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: 8512668
• 负责人: Ping-Ying Pan
• 金额: $ 33.06万
• 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/8512668
• 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）：移植物抗宿主病（GVHD）是同种异体造血干细胞（HSC）移植后发病率和死亡率的主要原因，是一种针对血液系统恶性肿瘤患者的既定治疗方法。目前减少GVHD的策略包括T细胞消耗和免疫抑制药物，这与肿瘤复发、机会性感染和/或毒性的风险增加有关。显然，我们需要从本质上对免疫系统起作用的新方法。在这方面，自然产生的免疫抑制细胞，骨髓源性抑制细胞（MDSCs）最近得到了相当大的关注。MDSCs通过多种机制抑制t细胞反应，如iNOS、精氨酸酶和活性氧。我们证明了MDSC在体内诱导肿瘤抗原特异性T调节细胞和T细胞能量。我们的初步结果表明，在小鼠模型中，MDSCs具有一些有吸引力的特性，可以作为抑制GVHD的辅助细胞，而不会显著影响移植物抗白血病/淋巴瘤（GVL），从而建立嵌合和长期存活。初步研究表明，大量的MDSCs可以在外周被动员和扩增。本提案的目的是优化方案，通过该方案可以动员和扩展MDSCs，并测试动员MDSCs在不显着抑制所需GVL活性的情况下抑制同种免疫反应的适用性。基于我们的初步研究结果，我们假设：(i)可以从骨髓中动员大量的MDSC，表现出与肿瘤宿主衍生的对应物相当的抑制功能；（ii） GA可以调节MDSC的分化和抑制功能，从而增强MDSC治疗GVHD的效果；（iii）从动员方案中获得的MDSCs可以强烈抑制CD4 T细胞介导的同种异体反应并诱导Treg扩增，但对CD8 T细胞的抑制作用较小；（iv） MDSC治疗优先消除主要活化的T细胞，并倾向于CD44+CD62L记忆性CD8和CD4 T细胞的选择性扩增，从而在不显著影响GVL活性的情况下预防GVHD；(v)照射后肿瘤细胞RAE-1 （NKG2D配体）表达增强，导致对NKG2D+ CD8 T细胞和/或NK细胞杀伤的易感性增加。研究将有三个具体目标：1)动员和扩增骨髓源性抑制细胞到外周，评估动员MDSCs联合GA治疗对GVHD的预防作用；2)研究动员MDSC对GVHD抑制的机制；3)研究MDSC在不显著影响GVL活性的前提下优先抑制GVHD的机制。这些信息将为人体MDSC的动员和扩展提供依据和科学原则，可用于未来临床试验的临床环境。