The Contribution of B Lymphocyte to T1D Reversal by Imatinib

B 淋巴细胞对伊马替尼逆转 T1D 的作用

• 批准号: 9181048
• 负责人: Daniel J. Moore
• 金额: $ 23.7万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-15 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9181048
• 关键词: Address; Aftercare; Alpha Cell; Animal Model; Antigens; Autoantibodies; Autoantigens; B-Lymphocyte Subsets; B-Lymphocytes; Beta Cell; Biology; Blood Glucose; Cell physiology; Cells; Clinical; Clinical Trials; Collaborations; Complement; Cytometry; Cytoprotection; Data; Diabetes Mellitus; Diabetic mouse; Disease; Failure; Functional disorder; Future; Genetic Transcription; Gleevec; Glucagon; Glucose; Health; Hormones; Human; Hyperglycemia; Imatinib; Immune; Immune Targeting; Immune Tolerance; Immune system; Immunity; Immunotherapy; Inbred NOD Mice; Individual; Insulin-Dependent Diabetes Mellitus; Investigation; Islet Cell; Link; Lymphocyte Depletion; Lymphocyte Function; Mediating; Mediator of activation protein; Modeling; Patients; Population; Process; Production; Recovery; Recovery of Function; Regulation; Research; Research Personnel; Role; Serum; Signal Transduction; T-Lymphocyte; Testing; Therapeutic; Therapeutic Effect; Time; Translating; Translations; Tyrosine Kinase Inhibitor; Work; base; cellular targeting; high risk; immune function; innovation; insulin dependent diabetes mellitus onset; insulin secretion; islet; mouse model; novel; pre-clinical; prevent; protective effect; response; restoration; targeted treatment; transcription factor

Summary Imatinib was previously established to prevent and reverse Type 1 diabetes (T1D) in the NOD mouse model of disease by investigators at UCSF including Arthur Weiss and Jeffrey Bluestone. Related to those findings and due to the potent action of imatinib, a tyrosine kinase inhibitor, on immune cells, it is presently in clinical trials for new onset T1D. The required cellular targets of imatinib therapy have not yet been elucidated, which may impede successful clinical translation of this otherwise promising approach. In the NOD mouse, autoreactive B lymphocytes are critical drivers of disease through their interactions with islet-reactive T cells. This autoreactive T-B collaboration also remains our best predictor of future disease in humans, as it results in the production of autoantibody that is found in the serum of individuals at high risk for T1D. Because B lymphocytes act at this critical node in T1D progression, we hypothesized that they could be the critical mediator of imatinib’s protective effect. Using multiple models in which we established T1D in the presence or absence of B lymphocytes, we have determined that diabetes is never reversed by imatinib in the absence of B lymphocytes. When B lymphocytes are present, the effect of imatinib is both rapid and durable; diabetes is reversed in a matter of days and does not recur after treatment is stopped. When B lymphocytes are absent, there is no effect on blood sugar in any time frame. Based on the durable effect, we hypothesize that imatinib has induced regulation by B lymphocytes that controls immunity. In Aim 1 we explore this immune effect by determining which B lymphocytes are modulated by imatinib using mass cytometry to identify the therapeutic effect on novel B cell subsets including the effect on autoantigen-reactive cells. We further investigate the immune targets of these B lymphocytes and the mechanism of effect. Because of the extremely rapid effect that only occurs with B lymphocytes, we also hypothesize that imatinib induces an effect on islet alpha and beta cell functional recovery through its induced B lymphocyte functions. In Aim 2, we will explore this innovative connection between the immune system and islet cell recovery by investigating the B cell dependent therapeutic effect on islet cell mass, hormone secretion, and transcription factor expression. Overall, our approach will shift our understanding of the role of B lymphocytes in targeted therapy for T1D by defining their inducible capacity to promote restoration of immune tolerance while simultaneously enhancing islet cell functional recovery.

总结 伊马替尼先前被确立用于预防和逆转NOD小鼠模型中的1型糖尿病（T1 D）， 包括亚瑟韦斯和杰弗里·布鲁斯通在内的加州大学旧金山分校的研究人员对这种疾病进行了研究。与这些调查结果有关， 由于伊马替尼（一种酪氨酸激酶抑制剂）对免疫细胞的强效作用， 新发T1 D伊马替尼治疗所需的细胞靶点尚未阐明， 阻碍了这种在其他方面有前途的方法的成功临床转化。在NOD小鼠中，自身反应性B 淋巴细胞通过与胰岛反应性T细胞的相互作用而成为疾病的关键驱动因素。这 自身反应性T-B协作也仍然是我们对人类未来疾病的最佳预测因子，因为它导致 在T1 D高风险个体的血清中发现的自身抗体的产生。因为B 淋巴细胞在T1 D进展中的这个关键节点起作用，我们假设它们可能是T1 D进展的关键节点。 伊马替尼的保护作用的介质。使用多个模型，其中我们在存在或不存在T1 D的情况下建立T1 D。 在缺乏B淋巴细胞的情况下，我们已经确定，在缺乏B淋巴细胞的情况下，伊马替尼决不能逆转糖尿病 淋巴细胞当存在B淋巴细胞时，伊马替尼的作用既迅速又持久;糖尿病是 在几天内逆转，停止治疗后不会复发。当B淋巴细胞不存在时， 在任何时间范围内对血糖都没有影响。基于持久的效果，我们假设伊马替尼 通过控制免疫的B淋巴细胞诱导调节。在目标1中，我们通过以下方式探索这种免疫效应： 使用质谱细胞术确定哪些B淋巴细胞被伊马替尼调节，以鉴定治疗性 对新的B细胞亚群的影响，包括对自身抗原反应性细胞的影响。我们进一步调查 这些B淋巴细胞的免疫靶点和作用机制。由于其极其迅速的影响， 仅发生于B淋巴细胞，我们还假设伊马替尼诱导对胰岛α和β细胞的影响， 通过其诱导的B淋巴细胞功能恢复功能。在目标2中，我们将探索这一创新 通过研究B细胞依赖性免疫系统和胰岛细胞恢复之间的联系 对胰岛细胞质量、激素分泌和转录因子表达的治疗作用。总的来说，我们的 这种方法将改变我们对B淋巴细胞在T1 D靶向治疗中作用的理解， 促进免疫耐受恢复同时增强胰岛细胞的诱导能力 功能恢复