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）：移植物抗宿主病（GVHD）是同种异体造血干细胞（HSC）移植后发病和死亡的主要原因，异体造血干细胞（HSC）移植是血液系统恶性肿瘤患者的一种既定疗法。目前减少 GVHD 的策略包括 T 细胞耗竭和免疫抑制药物，这些药物会增加肿瘤复发、机会性感染和/或毒性的风险。显然需要从本质上作用于免疫系统的新方法。在这方面，天然存在的免疫抑制细胞——骨髓源性抑制细胞（MDSC）最近引起了相当大的关注。 MDSC 通过多种机制抑制 T 细胞反应，例如iNOS、精氨酸酶和活性氧。我们证明 MDSC 在体内诱导肿瘤抗原特异性 T 调节细胞和 T 细胞无反应性。我们的初步结果表明，MDSC 作为辅助细胞具有几个有吸引力的属性，可以抑制 GVHD，而不会显着损害小鼠模型中的移植物抗白血病/淋巴瘤 (GVL)，从而导致嵌合体的建立和长期生存。初步研究表明，大量的MDSCs可以在外周被动员和扩张。该提案的目的是优化方案，通过该方案可以动员和扩增 MDSC，并测试动员的 MDSC 在抑制同种免疫反应而不显着抑制所需 GVL 活性方面​​的适用性。根据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，其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治疗预防GVHD的功效； (iii) 源自动员方案的 MDSC 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，并倾向于选择性扩增CD44+CD62L-记忆CD8和CD4 T细胞，从而预防GVHD而不显着损害GVL活性； (v) 肿瘤细胞的 RAE-1（NKG2D 配体）表达在辐射后增强，这导致 NKG2D+ CD8 T 细胞和/或 NK 细胞对杀伤的敏感性增加。将追求三个具体目标：1）动员并扩展骨髓源性抑制细胞从骨髓到外周，并评估动员的MDSC与GA治疗相结合对GVHD的预防作用； 2) 研究动员型MDSC介导的GVHD抑制机制； 3) 研究MDSC优先抑制GVHD而不显着损害现有肿瘤模型中GVL活性的机制。这些信息将为MDSC在人体中的动员和扩展提供基础和科学原理，可用于未来临床试验的临床环境。