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(申请人提供)：移植物抗宿主病(GVHD)是异基因造血干细胞(HSC)移植后发病率和死亡率的主要原因，HSC移植是治疗血液系统恶性肿瘤患者的公认疗法。目前减少GVHD的策略包括T细胞耗竭和免疫抑制药物，这些药物与肿瘤复发、机会性感染和/或毒性增加相关。显然需要从本质上作用于免疫系统的新方法。在这方面，自然产生的免疫抑制细胞，髓系来源的抑制细胞(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、精氨酸酶和活性氧等。我们在体内证明了MDSC可诱导肿瘤抗原特异性T调节细胞和T细胞无能。我们的初步结果表明，MDSCs在小鼠模型中具有几个吸引人的辅助细胞属性，可以在不显著损害移植物抗白血病/淋巴瘤(GVL)的情况下抑制GVHD，从而导致嵌合体的建立和长期存活。初步研究表明，大量的骨髓间充质干细胞可以在外围动员和扩增。该方案的目的是建立一种能够动员和扩增MDSCs的优化方案，并测试动员后的MDSCs在抑制同种免疫应答而不显著抑制所需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)骨髓中可以动员相当数量的MDSC，其抑制功能与肿瘤宿主来源的MDSC相当；(Ii)GA可以调节MDSC的分化和抑制功能，从而增强MDSC治疗GVHD的有效性；(Iii)动员方案来源的MDSC可以强烈抑制CD4T细胞介导的同种异体反应，诱导Treg扩增，但对CD8T细胞的抑制作用较小；(Iv)MDSC治疗优先消除主要激活的T细胞，并倾向于CD44+CD62L记忆CD8和CD4T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)肿瘤细胞在照射后RAE-1(NKG2D配体)的表达增强，从而增加了NKG2D+CD8 T细胞和/或NK细胞的杀伤敏感性。我们将追求三个具体目标：1)动员和扩增骨髓来源的抑制细胞至外周，评估动员的MDSC联合GA治疗对GVHD的预防作用；2)研究动员的MDSC抑制GVHD的机制；3)研究MDSC优先抑制GVHD而不显著影响现有肿瘤模型GVL活性的机制。这些信息将为动员和扩大人类骨髓间充质干细胞提供基础和科学原则，并可用于未来的临床试验。