Mixed Chimerism-Dependent Tolerance After Myeloablative Bone Marrow Transplantation

移植物抗宿主病(GVHD)是一种致命性和破坏性的造血细胞并发症 移植(HCT)或骨髓移植(BMT)，其中HCT/BMT构成主要的和 治疗血液系统恶性肿瘤和其他疾病的治疗方法。因为暴露在 对于环境制剂，如致癌剂橙色，美国军方成员面临着 在他们作为现役士兵或后来的退伍军人期间患上血液系统恶性肿瘤。GVHD是由 由供者(移植物)T细胞介导的对受体(宿主)组织的免疫攻击也使临床复杂化 骨髓与实体器官联合移植后的照片。退伍军人也面临更高的风险 发展为需要移植的终末期实体器官衰竭。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(GVT) 应对并抑制GVHD。在这方面，混合嵌合体的治疗成就，即 以移植后供者和接受者的造血细胞的存在为特征，结果是 供者T细胞对受体的免疫耐受及其对移植物抗宿主病的调节混合嵌合体也 容忍受者免疫细胞对抗供者，抑制实体器官移植后的排斥反应 联合移植，减少毒性免疫抑制药物的使用。当前临床 方案大多使用非清髓性制剂(较低剂量的化疗和/或放射治疗 完全根除受者的骨髓细胞)，以在BMT/HCT之前实现混合嵌合。这 这种方法有很高的肿瘤复发风险。相比之下，我们使用清髓制剂(较大剂量的 化疗和/或放疗完全根除受者的骨髓细胞)在我们的骨髓移植模型中 混合嵌合体，保存了GVT反应，降低了癌症复发的风险。我们 通过调节肠道免疫通路诱导嵌合体依赖的混合GVHD调节 全新的方法和自我限制的肠道蠕虫定植。我们在此之前已经展示过了 蠕虫通过刺激受体细胞Th2信号和Th2-1促进混合嵌合体的产生 转化生长因子β的依赖生成。在本申请中，在目标#1中，我们建议研究以下元素 Th2/转化生长因子β通路对混合嵌合体的产生至关重要。在目标2中，我们将探索不同的角色 GVHD和实体器官嵌合依赖混合调节的免疫调节回路 拒绝。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。 使用与骨髓移植受体株同基因的小鼠白血病/淋巴瘤模型进行反应。我们的长期合作 目标是剖析蠕虫诱导的混合嵌合体中重要的免疫调节途径并应用于 对临床移植的认识。活的蠕虫已经被安全地注射给免疫抑制的人 患者和具有免疫调节特性的蠕虫产品已被发现可能用于 临床实践。因此，以小分子、蠕虫为靶点 或者他们的产品可能是一种安全、有效和新颖的方法来促进移植耐受，而不需要使用 毒性免疫抑制药物和保存有益的GVT的作用。

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.