Intervention of Immune Tolerance by Small Molecules

小分子干预免疫耐受

• 批准号: 8704475
• 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/8704475
• 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; 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; Outcome; 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; public health relevance; receptor; response; small molecule; 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）是同种异性造血干细胞移植后发病和死亡率的主要原因，这是一种针对血液恶性肿瘤患者的已建立疗法。 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。 髓样衍生的抑制细胞（MDSC）由粒细胞前体细胞组成，这些细胞表现出有效的抑制活性，能够抑制抗肿瘤反应， 自身免疫性和移植物抗宿主疾病（GVHD）和器官移植中的同质反应。我们的初步结果表明，在鼠模型中，MDSC作为辅助细胞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），从而导致建立长期生存。 最近，我们还证明了MDSC通过调节PIR-B（成对的免疫蛋白样受体B和人类对应物抑制性免疫球蛋白样受体B，LILRB，LILRB）信号来获得M1或M2功能性巨噬细胞表型，这可能促进抗蛋白抑制的发育或培养基抑制剂。该提案的目的是了解MDSC生物学功能受到调节的机制，并设计一种优化的方案，用于指导MDSC的功能活动降低GVHD，同时允许足够的GVL活性消除肿瘤。 根据OU初步研究的结果，我们假设：（i）可以通过PIR-BL结扎调节MDSC的功能表型，并且（ii）具有持续的M2功能表型的MDSC可能足以防止GHVD并保持GVL能力。 将追求三个具体目标：目标1。研究MDSC功能的调节以及对GVHD的相关影响。 AIM 2。研究PIR-B连接对MDSC的影响，与抑制GVHD和辐照宿主中的相应信号调节有关。 AIM 3。通过PIR-B/LILRB参与小鼠GVHD模型和人异种移植NSG小鼠模型，研究MDSC介导的GVHD与GVL调节的机理和影响。 拟议的研究将为未来的临床翻译提供基础和科学原理。