Recurrence of T1D in Pancreas Transplantation

描述（由申请人提供）：自1990年以来，我们已经为1型糖尿病（T1D）和终末期肾病患者进行了超过275例胰腺和肾脏（SPK）同时移植。我们目前正在跟踪225名受助人。虽然所有患者都实现了胰岛素独立，但在平均5.7年的随访后，34例（15%）又复发为高血糖症。我们的初步数据表明，在大约65%的高血糖患者和40%的血糖正常的SPK受体中，在高血糖复发之前存在糖尿病相关自身抗体。观察到的与高血糖风险增加相关的自身免疫频率高于先前较小和早期研究的报道。对选择性胰岛素分泌丧失和无排斥反应证据的患者进行了详细研究，发现其具有自身免疫复发的主要特征，包括自身抗体、胰岛素炎和外周血中自身反应性T细胞的存在，这些特征通过最近开发的基于四聚体的检测来评估。因此，我们的数据提供了证据，证明复发性自身免疫是一个重要的临床问题，以前被低估了。我们组建了一个具有胰腺移植（Burke，迈阿密）和T1D免疫学（Pugliese，迈阿密；Nepom，西雅图）经验的研究小组，研究与SPK受体自身免疫复发相关的关键免疫学事件。我们计划：(1)对225例SPK患者进行回顾性和前瞻性分析，以确定自身抗体复发的频率和时间进程以及自身抗体对疾病复发的预测价值；(2)对胰腺移植受者进行前瞻性随访，通过以下方法评估随访样本的体液和细胞反应：(a)监测自身抗体水平，(b)监测外周血中的自身反应性T细胞并对其进行表型分析，(c)通过对多种自身抗体持续复发的受者进行活组织检查来评估胰岛/胰腺病理，(d)监测通过胰腺移植外植体和/或活组织检查获得的胰腺浸润的自身反应性T细胞并对其进行表型分析。拟建的研究将确定SPK受体自身抗体、自身反应性T细胞、胰岛素和胰岛素分泌之间的关系。方法上的进步，如基于四聚体的检测，提供了一个前所未有的机会来表征表位特异性、贪婪性和自身反应性T细胞的功能状态，并比较外周血细胞和胰腺浸润细胞中的这些参数。这些研究将提供调控SPK受者自身免疫复发的免疫学机制的关键信息，并评估可能在胰腺移植环境中找到临床应用的实验室检测的预测价值。所获得的知识也应该与胰岛细胞移植和自发性疾病有关。

DESCRIPTION (provided by applicant): Since 1990 we have performed over 275 simultaneous pancreas and kidney (SPK) transplants in patients with type 1 diabetes (T1D) and end-stage renal disease. We are presently following 225 recipients. While all patients became insulin-independent, 34 (15%) have returned to hyperglycemia after a mean follow-up of 5.7 years. Our preliminary data demonstrate the presence of diabetes-associated autoantibodies preceding the return of hyperglycemia in approximately 65% of the patients with hyperglycemia and in 40% of normoglycemic SPK recipients. The observed frequency of autoimmunity in association with increased risk of hyperglycemia is higher than previously reported in smaller and earlier studies. Patients with selective loss of insulin secretion and without evidence of rejection were studied in detail and were found to have the cardinal features of recurrence of autoimmunity, including autoantibodies, insulitis and the presence of autoreactive T cells in peripheral blood assessed by recently developed tetramer-based assays. Thus, our data provide evidence that recurrent autoimmunity is a clinical problem of great significance that was previously underestimated. We have assembled a team of investigators with experience in pancreas transplantation (Burke, Miami) and the immunology of T1D (Pugliese, Miami; Nepom, Seattle) to study the key immunological events associated with recurrence of autoimmunity in SPK recipients. We plan to (1) retrospectively and prospectively analyze our cohort of 225 SPK patients to determine the frequency and time course of autoantibody recurrence and the predictive value of autoantibodies for recurrence of disease; (2) prospectively follow pancreas transplant recipients and assess humoral and cellular responses on follow-up samples by: (a) monitoring autoantibody levels, (b) monitoring and phenotyping autoreactive T cells in peripheral blood, (c) assessing islet/pancreas pathology from biopsies performed in recipients with consistent recurrence of multiple autoantibodies and (d) monitoring and phenotyping autoreactive T cells from the pancreatic infiltrate obtained by pancreatic transplant explants and/or biopsies. The proposed studies will define the relationship between autoantibodies, autoreactive T cells, insulitis and insulin secretion in SPK recipients. Methodological advances such as tetramer-based assays offer an unprecedented opportunity to characterize epitope specificity, avidity and the functional status of autoreactive T cells and compare these parameters in cells from peripheral blood and the pancreatic infiltrate. These studies will provide critical information about the immunological mechanisms regulating recurrence of autoimmunity in SPK recipients and assess the predictive value of laboratory tests that may find clinical application in the pancreas transplant setting. The knowledge gained should also be relevant to islet cell transplantation and spontaneous disease.