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，其特征在于产生胰岛素的胰腺细胞的破坏。几种促炎细胞因子，如白细胞介素1 β、IL-1 β、肿瘤坏死因子α（TNF α）和干扰素γ（IFN-γ）参与胰岛中β细胞的免疫破坏。此外，通过诱导Th 1细胞发育的白细胞介素12（IL-12）已被证明是1型糖尿病发展的重要因素。移植胰岛自身免疫损伤的复发也是限制完全实现移植逆转1型糖尿病的一个因素。因此，开发新的方法来预防自身免疫性β细胞损伤或移植后复发可能会在该领域取得重大进展。Lisofylline（LSF）是一种抗炎化合物，已被证明可以阻断IL-12信号传导和Th 1细胞发育。LSF可以减少IL-1诱导的大鼠β细胞功能障碍。新的研究结果表明，LSF可以通过维持β细胞中正常的线粒体功能来部分预防尼古丁诱导的损伤。此外，数据表明，LSF可以显著减少NOD小鼠中自发的1型糖尿病发展。然而，LSF在临床上的应用有限，因为它具有非常短的半衰期，几乎没有口服生物利用度，并且是一种相对较弱的药剂，需要20 μ M的体外浓度才能看到这些效果。目前的试点提案将使用集中的组合化学设计来开发具有LSF相同活性谱的更有效、选择性和口服生物可利用的抗炎剂。目标#1将是设计和合成该文库并评估可能是口服稳定的药剂。目标#2将是使用我们开发的β细胞保护试验和IL-12信号传导试验筛选具有潜在口服稳定性和吸收的候选物。目标#3将在NOD小鼠中测试2种先导化合物，以确定它们在预防1型糖尿病发展中的作用。将进行功能和组织学研究。本提案的最终目标是确定一种主要口服候选药物，用于进一步详细的体外和体内开发，用于预防1型糖尿病的1/2期临床试验。该相同的化合物还应提供在胰岛细胞移植后维持β细胞功能的益处。

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.