Assessing Beta Cell Loss and Islet Engraftment after Islet Autotransplantation

评估胰岛自体移植后的β细胞损失和胰岛移植情况

基本信息

批准号：
8851586
负责人：
Melena D. Bellin
金额：
$ 7.6万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-01 至 2016-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8851586
关键词：
Acute Address Affect Age Allogenic Anti-Inflammatory Agents Anti-inflammatory Apoptosis Apoptotic Arginine Autoimmune Diseases Autoimmune Process Autoimmunity Autologous Autologous Transplantation Beta Cell Biological Assay Blood Blood Circulation C-Peptide Cell Death Cell physiology Cells Clinical Trials Clinical Trials Design Coagulation Process Complement DNA Data Deposition Diabetes Mellitus Drug Combinations Engraftment Enrollment Excision Future Glucose Goals Health Hour Individual Inflammation Inflammatory Inflammatory Response Infusion procedures Insulin Insulin-Dependent Diabetes Mellitus Intervention Islets of Langerhans Transplantation Measurement Measures Mediating Mediator of activation protein Medical Metabolic Minnesota Multicenter Trials Natural Immunity Operative Surgical Procedures Outcome Outcome Measure Pancreas Pancreatectomy Pathway interactions Patients Peptide Hydrolases Pharmaceutical Preparations Population Procedures Protocols documentation Randomized Clinical Trials Reaction Sampling Serum Staging Stress Techniques Testing Therapeutic Therapeutic Agents Therapeutic Trials Time Total Pancreatectomy Toxic effect Transplantation Universities allotransplant chemokine chronic pancreatitis cytokine design diabetic patient improved innovation insulin secretion intravenous glucose tolerance test islet non-diabetic novel pilot trial prevent primary outcome response success type I diabetic

项目摘要

DESCRIPTION (provided by applicant): Islet autotransplant (IAT) is performed at the time of total pancreatectomy (TP) in patients with chronic pancreatitis, to prevent or minimize postsurgical diabetes. Diabetes is completely prevented in only 40% of patients. The procedure of IAT is similar to allogenic islet transplantation performed in patients with type 1 diabetes, except that in the case of IAT, there is no rejection or autoimmunity, or toxicity from rejection drugs. The success of both forms of islet transplantation is limited by the loss of beta cell mass that occurs in the immediate posttransplant period, and suboptimal islet engraftment. However, we lack a uniform approach to measure engrafted islet mass early after transplant, and no techniques currently exist to directly measure islet loss. Furthermore, while we know that factors such as acute non-specific inflammation likely mediate much of this early islet loss, we lack any data to directly correlate these factors with engrafted islet mass. The aims of the current application are: 1) To determine which metabolic tests may serve as the best marker of islet engraftment at 90 days post-transplant and as a surrogate for long-term outcomes; 2) To validate the measurement of unmethylated insulin DNA-unique to the beta cell and released from dying beta cells into circulation-as a means to measure islet loss early after islet infusion; and 3) To measure and correlate measures of coagulation, complement deposition, and inflammation with islet loss and engraftment to identify which may be the best targets of future interventions. This study is a key first step towards clinical trials to identify new drug therapie that may improve islet engraftment. In order to efficiently conduct small pilot trials with new dru interventions, we must have reliable early measures of islet engraftment and islet loss as endpoints in these studies. Preliminary data is needed to identify which pathways may be most important to target therapeutically. To accomplish this, 20 non-diabetic patients age 10-65 years who are undergoing TP-IAT for management of severe chronic pancreatitis will be enrolled and studied prospectively, with a focus on early islet loss and early measures of islet engraftment. Patients will have multiple blood draws in the first week post-transplant aimed at measuring the innate inflammatory response and coagulation response upon infusion of the islets (proposed mediators of islet loss). A potential marker of beta cell death, the unmethylated insulin DNA level, will be measured at multiple time points over the first week and month after IAT, to validate this test as a novel measure of islet loss. Finally, patients will return for detailed metabolic testing at 90 days post-transplant, including mixed meal tolerance testing, intravenous glucose tolerance testing, and glucose potentiated arginine-induced insulin secretion studies. We will use this data to determine what test(s) may be most useful as a measure of islet engraftment, and which correlate best with 1 year insulin use outcomes. This will set the stage for metabolic protocols to be used in future clinical trials.

描述（由申请人提供）：胰岛自养植物（IAT）是在胰腺炎患者全胰腺切除术（TP）时进行的，以预防或最小化术后糖尿病。仅40％的患者完全阻止了糖尿病。 IAT的程序类似于1型糖尿病患者进行的同种异体胰岛移植，除了IAT，没有排斥反应或自身免疫性或拒绝药物的毒性。两种形式的胰岛移植的成功受到了在移植后立即发生的β细胞质量的损失和次优胰岛植入的限制。但是，我们缺乏一种统一的方法来早日测量植入的胰岛质量，并且目前没有直接测量胰岛损失的技术。此外，尽管我们知道诸如急性非特异性炎症之类的因素可能介导了早期胰岛的大部分损失，但我们缺乏将这些因素与植入的胰岛质量直接相关的数据。当前应用的目的是：1）确定在移植后90天，哪些代谢测试可以作为胰岛植入的最佳标志，并作为长期结果的替代物； 2）验证未甲基化的胰岛素DNA唯一对β细胞的测量并从垂死的β细胞释放到循环中 - 作为一种在胰岛输注后尽早测量胰岛损失的手段； 3）测量和关联凝结，补体沉积和炎症与胰岛损失和植入的量度，以确定哪些可能是将来干预措施的最佳目标。这项研究是迈向临床试验的关键第一步，以确定可以改善胰岛植入的新药物治疗。为了有效地进行新的DRU干预措施进行小型试验试验，我们必须对胰岛植入和胰岛损失的可靠量度作为这些研究的终点。需要初步数据来确定哪种途径对于靶向治疗可能最重要。为此，将有20名非糖尿病患者接受TP-IAT的10-65岁患者，以治疗严重的慢性胰腺炎，并前瞻性地进行了研究和研究，重点是早期的胰岛损失和早期的胰岛结构量。在移植后的第一周，患者将有多次抽血，旨在测量胰岛输注后先天炎症反应和凝结反应（提出的胰岛损失介体）。在IAT后的第一周和一个月，将在多个时间点测量β细胞死亡的潜在标记，即未甲基化的胰岛素DNA水平，以验证该测试是一种新的胰岛损失量度。最后，患者将在移植后90天进行详细的代谢测试返回，包括混合饮食测试，静脉葡萄糖耐受性测试以及葡萄糖增强的精氨酸诱导的胰岛素分泌研究。我们将使用此数据来确定哪种测试最有用，可以作为胰岛植入的量度，并且与1年胰岛素使用结果最有用。这将为将来的临床试验中使用代谢方案奠定阶段。