Repurposed Drugs to Inhibit Human T Cells and Autoimmunity

描述（由申请人提供）：适应性免疫系统在对病毒、细菌和寄生虫感染的应答中至关重要。虽然它可以执行这种基本的保护功能，但它也会引起疾病。这方面的例子包括自身免疫性疾病，如系统性红斑狼疮（SLE）、类风湿性关节炎（RA）和多发性硬化症（MS），其中不适当地产生针对自身的免疫应答。此外，在器官排斥、移植物抗宿主病（GVHD）和过敏期间的不需要的免疫应答是主要的临床问题。所有这些疾病的共同点是，T细胞必须被激活，增殖并执行其效应器功能才能发生病理。尽管药物在临床上用于治疗自身免疫综合征或预防器官排斥，但它们具有有害的副作用，包括高血压、高脂血症、疱疹病毒感染增加和肾病。因此，迫切需要开发更有效和更安全的治疗方法来抑制多种人类疾病中的T细胞。虽然我们迫切需要新的治疗方法，但开发小分子药物是一项长期而昂贵的奋进。在美国，10至15年的平均成本在5亿至20亿美元之间。然而，大多数药物通常由于对人类的毒性作用而在开发中失败。一种新兴的替代方法是将FDA批准的药物重新用于新的用途，而不是开发新药。正如我们在初步研究部分中所记录的，我们已经利用了“再利用”的力量，并确定阿达帕林、氟苯达唑、氟斯匹林和奥苯达唑抑制健康小鼠和MRL-lpr/lpr小鼠的小鼠T细胞增殖和细胞因子产生。我们假设这些化合物将抑制人T细胞的活化、增殖和细胞因子产生，并且在系统性红斑狼疮（SLE）的临床前模型中具有功效。特定目标1将确定阿达帕林、氟苯达唑、氟斯匹林和奥苯达唑是否抑制人CD 4+和CD 8 + T细胞的活化、增殖和细胞因子产生。为此，我们将从健康供体的血液中分离出CD 4+和CD 8 + T细胞，并确定我们的化合物是否可以抑制它们的活化和增殖。我们将在体外从每个供体产生极化的Th 1、Th 2、Th 17、Tc 1和Tc 2效应细胞，并确定我们的化合物是否可以抑制细胞因子的产生。具体目标2将确定阿达帕林、氟苯达唑、氟斯匹林和奥苯达唑是否可以预防MRL-lpr/lpr小鼠模型中的自身免疫性疾病。在这个目标中，我们将使用MRL-lpr/lpr模型确定这些化合物在体内预防自身免疫性疾病中的功效。在这些研究的结论中，我们将确定我们的化合物中的哪些能够抑制人T细胞的活化、增殖和细胞因子产生。此外，我们将确定哪些化合物能够在鼠模型中预防自身免疫性疾病。这将使我们处于有利地位，开始临床试验， 用于多种免疫疾病包括变态反应、移植和SLE的化合物。

DESCRIPTION (provided by applicant): The adaptive immune system is critical in the response to viral, bacterial and parasitic infections. While it can perform this essential protectie function, it also causes disease. Examples of this include autoimmune diseases, such as systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and multiple sclerosis (MS), where an immune response is inappropriately generated against self. In addition, unwanted immune responses during organ rejection, graft versus host disease (GVHD) and allergies are major clinical problems. What all of these diseases have in common is that T cells must become activated, proliferate and perform their effector functions for pathology to occur. Although drugs are used in the clinic to treat autoimmune syndromes or prevent organ rejection, they have deleterious side effects including hypertension, hyperlipidemia, increased herpesvirus infection, and renal nephropathy. Thus there is a pressing medical need to develop more effective and safer therapeutics to suppress T cells in a multitude of human diseases. While we desperately need new treatments, developing small molecule drugs is a long and costly endeavor. In the United States the average cost is between 500 million to 2 billion USD over 10 to 15 years. Yet most drugs will fail in development typically due to toxicity effects in humans. Instead of developing new drugs, an emerging alternative is to repurpose FDA-approved drugs for new purposes. As we document in the preliminary studies section, we have harnessed the power of "repurposing" and determined that adapalene, flubendazole, fluspirilene, and oxibendazole inhibit murine T cell proliferation and cytokine production from healthy and MRL-lpr/lpr mice. We hypothesize that these compounds will inhibit the activation, proliferation and cytokine production of human T cells and have efficacy in a preclinical model of systemic lupus erythematosus (SLE). Specific Aim 1 will determine if adapalene, flubendazole, fluspirilene, and oxibendazole inhibit the activation, proliferation and cytokine production of human CD4+ and CD8+ T cells. In this aim we will isolate CD4+ and CD8+ T cells from the blood of healthy donors and determine whether our compounds can inhibit their activation and proliferation. We will generate polarized Th1, Th2, Th17, Tc1, and Tc2 effector cells in vitro from each donor and determine whether the production of cytokines can be inhibited by our compounds. Specific Aim 2 will determine if adapalene, flubendazole, fluspirilene, and oxibendazole can prevent autoimmune disease in the MRL-lpr/lpr mouse model. In this aim we will determine the efficacy of these compounds in the prevention of autoimmune disease in vivo using the MRL-lpr/lpr model. At the conclusion of these studies we will have determined which of our compounds are able to inhibit the activation, proliferation and cytokine production of human T cells. Furthermore, we will have determined which compounds are capable of preventing autoimmune disease in a murine model. This will put us in a strong position to begin clinical testing of these compounds for use in multiple immunologic diseases including allergies, transplantation and SLE.