Therapeutic delivery of FoxP3+ T cells to the intestine

描述(由申请人提供)：项目摘要：Foxp3+调节性T细胞在维持肠道免疫耐受方面发挥关键作用。Foxp3+调节性T细胞不仅迁移到肠道，还迁移到其他器官，以调节免疫反应。指导FoxP3+T细胞向肠道迁移的机制以及它们对肠道相对于其他器官的特异性在很大程度上尚不清楚。这是将FoxP3+T细胞发展成专门针对肠炎性疾病的细胞疗法的一个重大问题。这项应用的目标是设计策略，通过这些策略，我们可以生成针对正常或炎症肠道的肠道归巢FoxP3+T细胞。这一应用的中心假设是，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。我们的理论基础是，在拟议的研究完成后，通过调节FoxP3+T细胞向正常或患病肠道的迁移，将有可能更有效地预防或抑制肠道炎症性疾病。此外，它将有可能提高FoxP3+T细胞对肠道炎症性疾病的特异性，但减少调节性T细胞疗法对其他器官中病原体或癌细胞的必要免疫反应的副作用。为了验证这一假设并实现这一目标，我们提出了以下目标。具体目标1：确定肠道归巢FoxP3+T细胞的时间和空间来源；具体目标2：建立策略以生成优先迁移到肠道而不是其他器官的FoxP3+调节性T细胞；特定目标3：建立针对肠道内炎症组织部位的FoxP3+调节性T细胞生成策略。作为结果，我们将有为正常肠道量身定做的FoxP3+T细胞来预防炎症，或为发炎的肠道定制以抑制已建立的炎症。一旦该策略被提议的研究验证，它也可以应用于对其他组织部位疾病的特定抑制。与公共健康相关：这项研究将提供产生FoxP3+调节性T细胞的策略，这种T细胞可以特异性地针对正常或炎症的肠道，并有效地预防或抑制炎症。因此，本研究对预防和控制肠道炎症性疾病具有积极意义。此外，研究结果将对其他慢性炎症性疾病的治疗产生深远影响。

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.