New Antiinflammatory Agents to Prevent Damage to Islets

描述(由申请人提供)： 1型糖尿病是一种自身免疫性疾病，其特征是产生胰岛素的胰腺细胞遭到破坏。几种促炎细胞因子，如IL-1β、IL-1β、肿瘤坏死因子α(TNFpha)和干扰素-γ(IFN-Gamma)参与了对胰岛β细胞的免疫破坏。此外，白介素12(IL-12)通过诱导Th1细胞的发育已被证明是1型糖尿病发生的一个重要因素。移植胰岛自身免疫损伤的复发也是限制通过移植完全逆转1型糖尿病的一个因素。因此，开发新的方法来预防移植后对β细胞的自身免疫损伤或其复发可能是该领域的重大进展。利索茶碱(LSF)是一种抗炎化合物，已被证明可以阻断IL-12信号和Th1细胞的发育。LSF可减轻IL-1诱导的大鼠胰岛β细胞功能障碍。新的结果表明，LSF可以部分地通过维持β细胞的正常线粒体功能来防止细胞因子诱导的损伤。此外，数据表明，LSF可以显著减少NOD小鼠自发性1型糖尿病的发生。然而，LSF的临床应用将受到限制，因为它的半衰期非常短，几乎没有口服生物利用度，而且是一种相对较弱的药物，需要20微米的体外浓度才能看到这些效果。目前的试点方案将使用有重点的组合化学设计来开发更有效、更有选择性和口服生物可用的抗炎药，具有与LSF相同的活性谱。第一个目标是设计和合成这个文库，并评估可能是口服稳定的药物。目标2将是使用我们开发的β细胞保护试验和IL-12信号试验来筛选具有潜在口服稳定性和吸收的候选药物。目的#3将在NOD小鼠身上测试这两种先导化合物，以确定它们在预防1型糖尿病发展方面的效果。将进行功能和组织学研究。这项建议的最终目标是为预防1型糖尿病的1/2期临床试验确定进一步详细的体外和体内开发的主要口服候选药物。同样的化合物(S)也应该有利于胰岛细胞移植后维持β细胞功能。

DESCRIPTION (provided by applicant): Type 1 diabetes is an autoimmune disorder characterized by the destruction of insulin-producing pancreatic ( cells. Several pro-inflammatory cytokines, such as interleukin 1 beta, IL-1beta, Tumor necrosis factor alpha (TNFalpha) and Interferon gamma (IFN-gamma) participate in the immune destruction of beta cells in the islet. Furthermore, interleukin 12 (IL-12) by inducing Th1 cell development has been shown to be an important factor in Type 1 diabetes development. Recurrence of autoimmune damage to transplanted islets also is one factor limiting the full realization of reversal of Type 1 diabetes with transplantation. Therefore, development of new methods to prevent autoimmune damage to beta cells or its recurrence after transplantation could provide a major advance in the field. Lisofylline (LSF) is an anti-inflammatory compound that has been shown to block IL-12 signaling and Th1 cell development. LSF can reduce IL-1-induced beta dysfunction in isolated rat beta cells. New results indicate that LSF can prevent cytokine-induced damage in part by maintaining normal mitochondrial function in beta cells. In addition, data suggests that LSF can significantly reduce spontaneous Type 1 diabetes development in the NOD mouse. However, LSF will have limited use clinically since it has a very short half-life and almost no oral bioavailability and is a relatively weak agent, requiring 20muM concentration in vitro for these effects to be seen. The current pilot proposal will use a focused combinatorial chemistry design to develop more potent, selective, and orally bioavailable anti-inflammatory agents with the same spectrum of activity of LSF. Aim #1 will be to design and synthesize this library and evaluate agents likely to be orally stable. Aim #2 will be to screen candidates with potential oral stability and absorption using both the beta cell protection assays and IL-12 signaling assays we have developed. Aim #3 will test the 2 lead compounds in the NOD mouse to determine their effects in preventing Type 1 diabetes development. Functional and histological studies will be performed. The ultimate goal of this proposal is to identify a lead oral candidate for further detailed in vitro and in vivo development for a Phase 1/2 clinical trial to prevent Type 1 diabetes. This same compound(s) should also provide benefit to maintain beta cell function after islet cell transplantation.