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

基本信息

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
项目类别：
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

项目摘要

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）：用于自身免疫性疾病的基于抗原的疗法（ABT）在理论上具有吸引力，因为它们可以诱导监管反应，而不会干扰免疫系统功能。虽然ABT有效地预防了NOD小鼠中1型糖尿病（T1D），但ABT几乎没有能力缓慢疾病进展，而疾病进展后会产生轻度的高血糖。此外，在人类的临床试验中，ABT迄今未显示出刚诊断为T1D的个体保留残留胰岛素产生的重要能力。因此，迫切需要进一步开发ABT与其他安全的治疗剂结合使用，以更好地保护新糖尿病动物中剩余的SS细胞。特别是，减少炎症自身免疫反应，促进调节反应并促进SS细胞恢复至关重要。我们提出了一种安全的联合疗法，可以实现所有这些目标。已经证明，免疫细胞G-氨基丁酸（GABA）受体（GABA-RS）的激活已证明可以预防小鼠模型中T1D，实验性自身免疫性脑脊髓炎（EAE）和类风湿关节炎。基于GABA抑制不同自身免疫性疾病的炎症反应及其出色的安全性的能力，我们测试了联合ABT和GABA疗法在糖尿病NOD小鼠中保留合成胰岛小鼠小鼠的能力，以及在新型糖尿病NOD小鼠中反向高血糖症。我们发现，这些处理结合起来协同作用，可在糖尿病点头小鼠中延长SS细胞存活。我们的试点研究表明，T细胞上GABAA-RS的激活还为促进体内Treg扩张提供了新的途径。此外，我们其他研究的工作表明，GABA可保护SS细胞免受氧化应激诱导的凋亡的影响，并促进高血糖诱导的SS细胞复制。因此，预计ABT和GABA处理将通过独立和相互互补的机制来起作用。我们将测试不同SS细胞抗原+GABA在新糖尿病小鼠中逆转高血糖的能力，并确定ABT+GABA在NOD小鼠中逆转T1D的机制。我们将测试以下假设：1）合并ABT+GABA治疗抑制了Th1反应并促进调节性T细胞反应，而2）ABT+GABA治疗可促进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，因此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。这些研究将提供所需的临床前信息，以启动联合治疗策略的临床试验，鉴于单疗法未能保留新糖尿病患者中残留的胰岛素产生的临床策略。我们还期望确定新的药理学方法，以帮助扩展Treg并以有益于抑制T1D以及其他T细胞介导的自身免疫性疾病的方式来调节效应T细胞和APC。