Analysis of beta cell death in Type 1 diabetes

免疫调节剂的临床试验减少了新发患者的C-肽丢失 1型糖尿病支持免疫介导的细胞破坏在疾病中的中心作用 发病机制。然而，对这些药物的反应一直是暂时的，这引发了一个问题，即是否所有这些药物 细胞的破坏是由免疫调节的，或者也受环境或遗传因素的影响。这 观察到年龄和血糖控制等非免疫因素改变了 对免疫治疗的反应和细胞死亡的动力学。我们假设有效的治疗方法 预防策略需要同时处理免疫介导的和非免疫介导的因素 触发细胞死亡。然而，我们解决这个问题的能力是有限的，因为我们没有办法 直接测量细胞死亡。环境因素，如葡萄糖，可以影响细胞的功能， 已成为临床试验中的原则读数。在这项提案中，我们计划使用一种新的细胞杀伤法， 包括检测细胞衍生的INS DNA以确定T1D进展中的细胞破坏率 以及免疫疗法对这一过程的影响。我们将检验三个相互关联的假设：第一，那个细胞 杀戮开始于免疫启动之后，但在疾病发作之前。我们的初步数据表明 细胞杀伤水平的增加可以在临床表现前一年首先被检测到。我们还将 确定INS DNA的表观遗传变化是否可以识别细胞对压力的反应 疾病的发展。第二，免疫疗法对细胞杀灭有不同的效果。两者的恢复都是 细胞功能失调和杀伤力降低可能是代谢后细胞功能恢复的原因 稳定，但不同的药剂可能不会有相同的效果。第三，环境和遗传因素 影响细胞杀伤率的因素。我们将使用这一测量方法以及现有的新陈代谢、人口统计学、遗传学、 和来自T1D预防和干预研究的临床数据，以确定药物的作用机制 以及改变疾病进展的因素。我们的研究代表了一种新的方法来识别 可能改变免疫治疗反应和疾病进展的因素。他们可能会发展成 基于对疾病动力学和机制的更好理解的新治疗策略 发病机制。

Clinical trials with immune modulatory agents have reduced the loss of C-peptide in patients with new onset Type 1 diabetes supporting the central role of immune mediated destruction of ¿ cells in the disease pathogenesis. However, the responses to these agents has been transient raising a question as to whether all of the destruction of ¿ cells is immune mediated or is also affected by environmental or genetic factors. This notion is supported by the observation that non-immunologic factors such as age and glucose control modify the responses to immune therapies and the kinetics of ¿ cell death. We hypothesize that effective treatment and prevention strategies need to address both the immune mediated and non-immune mediated factors that trigger ¿ cell death. However, our ability to address this issue is limited because we do not have a means of directly measuring ¿ cell death. The environmental factors, such as glucose, can affect ¿ cell function which has been the principle readout in clinical trials. In this proposal, we plan to use a novel assay of ¿ cell killing, involving detection of ¿ cell derived INS DNA to identify the rates of ¿ cell destruction in the progression of T1D and the effects of immune therapies on this process. We will test 3 interrelated hypotheses: First, that ¿ cell killing commences after immunologic initiation but prior to disease onset. Our preliminary data suggest that increased levels of ¿ cell killing can first be detected about 1 yr prior to clinical presentation. We will also determine whether epigenetic changes in the INS DNA can identify ¿ cell responses to stress during the progression of disease. Second, immune therapies have different effects on ¿ cell killing. Both recovery of dysfunctional ¿ cells and reduced killing may explain the recovery of ¿ cell function following metabolic stabilization but the different agents may not all have the same effects. Third, that environmental and genetic factors modify ¿ cell killing. We will use this measurement and the available metabolic, demographic, genetic, and clinical data from T1D prevention and intervention studies to identify the mechanisms of action of drugs and the factors that modify progression of the disease. Our studies represent a novel approach to identify factors that may modify responses to immune therapies and the progression of disease. They may develop new treatment strategies based on an improved understanding of the kinetics and mechanisms of disease pathogenesis.