HSC Derived MDSC for the Prevention of GHVD Without Suppressing GvL

HSC 衍生的 MDSC 在不抑制 GvL 的情况下预防 GHVD

• 批准号: 8323880
• 负责人: Ping-Ying Pan
• 金额: $ 35.17万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2016-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8323880
• 关键词: Allogenic; Antigen-Presenting Cells; Attention; Autoimmune Diseases; Bone Marrow; CD4 Positive T Lymphocytes; CD44 gene; CD8B1 gene; CSF1R gene; Chimerism; Clinic; Clinical; Clinical Trials; Copaxone; Development; Exhibits; Future; Generations; Goals; Graft-Versus-Tumor Induction; Helper-Inducer T-Lymphocyte; Hematologic Neoplasms; Hematopoietic Stem Cell Mobilization; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Human; Immune response; Immune system; Immunosuppressive Agents; In Vitro; Ligands; Mediating; Memory; Modeling; Morbidity - disease rate; Mus; Myelogenous; Myeloid Cells; Natural Killer Cells; Opportunistic Infections; Organ Transplantation; Patients; Pharmaceutical Preparations; Phase; Population; Predisposition; Prevention; Property; Protocols documentation; Reactive Oxygen Species; Regulatory T-Lymphocyte; Relapse; Risk; Role; SELL gene; Solid; Source; Suppressor-Effector T-Lymphocytes; System; T cell anergy; T cell response; T memory cell; T-Cell Depletion; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Translating; Tumor Antigens; Tumor-Derived; arginase; base; clinical application; copolymer 1; cytokine; embryonic stem cell; graft vs host disease; in vivo; interest; irradiation; killings; leukemia; leukemia/lymphoma; macrophage; mortality; neoplastic cell; novel; novel strategies; peripheral blood; prevent; response; tumor

DESCRIPTION (provided by applicant): Graft versus host disease (GVHD) is the leading cause of morbidity and mortality following allogeneic hematopoietic stem cell (HSC) transplantation, an established therapy for patients with hematological malignancies. Current strategies to diminish GVHD include T cell depletion and immunosuppressive drugs, which are associated with an increased risk of tumor relapse, opportunistic infection, and/or toxicity. Novel approaches acting intrinsically on the immune system are clearly needed. In this regard, naturally occurring immunosuppressive cells, myeloid-derived suppressor cells (MDSCs), have recently gained considerable attention. MDSCs suppress T-cell responses through multiple mechanisms, e.g. iNOS, arginase, and reactive oxygen species. We demonstrated that MDSC induced tumor antigen specific T regulatory cells and T-cell anergy in vivo. Our preliminary results indicate that MDSCs have several attractive attributes as helper cells to inhibit GVHD without significantly compromising graft-versus-leukemia/lymphoma (GVL) in a murine model that results in the establishment of chimerism and long-term survival. The preliminary study showed that a significant number of MDSCs could be mobilized and expanded in the periphery. The objective of this proposal is to an optimized protocol by which MDSCs can be mobilized and expanded and to test the applicability of mobilized MDSCs in suppressing the allo-immune response without significantly suppressing the desirable GVL activity. Based on the results of our preliminary studies, we hypothesize that: (i) A significant amount of MDSC, exhibiting comparable suppressive functions as the tumor-host-derived counterpart, can be mobilized from bone marrow; (ii) GA can modulate differentiation and suppressive function of MDSC, thereby enhancing the efficacy of MDSC treatment in preventing GVHD; (iii) MDSCs derived from mobilization protocols can strongly suppress allo-responses mediated by CD4 T cells and induce Treg expansion, but exhibit less suppressive effect on CD8 T cells; (iv) MDSC treatment preferentially eliminates primarily activated T cells and skews toward the selective expansion of CD44+CD62L- memory CD8 and CD4 T cells, thereby preventing GVHD without significantly compromising the GVL activity; (v) RAE-1 (NKG2D ligand) expression by tumor cell is enhanced upon irradiation, which leads to increased susceptibility to killing by NKG2D+ CD8 T cells and/or NK cells. Three specific aims will be pursued: 1) Mobilize and expand myeloid-derived suppressor cells from bone marrow into the periphery and assess the prevention of GVHD by mobilized MDSCs in combination with GA treatment; 2) Study the mechanisms underlying the inhibition of GVHD mediated by mobilized MDSC; 3) Study the mechanisms underpinning the preferential suppression of GVHD by MDSC without significantly compromising GVL activity in pre-existing tumor models. The information will provide the basis and scientific principles for the mobilization and expansion of MDSC in human that can be used in clinical settings for future clinical trials.

描述（由申请人提供）：GRAFT与宿主疾病（GVHD）是同种异性造血干细胞（HSC）移植后发病和死亡率的主要原因，这是一种针对血液系统恶性肿瘤患者的既定疗法。当前减少GVHD的策略包括T细胞耗竭和免疫抑制药物，这与肿瘤复发，机会性感染和/或毒性的风险增加有关。显然需要在本质上作用于免疫系统的新颖方法。在这方面，自然存在的免疫抑制细胞，髓样衍生的抑制细胞（MDSC）最近引起了广泛的关注。 MDSC通过多种机制抑制T细胞响应，例如iNOS，精氨酸酶和活性氧。我们证明了MDSC诱导肿瘤抗原特异性T调节细胞和体内T细胞反感。我们的初步结果表明，在鼠模型中，MDSC具有几种有吸引力的属性作为辅助细胞，可以抑制GVHD，而不会显着损害移植物 - 白血病/淋巴瘤（GVL），从而导致建立嵌合和长期存活。初步研究表明，大量的MDSC可以在外围动员和扩展。该提案的目的是针对优化的方案，通过该方案可以通过该方案进行动员和扩展，并测试动员MDSC在抑制同种免疫反应的情况下的适用性，而无需显着抑制所需的GVL活性。基于我们的初步研究的结果，我们假设：（i）大量的MDSC可以从骨髓中动员，表现出可比的抑制功能作为肿瘤宿主衍生的对应物； （ii）GA可以调节MDSC的分化和抑制功能，从而增强MDSC处理在预防GVHD方面的功效； （iii）从动员方案中得出的MDSC可以强烈抑制由CD4 T细胞介导的同异质反应并诱导Treg膨胀，但对CD8 T细胞的抑制作用较小。 （iv）MDSC治疗优先消除了主要激活的T细胞，并偏向于选择性扩展CD44+CD62L-内存CD8和CD4 T细胞，从而防止GVHD而不显着损害GVL活性； （v）辐照时肿瘤细胞的RAE-1（NKG2D配体）表达会增强，从而提高了通过NKG2D+ CD8 T细胞和/或NK细胞杀死的敏感性。将追求三个具体目标：1）动员和扩展髓样衍生的抑制细胞从骨髓到周围的抑制细胞，并评估动员MDSC与GA处理结合使用的GVHD的预防； 2）研究动员MDSC介导的GVHD抑制的基础机制； 3）研究MDSC优先抑制GVHD的机制，而没有显着损害现有肿瘤模型的GVL活性。该信息将为人类中MDSC的动员和扩展提供基础和科学原理，该原则可用于临床环境中，以供将来的临床试验。