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啮齿动物和灵长类动物的胰岛和同种异体皮肤移植存活时间。我们现在建议将这些基础研究转化为用于人类同种异体胰岛移植。我们假设，由单一供者特异性输血(DST)和短程cmti-CD154(抗CD40配体)抗体组成的两组分方案将诱导继发于外科胰腺切除术的糖尿病患者的胰岛移植物永久存活。我们进一步假设，在没有慢性免疫抑制的情况下，这些同种异体胰岛移植物将存活。这些假设是基于我们的观察，即两种成分的方案可以诱导化学性糖尿病小鼠的永久胰岛移植存活，以及非人类灵长类动物的长期同种异体皮肤移植存活(&gt；185天，目前仍在进行中)。我们建议启动一项临床试验，使用一种新的研究性抗CD154单抗试剂IDEC-131，该试剂专门为此目的而提供给我们的实验室。我们建议通过肝内胰岛移植来移植我们的二元方案，用于治疗人类糖尿病。具体目标1是对因全胰腺或次全胰腺切除而导致的“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。这种形式的糖尿病通常很难控制，并与显著的发病率相关。此外，它发生在没有自身免疫和胰岛素抵抗的情况下，这两个因素可能会混淆II期翻译临床试验的结果。通过注射胰岛素治疗胰腺全切除或部分切除后发生的继发性需要胰岛素的糖尿病是不能治愈的；移植是当代治愈的唯一希望。糖尿病的治疗不求助于慢性免疫抑制，在任何情况下，这在很大程度上对同种异体胰岛移植无效，可以说是糖尿病专家的圣杯2启动一项关于同种异体胰岛移植耐受诱导机制的研究(S)，并评估一种使用外周血淋巴细胞的新的细胞因子分析，使我们能够预测同种异体移植排斥反应的发生。这些研究将与哈佛和康奈尔医学院的研究人员合作进行。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。表演网站========================================Section End===========================================

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. PERFORMANCE SITE ========================================Section End===========================================