Use of Monocyte-Derived Cells to Control Autoimmune Reactions in Patients with Chronic Inflammatory Bowel Disease

我们的目标是开发一种治疗自身免疫性炎症性肠病(IBD)的床边方案，该方案采用一种新的细胞治疗方法，使用产生耐受性的干扰素刺激的单核细胞来源的细胞群(称为干扰素-MDC)。这一概念涉及消除和控制导致IBD的自身反应性淋巴细胞。我们的早期工作表明，这种细胞群具有独特的特征，这种细胞的治疗应用可以减少小鼠的IBD。此外，我们认为，干扰素-MDC对其他自身免疫性疾病具有更广泛的治疗适用性，在这些疾病中，T调节细胞被认为能够控制和逆转疾病状态。本研究将围绕三个基本目标展开。首先，我们将进行实验，以更好地表征我们发现在体外和体内都有效的干扰素-MDC群体。我们将重点了解用于产生干扰素-MDC的哪些生长因子对其免疫抑制活性最关键。此外，我们将确定干扰素-MDC混合群体中调节其活性的更确切的细胞类型，并确定哪些辅助细胞可能支持它们的发育。其目标将是从根本上创造一种生产功能最佳的干扰素-MDC的配方，其中包括混合不同纯化细胞类型(例如单核细胞+CD4细胞)的特定比例。这是开始临床研究之前的关键一步，因为确定用于生产干扰素-MDC的细胞和条件将使它们在治疗上更具重复性。这项研究的第二个目的将是确定干扰素-MDC的作用机制。我们预计这是一个复杂的机制，可能涉及细胞表面(接触)分子和细胞因子。最后，第三项研究的目标是将干扰素-MDC用于治疗人类IBD。基于前两个目标中的发现，我们将制定治疗克罗恩？S病患者的临床方案。这方面的研究可能会在资助期晚些时候进行，但这仍然是该项目的一个现实目标。因此，我们目前的建议旨在更好地描述、机械地理解和完善干扰素-MDC的最佳临床应用。这些目标的成功实现可能会为某些类型的自身免疫性疾病患者带来新的治疗选择，特别是IBD。

Our aim is to develop a bench-to-bedside protocol to treat autoimmune inflammatory bowel diseases (IBD) with a novel cell therapy approach using a tolerogenic, interferon-¿ stimulated, monocyte-derived, cell population (referred to as IFN¿-MdC). The concept involves the elimination and control of IBD-causing auto-reactive lymphocytes. Our early work shows this cell population has unique characteristics, and therapeutic application of the cells reduces IBD in mice. Moreover, we suggest that IFN¿-MdC have a broader therapeutic applicability to other autoimmune diseases where T regulatory cells are thought to be capable of controlling and reversing the disease state. This study will focus on three basic aims. First, experiments will be performed to better characterize the IFN¿-MdC population that we find to be effective both in vitro and in vivo. We will focus on learning which growth factors used for IFN¿-MdC generation are most critical for their immunosuppressive activities. Moreover, we will pinpoint the more exact cell type in the IFN¿-MdC mixed population that mediates their activity and determine what ¿accessory cells¿ may support their development. The goal will be to essentially create a formula for the production of optimally functioning IFN¿-MdC that would involve mixing specific proportions of different purified cell types (e.g. monocytes + CD4 cells). This is a critical step before beginning clinical studies because defining the cells and conditions used to produce IFN¿-MdC will make them therapeutically more reproducibly effective. A second aim of the study will be to determine the mechanism by which IFN¿-MdC function. We expect this is a complex mechanism, likely involving both cell surface (contact) molecules and cytokines. Finally, the third study aim will be to use IFN¿-MdC for the treatment of IBD in humans. Based on the findings in the first two aims, we will develop a clinical protocol for the treatment of Crohn¿s disease in patients. This aspect of the study will likely take place later in the funding period, but nonetheless is a realistic goal of the project. Therefore, we aim with the current proposal to better characterize, mechanistically understand, and refine the optimal clinical use of IFN¿-MdC. Successful accomplishment of the aims could yield a new treatment option for patients with certain types of autoimmune diseases, particularly IBD.