Induction of tolerance to islet cell transplants

描述（由申请人提供）： 最近的几项进展为建立胰岛素依赖型糖尿病（IDDM）的有效预防和治疗策略带来了新的希望：1）在理解调节性T细胞功能方面取得的进展，2）CTLA-4共刺激分子在下调T细胞功能和诱导耐受中的作用的新知识3）胰岛细胞移植的强大治疗潜力4）从异种来源或从同种异体干细胞系的操作中无限获得胰岛细胞的可能性。这些策略的结合，沿着对β细胞生理学的清楚理解，可能最终为治疗IDDM及其最终预防提供所需的治疗工具。此时，胰岛细胞移植为终身胰岛素治疗提供了强有力的替代方案。不幸的是，胰岛细胞移植的效用是有限的，由于移植排斥，毒性和全球免疫抑制与目前的许多免疫抑制疗法。胰岛特异性自身反应性T细胞的耐受将有助于预防IDDM和/或恢复胰岛细胞功能。因此，迫切需要开发新的治疗模式，其选择性地抑制针对胰岛的同种、异种或自身免疫应答，而对整体免疫应答几乎没有影响或没有影响。 在我们之前的工作中，我们表明由抗TSHR和抗CTLA-4抗体组成的双特异性抗体（BiAb）可以将抗CTLA-4递送至表达TSHR的细胞或组织（甲状腺），并诱导组织特异性耐受并预防自身免疫性甲状腺炎的发展。在本申请中，在目的1下，我们提出测试抗同种异体抗原（抗H2 d）/抗CTLA-4 BiAb在胰岛移植后诱导同种异体特异性免疫耐受的潜力。在目标2下，我们将测试由BiAb引发的T细胞调节的特异性和机制。在目标3下：我们将使用胰岛细胞特异性抗体和抗CTLA-4抗体制备新的BiAb，以测试在自发性糖尿病的鼠模型中预防和治疗I型DM的能力。

DESCRIPTION (provided by applicant): Several recent developments have instilled new hope for the establishment of effective prevention and treatment strategies for insulin depedent diabetes mellitus (IDDM): 1) Advances made in the understanding of regulatory T cell function, 2) New knowledge of the role the CTLA-4 costimulation molecule has in the down-modulation of T cell function and tolerance induction 3) the powerful therapeutic potential of islet cell transplantation 4) the possibility for the unlimited availability of islet cells from xenogeneic sources or from manipulations of allogeneic stem cell lines. A combination of these strategies, along with a clear understanding of beta cell physiology might eventually provide the required therapeutic tools for the treatment of IDDM and for its ultimate prevention. At this time, the islet cell transplantation provides a powerful alternative to a lifetime of insulin therapy. Unfortunately, the utility of islet cell transplants is limited due to graft rejection, toxicity and the global immunosuppression associated with many of the current immunosuppressive therapies. Tolerization of islet specific autoreactive T cells will help to prevent IDDM and/or restore islet cell function. Therefore, it is imperative to develop new modal/ties of treatment that selectively inhibit allo-, xeno- or autoimmune responses directed against islets with little or no effect on the global immune responses. In our previous work, we showed that a bispecific antibody (BiAb), consisting of anti-TSHR and anti-CTLA-4 antibodies can deliver anti-CTLA-4 to either cells or tissue (thyroid), that express TSHR and induce tissue-specific tolerance and prevent the development of autoimmune thyroiditis. In this application, under aim 1, we propose to test the potential of an anti-alloantigen (anti-H2d)/anti-CTLA-4 BiAb to induce allospecific immune tolerance upon islet transplantation. Under aim 2, we will test the specificity and mechanism of T cell modulation initiated by the BiAb. Under aim 3: we will prepare a new BiAb using an islet cell specific antibody and anti-CTLA-4 antibody to test ability to prevent and treat Type I DM in a murine model of spontaneous diabetes.