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: 8665415
• 负责人: DANIEL KAUFMAN
• 金额: $ 33.5万
• 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/8665415
• 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）：基于抗原的自身免疫性疾病治疗（ABTs）在理论上具有吸引力，因为它们可以诱导调节反应，而对免疫系统功能几乎没有干扰。虽然ABTs可以有效预防NOD小鼠的1型糖尿病（T1D），但在NOD小鼠发生轻度高血糖后，ABTs几乎没有减缓疾病进展的能力。此外，在人体临床试验中，ABT到目前为止还没有显示出在新诊断为T1D的个体中保持剩余胰岛素产生的显著能力。因此，迫切需要进一步开发ABTs与其他安全治疗药物联合使用，以更好地保护新发糖尿病动物的剩余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方法，可以达到所有这些目的。在小鼠模型中，免疫细胞g-氨基丁酸（GABA）受体（GABA- rs）的激活已被证明可预防T1D、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良好的安全性，我们测试了ABT和GABA联合治疗在糖尿病NOD小鼠中保存同源胰岛移植小鼠的能力，以及在新发糖尿病NOD小鼠中逆转高血糖的能力。我们发现，这些治疗组合在一起，协同作用，延长糖尿病NOD小鼠的细胞存活。我们的前期研究表明，GABAA-Rs在T细胞上的激活也提供了一种促进Treg在体内扩增的新途径。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，ABTs和GABA治疗有望通过相互独立和互补的机制发挥作用。我们将测试不同的ss细胞抗原+GABA逆转新发糖尿病小鼠高血糖的能力，并确定ABT+GABA逆转NOD小鼠T1D的机制。我们将验证以下假设：1)ABT+GABA联合治疗抑制Th1反应并促进调节性T细胞反应；2)ABT+GABA治疗促进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，我们将描述不同免疫细胞群上的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，这是迫切需要的，因为单一治疗无法在新发糖尿病患者中保持剩余胰岛素的产生。我们还希望找到新的药理学方法，以有助于扩大treg和调节效应T细胞和apc的方式，这将有利于抑制T1D以及其他T细胞介导的自身免疫性疾病。