ISLET TOLERANCE INDUCTION BASED ON ANTI-CD154 ANTIBODY

超出提供的空间。 阻断共刺激诱导移植耐受可显著延长胰岛和同种异体皮肤移植存活时间 在啮齿动物和灵长类动物中存活。我们现在建议将这些基础研究转化为用于人类胰岛同种异体移植。 种植园。我们假设一个由单一供者特异性输血(DST)加上 CMTI-CD154(抗CD40配体)抗体的短期治疗将诱导同种异体胰岛移植的永久存活 外科胰腺切除术后继发的糖尿病。我们进一步假设这些同种异体胰岛移植物在 没有慢性免疫抑制。这些假设是基于我们观察到的两元素方案 诱导化学性糖尿病小鼠同种异体胰岛移植的永久存活和非人类同种异体皮肤的长期存活 灵长类动物(&gt；185天，仍在继续)。我们建议使用一种新的研究性抗CD154来启动一项临床试验 为此，我们实验室专门提供了一种名为IDEC-131的单抗试剂。我们建议将- 我们的肝内胰岛移植治疗人类糖尿病的二联疗法。 具体目标1是对“继发性”需要胰岛素的糖尿病患者进行根治性同种异体胰岛移植 由于全胰腺或次全胰腺切除。这种形式的糖尿病通常很难控制，并与显著的 不能发病。此外，它发生在缺乏自身免疫和胰岛素抵抗的情况下，这两个因素可能会令人困惑 II期转化性临床试验的结果。继发性胰岛素依赖型糖尿病的治疗 通过注射胰岛素进行胰腺全切除或部分切除是不能治愈的；移植提供了当代唯一的希望。 解药。治愈糖尿病而不求助于慢性免疫抑制，这在任何情况下对胰岛基本上无效 同种异体移植可以说是糖尿病专家的圣杯 特定目的2启动同种异体胰岛移植耐受诱导机制的研究(S) 并使用外周血淋巴细胞评估一种新的细胞因子分析，这将使我们能够预测 同种异体移植排斥反应的发作。这些研究将与哈佛大学和康奈尔大学的研究人员合作进行 医学院。 我们希望这项试验可以为同种异体移植开辟一条新的道路。

EXCEED THE SPACE PROVIDED. Transplantation tolerance induction based on blockade of co-stimulation greatly prolongs islet and skin allograft sur- vival in rodents and primates. We now propose to translate these basic research studies for use in human islet allotrans- plantation. Wehypothesize that a two-elementprotocol consisting of a single donor-specific transfusion (DST) plus a brief course ofcmti-CD154 (anti-CD40 ligand) antibody will induce permanent islet allograft survival in humans with diabetes mellitus secondary to surgical pancreatectomy. We further hypothesize that these islet allografts will survive in the absence of chronic immunosuppression. These hypotheses are based on our observation that the two-element protocol induces permanent islet allograft survival in chemically diabetic mice and long-term skin allograft survival in non-human primates (>185 days and still ongoing). We propose to initiate a clinical trial using a novel investigational anti-CD 154 monoclonal reagent, IDEC-131, being made available to our laboratory specifically for this purpose. We propose to trans- late our two-element protocol for use in treating human diabetes mellitusby intrahepatic islet transplantation. Specific Aim 1 is to perform curative islet allotransplantation in patients with "secondary" insulin-requiring diabetes due to total or sub-total pancreatectomy. This form of diabetes is typically difficult to control and associated with signifi- cant morbidity. In addition, it occurs in the absence of autoimmunity and insulin resistance, two factors that could confound the outcome of a phase II translational clinical trial. Treatment of the secondary insulin-requiring diabetes that occurs after total or partial pancreatectomy by insulin injection is not curative; transplantation offers the only contemporary hope of a cure. Cure of diabetes without recourse to chronic immunosuppressionwhich in any event is largely ineffective for islet allograftsis arguably the Holy Grail of diabetologists Specific Aim 2 to initiate an investigation of the mechanism(s) by which allograft tolerance is induced in islet allograft recipients and to assess a novel cytokine analysis using peripheral blood lymphocytes that will permit us to anticipate episodes of allograft rejection. These studies will be undertaken in collaboration with investigators at Harvard and Cornell Medical Schools. It is our hope that this trial may open the way to a new approach to allotransplantation in general.