Regulation of graft versus host disease with in vivo generated regulatory T cells

骨髓移植（BMT）是治疗血液病的有效方法。 恶性肿瘤和其他危及生命的疾病。军人面临发展风险 这种致命的条件是由于暴露于致癌物-如橙子-在他们的 现役BMT的成功受到移植物抗宿主病（GVHD）的限制，这是一种致命的疾病。 骨髓移植炎性并发症。GVHD由供体白细胞亚群驱动，例如供体白细胞亚群。 T淋巴细胞对骨髓移植和肿瘤预防都很重要 复发需要新的治疗策略来保持移植物中的供体T淋巴细胞， 为了维持供体T淋巴细胞介导的抗肿瘤（移植物抗肿瘤; GVT）免疫 同时抑制GVHD一种新的方法是治疗性刺激 调节性T细胞（Tcells）我们的实验表明， 免疫调节在体内诱导T细胞增殖，导致GVHD的抑制和移植物抗宿主病。 保持抗肿瘤免疫力。我们诱导肠道免疫调节，或“条件反射”， 使用一种全新的方法：蠕虫在肠道的自限性定植， 刺激辅助性T细胞2（Th 2）免疫途径。在本申请中，我们建议测试中央 假设Th 2途径在肠道免疫调节中至关重要， 导致体内TdR的产生。我们将使用鼠线虫Heligmosomoides 巴氏多脑回（polygyrusbakeri，Hpb）感染小鼠。我们会在未感染者和寄生虫身上诱发急性移植物抗宿主病- MHC I/II主要错配供体的受感染BMT受体。为了评估Th 2的作用， Th 2相关通路在调节GVHD和体内诱导TcB中的作用， 互补的遗传学和药理学方法。我们将确定 肠道免疫调节通过其增加了TdR的调节活性，和 在小鼠肿瘤模型中确定蠕虫感染影响GVT免疫的程度。 此外，我们将提供免疫调节和Th 2相关细胞因子，白细胞介素10， 通过经口管饲法将微颗粒植入未感染小鼠的肠道中，以模拟蠕虫诱导的 肠道免疫调节这些研究的结果有望帮助我们实现 我们的长期目标是：确定细胞和分子免疫调节 在临床前模型中对蠕虫免疫调节起关键作用的途径;并将其应用于 知识的退伍军人和其他患者群体接受BMT。无明显副 在免疫抑制的患者群体中， 患有炎症性肠病或多发性硬化症的个体。因此， 蠕虫调节的信号通路-使用小分子，蠕虫产品或可能 即使是完整的蠕虫-可能是一种安全有效的治疗GVHD的方法， GVT免疫系统完好

Bone marrow transplantation (BMT) is a curative approach for treating hematological malignancies and other life-threatening disorders. Military servicemen are under risk to develop such lethal conditions as a result of exposure to carcinogens – like agent orange – during their active service. The success of BMT is limited by graft versus host disease (GVHD), a lethal inflammatory complication of BMT. GVHD is driven by donor leukocyte subsets, such as donor T lymphocytes that are important for both bone marrow engraftment and the prevention of tumor recurrence. Novel treatment strategies are needed to keep donor T lymphocytes in the graft in order to maintain donor T lymphocyte-mediated anti-tumor (graft versus tumor; GVT) immunity while suppressing the GVHD. One novel approach to this is therapeutic stimulation of the function of regulatory T cells (Tregs). Our experiments show that augmentation of intestinal immune regulation induces Tregs in vivo, resulting in the suppression of GVHD and the preservation of anti-tumor immunity. We induce intestinal immune regulation, or “conditioning,” using a completely novel approach: self-limited colonization of the gut with helminths, to stimulate T helper 2 (Th2) immune pathways. In this application, we propose to test the central hypothesis that the Th2 pathways are critical in intestinal immune conditioning, and that they lead to the generation of Tregs in vivo. We will use the murine nematode, Heligmosomoides polygyrus bakeri (Hpb) to infect mice. We will induce acute GVHD in uninfected and helminth- infected BMT recipients of MHC I/II major mismatch donors. To assess the roles of Th2 and Th2-associated pathways in regulating GVHD and the in vivo induction of Tregs, we will employ complementary genetic and pharmacological approaches. We will determine the mechanisms through which intestinal immune conditioning increases the regulatory activity of Tregs, and establish the extent to which helminth infection affects GVT immunity in mouse tumor models. Furthermore, we will deliver immune regulatory and Th2-associated cytokine, interleukin 10 microparticles into the gut of uninfected mice by oral gavage, to mimic helminth-induced intestinal immune conditioning. The findings from these studies are expected to help us achieve our long-term goals, which are to: identify the cellular and molecular immune regulatory pathways that are key to helminthic immune conditioning in preclinical models; and to apply this knowledge to veterans and other patient populations that undergo BMT. No significant side effects have been associated with helminth infection in immune suppressed patient groups, like individuals with inflammatory bowel disease or multiple sclerosis. Thus, the targeting of helminth-modulated signaling pathways – using small molecules, helminth products or possibly even intact helminths – may be a safe and potent treatment for GVHD that leaves the beneficial GVT immunity intact.