Safety; Signal Transduction; T cell response; T-Lymphocyte; Testing; Therapeutic; Work; base; design; diabetic; effective therapy; in vivo; insulin dependent diabetes mellitus onset; interest; islet; mouse model; neurogenesis; novel strategies; pre-clinical; prevent; receptor; response; restoration

DESCRIPTION (provided by applicant): Antigen-based therapies (ABTs) for autoimmune disease are theoretically appealing because they can induce regulatory responses with little interference with immune system function. While ABTs effectively prevent type 1 diabetes (T1D) in NOD mice, ABTs have little to no ability to slow disease progression after NOD mice develop mild hyperglycemia. Moreover, in human clinical trials, ABT's have thus far not shown a significant ability to preserve residual insulin production in individuals newly diagnosed with T1D. Therefore, there is an urgent need to further develop ABTs in combination with other safe therapeutics to better protect remaining ss-cells in newly diabetic animals. In particular, it willbe critical to reduce inflammatory autoimmune responses, promote regulatory responses and promote ss-cell restoration. We propose a safe combination therapy which achieves all these aims. The activation of immune cell g-aminobutyric acid (GABA) receptors (GABA-Rs) has been shown to prevent T1D, experimental autoimmune encephalomyelitis (EAE) and rheumatoid arthritis in mouse models. Based on GABA's ability to inhibit inflammatory responses in different autoimmune diseases and its excellent safety profile, we tested the ability of combined ABT and GABA therapy to preserve syngenic islet grafts mice in diabetic NOD mice, as well as to reverse hyperglycemia in newly diabetic NOD mice. We found that in combination, these treatments act synergistically to prolong ss-cell survival in diabetic NOD mice. Our pilot studies suggest that the activation of GABAA-Rs on T cells also offers a new pathway to promote Treg expansion in vivo. Moreover work from our other studies demonstrate that GABA protects ss-cells from oxidative stress-induced apoptosis and promotes hyperglycemia-induced ss-cell replication. Thus, ABTs and GABA treatments are expected to work by mechanisms that are independent and mutually complementary. We will test the ability of different ss-cell antigens+GABA to reverse hyperglycemia in newly diabetic mice and determine the mechanisms by which ABT+GABA reverses T1D in NOD mice. We will test the hypotheses that 1) combined ABT+GABA treatment inhibits Th1 responses and promotes regulatory T cell responses and 2) that ABT+GABA treatment promotes ss-cell replication. Additionally, because little is known about the biology of GABA-receptors on immune cells, we will characterize GABA-receptors on different immune cell populations and how activation of GABA-Rs affects stimulation-mediated intracellular signaling. These studies will provide the preclinical information needed to initiate clinical trials of a combined therapeutic strategy that s urgently needed given the failure of monotherapies to preserve residual insulin production in newly diabetic individuals. We also expect to identify new pharmacological approaches to help expand Tregs and modulate effector T cells and APCs in ways that will be beneficial for inhibiting T1D as well as other T-cell mediated autoimmune diseases.

描述（由申请人提供）：自身免疫性疾病的基于抗原的疗法（ABT）在理论上是有吸引力的，因为它们可以诱导调节反应，对免疫系统功能的干扰很小。虽然ABT有效预防NOD小鼠的1型糖尿病（T1 D），但在NOD小鼠出现轻度高血糖症后，ABT几乎没有减缓疾病进展的能力。此外，在人类临床试验中，ABT’s迄今尚未显示出在新诊断患有T1 D的个体中保持残余胰岛素产生的显著能力。因此，迫切需要进一步开发ABT与其他安全疗法的组合，以更好地保护新糖尿病动物中剩余的ss细胞。特别是，减少炎症性自身免疫反应，促进调节反应和促进ss细胞恢复将是至关重要的。我们提出了一种安全的联合治疗，实现所有这些目标。 免疫细胞γ-氨基丁酸（GABA）受体（GABA-Rs）的激活已被证明可以预防小鼠模型中的T1 D、实验性自身免疫性脑脊髓炎（EAE）和类风湿性关节炎。基于GABA在不同自身免疫性疾病中抑制炎症反应的能力及其优异的安全性特征，我们测试了ABT和GABA联合治疗在糖尿病NOD小鼠中保存同系胰岛移植物小鼠以及在新糖尿病NOD小鼠中逆转高血糖症的能力。我们发现，在组合中，这些治疗协同作用，以延长糖尿病NOD小鼠的ss细胞存活。我们的初步研究表明，T细胞上GABAA-R的激活也提供了一种新的途径来促进体内Treg扩增。 此外，我们的其他研究表明，GABA保护SS细胞免受氧化应激诱导的凋亡，并促进高血糖诱导的SS细胞复制。因此，预期ABT和GABA治疗通过独立且相互补充的机制起作用。 我们将测试不同ss细胞抗原+GABA逆转新糖尿病小鼠高血糖症的能力，并确定ABT+GABA逆转NOD小鼠T1 D的机制。我们将测试以下假设：1）组合的ABT+GABA处理抑制Th 1应答并促进调节性T细胞应答，以及2）ABT+GABA处理促进ss细胞复制。此外，由于对免疫细胞上GABA受体的生物学知之甚少，我们将表征不同免疫细胞群体上的GABA受体以及GABA-Rs的激活如何影响刺激介导的细胞内信号传导。这些研究将提供启动联合治疗策略的临床试验所需的临床前信息，鉴于单药治疗无法保持新糖尿病个体的残余胰岛素产生，因此迫切需要联合治疗策略。我们还希望确定新的药理学方法，以帮助扩大TlD和调节效应T细胞和APC的方式，这将有利于抑制T1 D以及其他T细胞介导的自身免疫性疾病。