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

骨髓移植是治疗血液病的一种有效方法。 恶性肿瘤和其他危及生命的疾病。军人面临发展的风险 这种致命的条件是在他们的生命中接触致癌物质--如橙剂--的结果 现役军人。骨髓移植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 骨髓移植的炎性并发症。GVHD由供者白细胞亚群驱动，如供者 T淋巴细胞对骨髓植入和肿瘤预防都很重要 复发。需要新的治疗策略来保持供者T淋巴细胞在移植物中 为维持供者T淋巴细胞介导的抗肿瘤(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(Treg)的功能。我们的实验表明，肠道扩大术 免疫调节在体内诱导Tregs，从而抑制GVHD和 保存抗肿瘤免疫。我们诱导肠道免疫调节，或称“条件反射”。 使用一种全新的方法：用蠕虫对肠道进行自我限制的定植，以 刺激辅助性T细胞(Th2)免疫途径。在此应用程序中，我们建议测试中央 假设Th2通路在肠道免疫调节中起关键作用，并且它们 导致在体内产生Tregs。我们将使用小鼠线虫，Heligmosomoides 多回贝克氏杆菌(HPB)感染小鼠。我们将在未感染和蠕虫中诱发急性GVHD- MHC I/II重大错配供者感染的骨髓移植受者。评估Th2和Th2的作用 调节GVHD的Th2相关通路和Tregs的体内诱导，我们将使用 互补的遗传和药理学方法。我们将确定这些机制 通过肠道免疫调节增加Treg的调节活性，以及 建立小鼠肿瘤模型中蠕虫感染对GVT免疫的影响程度。 此外，我们将提供免疫调节和Th2相关细胞因子，白介素10 口服微粒进入未感染小鼠的肠道，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：识别细胞和分子免疫调节 在临床前模型中寄生虫免疫调节的关键途径；并应用这一点 向退伍军人和其他接受骨髓移植的患者群体提供知识。没有重要的一面 在免疫抑制的患者群体中，影响与蠕虫感染有关，如 患有炎症性肠病或多发性硬化症的个人。因此，目标是 蠕虫调节的信号通路-使用小分子、蠕虫产物或可能的 即使是完整的蠕虫-可能是一种安全而有效的GVHD治疗方法，使 GVT免疫力完好无损。

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.