Repurposed Drugs to Inhibit Human T Cells and Autoimmunity

描述(由申请人提供)：适应性免疫系统在应对病毒、细菌和寄生虫感染方面至关重要。虽然它可以执行这种基本的保护功能，但它也会导致疾病。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)，这些疾病不适当地产生针对自身的免疫反应。此外，器官排斥反应、移植物抗宿主病(GVHD)和过敏是主要的临床问题。所有这些疾病的共同点是，T细胞必须被激活、增殖并发挥其效应功能，才能发生病理学。虽然药物在临床上用于治疗自身免疫综合征或预防器官排斥反应，但它们有有害的副作用，包括高血压、高脂血症、疱疹病毒感染增加和肾脏肾病。因此，医学上迫切需要开发更有效和更安全的疗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漫长而昂贵的努力。在美国，10到15年的平均成本在5亿到20亿美元之间。然而，大多数药物在开发过程中都会失败，通常是因为对人体的毒性影响。代替开发新药，一种新兴的替代方案是将FDA批准的药物重新用于新用途。正如我们在初步研究部分中所述，我们已经利用了“再利用”的力量，并确定阿达帕林、氟苯达唑、氟螺环烯和奥苯达唑可以抑制健康和MRL-LPR/LPR小鼠的T细胞增殖和细胞因子的产生。我们假设这些化合物将抑制人类T细胞的激活、增殖和细胞因子的产生，并在系统性红斑狼疮(SLE)的临床前模型中具有疗效。具体目标1将确定阿达帕林、氟苯达唑、氟螺环烯和奥苯达唑是否抑制人类CD4+和CD8+T细胞的激活、增殖和细胞因子的产生。在这个目标中，我们将从健康捐赠者的血液中分离出CD4+和CD8+T细胞，并确定我们的化合物是否可以抑制它们的激活和增殖。我们将在体外从每个捐赠者身上产生极化的Th1、Th2、Th17、Tc1和Tc2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、氟螺环烯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。为此，我们将使用MRL-LPR/LPR模型在体内确定这些化合物在预防自身免疫性疾病方面的有效性。在这些研究的结论中，我们将确定我们的哪些化合物能够抑制人类T细胞的激活、增殖和细胞因子的产生。此外，我们将在小鼠模型中确定哪些化合物能够预防自身免疫性疾病。这将使我们处于有利地位，可以开始对这些药物进行临床测试 用于多种免疫疾病的化合物，包括过敏、移植和系统性红斑狼疮。

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.