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核心作用 发病机制然而，对这些代理人的反应是短暂的，这就提出了一个问题，即是否所有代理人都 细胞的破坏是免疫介导的，或者也受环境或遗传因素的影响。这 这一观点得到了以下观察结果的支持，即非免疫因素如年龄和血糖控制会改变 对免疫疗法的反应和细胞死亡的动力学。我们假设有效的治疗 预防策略需要解决免疫介导和非免疫介导的因素， 触发细胞死亡。然而，我们解决这一问题的能力有限，因为我们没有办法 直接测量细胞死亡。环境因素，如葡萄糖，可以影响细胞功能， 一直是临床试验中的主要读数。在这项提议中，我们计划使用一种新的细胞杀伤试验， 包括检测源自细胞的INS DNA，以确定T1D进展中细胞破坏的速率 以及免疫疗法对这一过程的影响。我们将测试3个相互关联的假设：首先， 杀伤在免疫启动之后但在疾病发作之前开始。我们的初步数据显示， 在临床表现前约1年可首先检测到细胞杀伤水平的增加。我们还将 确定INS DNA中的表观遗传变化是否可以识别细胞在应激过程中对应激的反应。 疾病的进展。其次，免疫疗法对细胞杀伤有不同的影响。两次恢复 功能失调的细胞和减少的杀伤可以解释代谢后细胞功能的恢复。 但是不同的试剂可能并不都具有相同的效果。第三，环境和遗传 因子改变细胞杀伤。我们将使用这种测量和现有的代谢，人口统计学，遗传， 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， 可能改变免疫治疗反应和疾病进展的因素。他们可能发展 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.