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从实验室到床边的方案，用一种新的细胞治疗方法治疗自身免疫性炎症性肠病（IBD），该方法使用致耐受性的、干扰素刺激的、单核细胞衍生的细胞群（称为IFN-MdC）。该概念涉及消除和控制IBD引起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，并且细胞的治疗应用减少了小鼠的IBD。此外，我们认为IFN-γ-MdC对其他自身免疫性疾病具有更广泛的治疗适用性，其中T调节细胞被认为能够控制和逆转疾病状态。本研究将侧重于三个基本目标。首先，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IFN-γ-MdC群体。我们将重点学习哪些生长因子用于IFN-γ-MdC的产生是最关键的免疫抑制活性。此外，我们将查明IFN-MdC混合群体中介导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其发育。我们的目标将是从根本上创造一个配方，用于生产最佳功能的IFN-γ-MdC，这将涉及混合特定比例的不同纯化细胞类型（例如单核细胞+CD 4细胞）。这是开始临床研究之前的关键一步，因为确定用于产生IFN？-MdC的细胞和条件将使它们在治疗上更具重现性。该研究的第二个目的是确定IFN？-MdC发挥作用的机制。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，第三个研究目标是使用IFN-γ-MdC治疗人类IBD。基于前两个目标的发现，我们将制定一项治疗克罗恩病患者的临床方案。这方面的研究可能会在供资期的晚些时候进行，但仍然是项目的一个现实目标。因此，我们的目的是与目前的建议，以更好地表征，机械地理解，并完善最佳的临床使用的干扰素MdC。这些目标的成功实现可能为某些类型的自身免疫性疾病，特别是IBD患者提供新的治疗选择。

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.