Intervention of Immune Tolerance by Small Molecules

小分子干预免疫耐受

• 批准号: 9068841
• 负责人: Shu-Hsia Chen
• 金额: $ 34.12万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9068841
• 关键词: Adoptive Transfer; Affinity; Allogenic; Angiopoietins; Anti-Inflammatory Agents; Anti-inflammatory; Antitumor Response; Autoimmunity; B-Lymphocytes; Binding; Biological; Biological Process; Blood; Bone Marrow; CD4 Positive T Lymphocytes; CD8B1 gene; CSF1R gene; Cell Differentiation process; Cell Lineage; Cell physiology; Clinical; Data; Development; Disease model; Disease remission; Exhibits; Funding; Future; Goals; Health; Helper-Inducer T-Lymphocyte; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Human; Immune; Immune Tolerance; Immune system; Immunoglobulins; Immunosuppression; Immunosuppressive Agents; In Vitro; Intervention; Knock-out; Knockout Mice; Ligands; Ligation; MHC Class I Genes; Mediating; Membrane; Memory; Modeling; Morbidity - disease rate; Mus; Myelogenous; Opportunistic Infections; Organ Transplantation; Patients; Pharmaceutical Preparations; Phenotype; Population; Prevention; Proteins; Protocols documentation; Regulation; Regulatory T-Lymphocyte; Relapse; Risk; Signal Transduction; Suppressor-Effector T-Lymphocytes; T cell anergy; T memory cell; T-Cell Depletion; T-Cell Development; T-Lymphocyte; Testing; Therapeutic; Toxic effect; Translations; Work; Xenograft procedure; base; cytokine; embryonic stem cell; graft vs host disease; immunoglobulin receptor; in vivo; inhibitor/antagonist; leukemia/lymphoma; macrophage; mortality; mouse model; novel strategies; novel therapeutics; precursor cell; prevent; protein B; receptor; response; small molecule; therapy outcome; tumor; tumor microenvironment

DESCRIPTION (provided by applicant): Graft-versus-host disease (GVHD) is the leading cause of morbidity and mortality following allogeneic hematopoietic stem cell 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. Myeloid-derived suppressor cells (MDSCs) consist of a population of myeloid precursor cells that exhibit potent suppressive activities capable of dampening anti-tumor responses, autoimmunity, and allo-responses in graft-versus-host diseases (GVHD) and organ transplantation. 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, resulting in the establishment of long-term survival. Recently, we also demonstrated that MDSCs acquire M1 or M2 functional macrophage phenotypes through regulation of PIR-B (paired immunoblobulin-like receptor B and human counterpart inhibitory immunoglobulin-like receptors B, LILRBs) signaling, which may facilitate the development of antitumor responses or mediate immune suppression and Treg activation, respectively. The objective of this proposal is to understand the mechanism by which MDSC biological function is regulated and to devise an optimized protocol for directing the functional activities of MDSC toward suppression of GVHD while allowing sufficient GVL activity to eradicate tumors. Based on the results of ou preliminary studies, we hypothesize that: (i) The functional phenotype of MDSC can be modulated by PIR-BL ligation and (ii) The presence of MDSCs with a persistent M2 functional phenotype may be sufficient to prevent GHVD and retain GVL ability. Three specific aims will be pursued: Aim 1. Study the regulation of MDSC function and the associated effects on GVHD. Aim 2. Study the effects of PIR-B ligation on MDSC as related to inhibition of GVHD and the corresponding signaling regulation in an irradiated host. Aim 3. Study the mechanism and effects of MDSC mediated regulation of GVHD vs. GVL through PIR-B/LILRB engagement in mouse GVHD models and in a human xenograft NSG mouse model. The proposed studies will provide the basis and scientific principles for future clinical translation.

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移植后发病和死亡的主要原因，同种异体造血干细胞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。 骨髓源性抑制细胞（MDSC）由一群骨髓前体细胞组成，它们表现出有效的抑制活性，能够抑制抗肿瘤反应， 自身免疫以及移植物抗宿主疾病（GVHD）和器官移植中的同种异体反应。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)，从而建立长期生存。 最近，我们还证明MDSC通过调节PIR-B（配对免疫球蛋白样受体B和人类对应的抑制性免疫球蛋白样受体B，LILRB）信号获得M1或M2功能性巨噬细胞表型，这可能分别促进抗肿瘤反应的发展或介导免疫抑制和Treg激活。该提案的目的是了解 MDSC 生物学功能的调节机制，并设计一种优化方案，引导 MDSC 的功能活性抑制 GVHD，同时允许足够的 GVL 活性来根除肿瘤。 根据初步研究的结果，我们假设：（i）MDSC 的功能表型可以通过 PIR-BL 连接来调节；（ii）具有持久 M2 功能表型的 MDSC 的存在可能足以预防 GHVD 并保留 GVL 能力。 我们将追求三个具体目标： 目标 1. 研究 MDSC 功能的调节及其对 GVHD 的相关影响。目标 2. 研究 PIR-B 连接对 MDSC 的影响，与 GVHD 的抑制以及受辐射宿主中相应的信号传导调节相关。 目标 3. 在小鼠 GVHD 模型和人类异种移植 NSG 小鼠模型中研究 MDSC 通过 PIR-B/LILRB 参与调节 GVHD 与 GVL 的机制和效果。 拟议的研究将为未来的临床转化提供基础和科学原理。