Therapeutic delivery of FoxP3+ T cells to the intestine

项目概述：FoxP3+调节性T细胞在维持肠道免疫耐受中发挥关键作用。FoxP3+调节性T细胞不仅迁移到肠道，还迁移到其他器官调节免疫反应。引导FoxP3+ T细胞迁移到肠道的机制及其对肠道与其他器官的特异性在很大程度上是未知的。这是将FoxP3+ T细胞发展成专门针对肠道炎症性疾病的细胞疗法的一个重要问题。这项应用的目的是设计策略，我们可以产生肠道归巢FoxP3+ T细胞特异性为正常或发炎的肠道。该应用的中心假设是FoxP3+ T细胞向正常和炎症肠道的迁移可以通过调节FoxP3+ T细胞中肠道归巢受体的表达来控制。我们的理由是，在本研究完成后，通过调节FoxP3+ T细胞向正常或病变肠道的迁移，将有可能更有效地预防或抑制肠道炎症性疾病。此外，有可能增加FoxP3+ T细胞对肠道炎症性疾病的特异性，但减少调节性T细胞治疗对其他器官中病原体或癌细胞的必要免疫反应的副作用。我们提出以下目标来验证假设并实现目标。具体目标#1：确定肠道归巢FoxP3+ T细胞的时空起源；具体目标#2：建立策略，生成优先迁移到肠道而不是其他器官的FoxP3+调节性T细胞；具体目标#3：建立策略，产生FoxP3+调节性T细胞，靶向肠内炎症组织部位。结果，我们将为正常肠道量身定制FoxP3+ T细胞，以预防炎症或为炎症肠道抑制已建立的炎症。一旦该策略被提出的研究证实，它也可以应用于其他组织部位的疾病的特异性抑制。与公共卫生相关：该研究将为FoxP3+调节性T细胞的产生提供策略，FoxP3+调节性T细胞可以特异性靶向正常或炎症肠道，并有效预防或抑制炎症。因此，本研究将对肠道炎症性疾病的预防和控制产生积极影响。此外，该结果将对其他慢性炎症性疾病的治疗产生深远的影响。

DESCRIPTION (provided by applicant): Project Summary: FoxP3+ regulatory T cells play critical roles in maintaining immune tolerance in the intestine. FoxP3+ regulatory T cells migrate not only to the intestine but also to other organs for regulation of immune responses. The mechanisms that direct the migration of FoxP3+ T cells to the intestine and their specificity for the intestine versus other organs are largely unknown. This is a significant problem in developing FoxP3+ T cells into cellular therapeutics specifically targeting inflammatory diseases of the intestine. The objective of this application is to devise strategies by which we can generate gut-homing FoxP3+ T cells specific for normal or inflamed intestine. The central hypothesis of this application is that migration of FoxP3+ T cells to normal and inflamed intestine can be controlled by regulating the expression of gut-homing receptors in FoxP3+ T cells. Our rationale is that it will become possible to more effectively prevent or suppress inflammatory diseases in the intestine by regulating the migration of FoxP3+ T cells to normal or diseased intestine after the proposed research is completed. Also, it will be possible to increase the specificity of FoxP3+ T cells for inflammatory diseases in the intestine but reduce the side effect of the regulatory T cell therapy on necessary immune responses to pathogens or cancer cells in other organs. We propose the following aims to validate the hypothesis and accomplish the goal. Specific aim #1: Determine the temporal and spatial origin of gut- homing FoxP3+ T cells; Specific aim #2: Establish strategies to generate FoxP3+ regulatory T cells that preferentially migrate to intestine versus other organs; Specific aim #3: Establish strategies to generate FoxP3+ regulatory T cells that target inflamed tissue sites within the intestine. As the outcome, we will have the FoxP3+ T cells tailor-made for normal intestine to prevent inflammation or for inflamed intestine to suppress established inflammation. Once the strategy is validated by the proposed studies, it can be applied also to specific suppression of diseases at other tissue sites. Relevance to Public Health: The research will provide strategies for generation of FoxP3+ regulatory T cells that can specifically target normal or inflamed intestine and effectively prevent or suppress inflammation. Therefore, the proposed research will have positive impacts on prevention and control of inflammatory diseases in the intestine. In addition, the outcomes will have far-reaching implications for treatment of other chronic inflammatory disorders.