ISLET TRANSPLANTATION IN NON-UREMIC DIABETIC PATIENTS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。据估计，美国I型糖尿病的患病率约为80万人，每年新增病例约为3万例。迄今为止，尚无彻底的预防或治疗措施。最接近的是糖尿病控制和并发症试验，该试验证明强化治疗有效地延缓了糖尿病视网膜病变（视力恶化）、肾病（肾脏损害）和神经病变（手/脚/手臂/腿的感觉下降/感觉改变）的发病和进展。用整个胰腺移植替代β细胞（胰腺中产生胰岛素的细胞）是控制血糖最成功的方法。胰岛移植作为游离移植物扩展了I型糖尿病患者β细胞替代疗法的概念。与传统胰腺移植相比，胰岛移植的吸引力在于其发病率低（副作用严重）和相对较少的医院资源使用。通过胰岛细胞移植的β细胞替代疗法，如果成功，可以逆转高血糖和对外源性胰岛素的需求（不是由服用它的人产生的胰岛素）。胰岛移植成功的主要障碍是排斥反应。胰岛移植排斥反应的研究揭示了t细胞的重要性。然而，t细胞介导的胰岛排斥反应并不是胰岛移植后损伤的唯一机制。涉及巨噬细胞和巨噬细胞产生的副产物的非特异性宿主免疫反应也不利于胰岛的植入和功能。通过胰岛细胞移植的β细胞替代疗法，如果成功，可以逆转高血糖和对外源性胰岛素治疗的需求。不幸的是，它不是常规有效的。在1990年1月1日至1998年12月31日期间，国际移植登记处报告了267例I型糖尿病患者接受胰岛异体移植的病例。在这些病例中，有245例进行了一年的随访，只有20例（8%）患者在一年时胰岛素独立。绝大多数（95%）胰岛移植是在同时接受肾移植或已经接受肾移植的患者中进行的，因此承诺接受全身免疫抑制治疗。胰岛移植的目标是能够在疾病过程中尽早应用，从而预防继发性血管并发症。要做到这一点，必须设计出抗排斥治疗方案，使器官特异性副作用最小化，同时提供实质性的排斥保护。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The prevalence of type I diabetes in the United States is estimated to be about 800,000 individuals, and the incidence is approximately 30,000 new cases yearly. To date, there are no thoroughly preventative or curative measures available. The closest has been the Diabetes Control and Complications Trial that demonstrated intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy (worsening eye sight), nephropathy (kidney damage), and neuropathy (decreased sensation/changing sensation in hands/feet/arms/legs). The modality of beta cell (insulin producing cells in the pancreas) replacement by transplantation of the whole pancreas is the most successful method to control glycemia. Transplantation of the islets as free grafts extends the concept of beta cell replacement therapy for patients with type I diabetes. The attraction of islet transplantation compared to conventional pancreas transplantation is its minimal morbidity (severe side-effects) and relative little use of hospital resources. Beta cell replacement therapy by means of islet cell transplantation, when successful, reverses hyperglycemia and the need for exogenous insulin (insulin not produced by the person taking it). The primary barrier to successful human islet transplantation is rejection. The study of islet transplant rejection has revealed the importance of T-cells. However, T-cell mediated islet rejection is not the sole mechanism of islet graft injury post-transplantation. Non-specific host immune responses involving macrophages and macrophage-generated by-products are also detrimental to islet engraftment and function. Beta cell replacement therapy by means of islet cell transplantation, when successful, reverses hyperglycemia and the need for exogenous insulin therapy. Unfortunately, it is not routinely effective. Between January 1, 1990 and December 31, 1998, 267 cases of islet allotransplantation in type I diabetic recipients have been reported to the International Transplant Registry. Of these cases 245 were reported with one year follow-up and only 20 patients (8%) were insulin independent at one year. The vast majority (95%) of islet transplants have been performed in patients who are either simultaneously receiving a kidney transplant or who have already received one and thus are committed to receiving systemic immunosuppressive therapy. The goal of islet transplantation is to be able to apply it early enough in the course of the disease so that these secondary vascular complications are prevented. For this to occur, anti-rejection regimens must be devised that minimize organ specific side effects while providing substantial protection from rejection.