Recurrence of T1D in Pancreas Transplantation

描述(申请人提供)：自1990年以来，我们为患有1型糖尿病(T1D)和终末期肾脏疾病的患者进行了超过275例胰腺和肾脏(SPK)联合移植。我们目前正在跟踪225名获奖者。虽然所有患者都获得了胰岛素依赖，但34名患者(15%)在平均5.7年的随访期后恢复了高血糖。我们的初步数据显示，在大约65%的高血糖患者和40%血糖正常的SPK接受者中，在高血糖复发之前存在糖尿病相关自身抗体。观察到的自身免疫与高血糖风险增加相关的频率高于先前在较小规模和更早的研究中报告的频率。对选择性胰岛素分泌丧失和无排斥证据的患者进行了详细的研究，发现他们具有自身免疫复发的基本特征，包括自身抗体、胰岛素炎和最近发展起来的基于四聚体的检测方法评估外周血中存在自身反应性T细胞。因此，我们的数据提供了证据，表明复发性自身免疫是一个先前被低估的重要临床问题。我们组建了一个在胰腺移植(伯克，迈阿密)和T1D免疫学(Pugliese，迈阿密；Nepom，西雅图)方面有经验的研究团队，以研究与SPK接受者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)前瞻性跟踪胰腺移植受者，并通过以下方式评估后续样本的体液和细胞反应：(A)监测自身抗体水平，(B)监测外周血中反应性T细胞并进行表型鉴定，(C)从多种自身抗体持续复发的受者的活检组织中评估胰岛/胰腺病理，以及(D)监测和表型从胰腺移植植片和/或活检组织中获得的胰腺浸润物中的自体反应性T细胞。这项拟议的研究将确定SPK接受者的自身抗体、自身反应性T细胞、胰岛素炎症和胰岛素分泌之间的关系。方法学的进步，如基于四聚体的分析，提供了一个前所未有的机会来表征自身反应性T细胞的表位特异性、亲和力和功能状态，并比较来自外周血和胰腺浸润液的细胞中的这些参数。这些研究将提供调节SPK受者自身免疫复发的免疫学机制的关键信息，并评估实验室检测的预测价值，这些检测可能会在胰腺移植环境中找到临床应用。所获得的知识也应该与胰岛细胞移植和自发性疾病相关。

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.