Mixed Chimerism-Dependent Tolerance After Myeloablative Bone Marrow Transplantation

移植物抗宿主病（GVHD）是造血干细胞移植后的一种严重并发症， 移植（HCT）或骨髓移植（BMT），其中HCT/BMT构成主要的并且 用于治疗血液恶性肿瘤和其它病症的治愈性方法。因为暴露 环境因素，如致癌剂橙子，美国军方成员面临的风险， 在现役军人或退伍军人期间患上血液恶性肿瘤。GVHD是由 受者（宿主）组织的供体（移植物）T细胞介导的免疫攻击，并且也使临床 骨髓和实体器官联合移植后的照片。退伍军人也面临更高的风险 最终导致实体器官衰竭需要移植需要新的治疗策略， BMT/HCT患者维持供者T淋巴细胞介导的抗肿瘤免疫（移植物抗肿瘤（GVT）） 反应和抑制GVHD。在这种情况下，混合嵌合体的治疗成就， 其特征在于移植后供体和受体造血细胞的存在， 供体T细胞对受体的免疫耐受和GVHD的调节。混合嵌合体也 耐受受体的免疫细胞对抗供体，抑制实体器官移植后的排斥反应。 联合移植和减少使用有毒的免疫抑制药物。当前临床 方案大多使用非清髓性准备（较低剂量的化疗和/或放疗， 完全根除受体的骨髓细胞）以获得混合嵌合体。这 这种方法有很高的肿瘤复发风险。相比之下，我们使用清髓性准备（更高剂量的 化疗和/或放疗，同时完全根除受体的骨髓细胞 与混合嵌合体，其中GVT反应被保留，癌症复发的风险降低。我们 通过调节肠道免疫途径诱导GVHD混合嵌合体依赖性调节 这是一种全新的方法，并且具有肠道的自限性蠕虫定植。在此之前我们已经证明 寄生虫通过刺激受体细胞Th 2信号和Th 2- TGFβ依赖性生成。在本申请中，在目标#1中，我们提出研究以下要素： Th 2/TGFβ通路对混合嵌合体的产生至关重要。在目标#2中，我们将探讨不同的 与GVHD和实体器官的混合嵌合体依赖性调节相关的免疫调节回路 排斥反应在目标#3中，我们将研究混合嵌合体诱导的免疫调节对GVT的影响。 使用与BMT受体品系同基因的小鼠白血病/淋巴瘤模型来观察免疫应答。我们的长期 目的是剖析蠕虫诱导的混合嵌合体中重要的免疫调节途径， 临床移植知识。活蠕虫已经安全地用于免疫抑制 已经发现具有免疫调节特性的蠕虫产品可用于 临床实践因此，用小分子靶向蠕虫调节的信号通路， 或其产品可能是一种安全、有效和新的促进移植耐受的方法， 有毒的免疫抑制药物，并保持有益的GVT效果。

Graft-versus-host disease (GVHD) is a lethal and devastating complication of hematopoietic cell transplantation (HCT) or bone marrow transplantation (BMT), where HCT/BMT constitutes a predominant and curative approach for the treatment of hematological malignancies and other disorders. Because of exposure to environmental agents, such as the carcinogen agent orange, members of the US Military are under risk to develop hematological malignancies during their years as active soldiers or later as veterans. GVHD is caused by donor (graft) T cell-mediated immune attack of recipient (host) tissues and also complicates the clinical picture after combined transplantation of bone marrow and a solid organ. Veterans are also under higher risk to develop end-stage solid organ failure that requires transplantation. Novel treatment strategies are needed in BMT/HCT patients to maintain the donor T lymphocyte-mediated anti-tumor immune (graft-versus-tumor (GVT) response and suppress the GVHD. In this context, therapeutic achievement of mixed chimerism, which is characterized by the presence of donor and recipient hematopoietic cell after transplantation, results in immune tolerance by donor T cells against the recipient and in regulation of GVHD. Mixed chimerism also tolerizes recipient’s immune cells against the donor, suppressing the rejection of solid organ graft after combined transplantation and reduces the use of toxic immune suppressive medications. Current clinical protocols mostly use nonmyeloablative preparation (lower dose of chemotherapy and/or radiation without completely eradicating recipient’s bone marrow cells) before the BMT/HCT to achieve mixed chimerism. This approach carries a high risk of tumor relapse. By contrast, we use myeloablative preparation (higher dose of chemotherapy and/or radiation with complete eradication of recipient’s bone marrow cells) in our BMT model with mixed chimerism, where the GVT response is preserved and the risk of cancer relapse is reduced. We induce mixed chimerism-dependent regulation of GVHD by modulation of intestinal immune pathways using a completely novel approach and with self-limited helminth colonization of the gut. We have shown before that helminths promote the generation of mixed chimerism by stimulating recipient cell Th2 signaling and Th2- dependent generation of TGFβ. In this application, in Aim #1 we propose to investigate the elements of Th2/TGFβ pathways critical to generation of mixed chimerism. In Aim #2, we will explore the role of different immune regulatory circuitries relevant to mixed chimerism-dependent regulation of GVHD and solid organ rejection. In Aim #3, we will investigate the effect of mixed chimerism-induced immune regulation on the GVT response using a mouse leukemia/lymphoma model syngeneic with the BMT recipient strain. Our long-term goals are to dissect immune regulatory pathways important in helminth-induced mixed chimerism and apply the knowledge to clinical transplantation. Live helminths have been safely administered to immune suppressed patients, and helminth products with immune regulatory properties have been discovered for potential use in clinical practice. Therefore, targeting helminth-modulated signaling pathways with small molecules, helminths or their products may be a safe, potent and novel approach to promote transplantation tolerance without using toxic immune suppressive medications and preserve the beneficial GVT effect.