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

• 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
• 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

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）：胰岛自体移植（IAT）是在慢性胰腺炎患者全胰腺切除术（TP）时进行的，以预防或减少术后糖尿病。只有40%的患者可以完全预防糖尿病。IAT的程序类似于在1型糖尿病患者中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反应，也没有排斥药物的毒性。两种形式的胰岛移植的成功都受到移植后立即发生的β细胞质量损失和不理想的胰岛移植的限制。然而，我们缺乏一种统一的方法来测量移植后早期移植的胰岛质量，目前也没有直接测量胰岛损失的技术。此外，虽然我们知道急性非特异性炎症等因素可能介导了早期胰岛的损失，但我们缺乏任何数据来直接将这些因素与植入的胰岛肿块联系起来。当前应用的目的是：1)确定哪些代谢测试可以作为移植后90天胰岛移植的最佳标记，并作为长期结果的替代指标；2)验证测量未甲基化胰岛素dna （β细胞特有的，从垂死的β细胞释放到循环中）作为胰岛输注后早期测量胰岛损失的手段；