Targeting immune inhibitory molecule SUSD2 to reverse immunosuppression

靶向免疫抑制分子SUSD2逆转免疫抑制

• 批准号: 10631911
• 负责人: Haitao Wen
• 金额: $ 46.84万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-17 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10631911
• 关键词: Ablation; Animals; Antibodies; Antibody Therapy; Apoptosis; Attenuated; Automobile Driving; Biochemical; Biological Assay; Cancer Model; Cause of Death; Cell Death; Cell Death Induction; Cell Separation; Cell Survival; Cell physiology; Cell surface; Cells; Clinical; Clinical Research; Complex; Development; Disease; Disease Outcome; Functional disorder; Generations; Genes; Genetic; Goals; Healthcare Systems; Immune; Immune Targeting; Immune response; Immunosuppression; Immunotherapy; Impairment; In Vitro; Infection; Inflammation; Inflammatory; Intensive Care; Intensive Care Units; Interleukin 2 Receptor; Interleukin-2; Life; Lymphocyte; Maps; Mechanical Ventilators; Mediating; Modeling; Mus; Organ; Pathway interactions; Patients; Phase; Phenotype; Prevention; Proteins; Receptor Signaling; Regimen; Repression; Role; STAT protein; Sepsis; Signal Transduction; Sushi Domain; Syndrome; T cell response; T cell therapy; T-Lymphocyte; Technology; Testing; Therapeutic; Translating; Trauma; activating transcription factor; anti-PD-1; anti-PD1 antibodies; bZIP Domain; cecal ligation puncture; early phase clinical trial; effector T cell; experimental study; immune checkpoint blockade; improved; insight; loss of function; microbial; mitochondrial fitness; mortality; new therapeutic target; novel strategies; pharmacologic; polymicrobial sepsis; programmed cell death protein 1; restoration; septic; septic patients; single molecule; single-cell RNA sequencing; transcription factor; tumor

Project Summary/Abstract Sepsis is the most common cause of death in many intensive care units and represents a major burden to the US health care system. Despite advances in intensive care technology and mechanical ventilator support, pharmacological options for sepsis are limited, which reflects an insufficient understanding of host-dependent mechanisms that underlie this pathophysiological disorder. A wealth of evidence from recent clinical and experimental sepsis studies indicates that a prolonged immunosuppressive status, due to profound cell death and dysfunction of lymphocytes, is a critical determinant of sepsis-elicited mortality. Therefore, restoration of lymphocyte cell survival and functions by blocking immune inhibitory molecule(s) may represent a promising therapeutic regimen for treating sepsis. In this Proposal, we aim to study the role and mechanism of a previously unrecognized immune inhibitory molecule called SUSD2 (sushi domain containing 2) in promoting sepsis-induced immunosuppression. Through an unbiased gene profiling assay, our previous study has identified a cell surface molecule SUSD2 whose high expression correlated with an immunosuppressive phenotype in an experimental cancer model. In this Proposal, we observed elevated Susd2 expression in T lymphocytes in experimental septic animals and patients with sepsis compared to non-septic controls. Genetic deletion of SUSD2 (Susd2−/−) resulted in a significantly improved animal survival and attenuated apoptosis of T lymphocytes in the cecal ligation and puncture (CLP)-induced polymicrobial sepsis model. Mechanistically, our preliminary studies discovered an inhibitory effect of SUSD2 on interleukin-2 receptor (IL-2R) signaling, a well- established pathway essential for T cell survival and effector functions. The goal of the proposal is to examine the causal effect of SUSD2 on cell death and dysfunction of T lymphocytes in microbial sepsis. We hypothesize that 1) elevated SUSD2 expression leads to diminished IL-2-dependent cell survival and effector functions in T lymphocytes, resulting in a sustained immunosuppressive state and worse disease outcome in sepsis; 2) enhanced activation of STAT5 (signal transducer and activator of transcription 5) and BATF (basic leucine zipper ATF-like transcription factor) signaling maintains cell survival and effector functions in Susd2−/− T cells post sepsis; 3) SUSD2 blockade reverses sepsis-induced cell death and dysfunction of T lymphocytes. Single-cell RNA sequencing analysis of circulatory immune cells will be performed to examine the inhibitory effect of SUSD2 on T cell response post sepsis at the single-cell level. We will test whether treatment with a neutralizing anti-SUSD2 antibody reverses dysfunctional T cells isolated from septic patients. Results of these studies will provide both experimental and clinical evidence to support a promoting function of SUSD2 on sepsis-induced immunosuppression, which can potentially lead to the development of new approach for sepsis treatment.

项目概要/摘要 脓毒症是许多重症监护病房最常见的死亡原因，也是重症监护室的主要负担 美国的医疗保健系统。尽管重症监护技术和机械呼吸机支持取得了进步， 脓毒症的药理学选择有限，这反映出对宿主依赖性的认识不足 这种病理生理障碍的机制。来自近期临床和临床的大量证据 实验性败血症研究表明，由于严重的细胞死亡，长期的免疫抑制状态 和淋巴细胞功能障碍，是脓毒症引起的死亡率的关键决定因素。因此，恢复 通过阻断免疫抑制分子来维持淋巴细胞的存活和功能可能是一种有前途的方法 治疗脓毒症的治疗方案。在本提案中，我们旨在研究a的作用和机制 以前未被识别的免疫抑制分子 SUSD2（包含 2 的寿司结构域）在促进 脓毒症引起的免疫抑制。通过无偏见的基因分析测定，我们之前的研究已经 鉴定出一种细胞表面分子 SUSD2，其高表达与免疫抑制相关 实验癌症模型中的表型。在此提案中，我们观察到 T 中 Susd2 表达升高 与非脓毒症对照相比，实验性脓毒症动物和脓毒症患者的淋巴细胞。遗传 删除 SUSD2 (Susd2−/−) 可显着提高动物存活率并减弱 T 细胞凋亡 盲肠结扎穿刺（CLP）诱导的多种微生物脓毒症模型中的淋巴细胞。从机制上讲，我们的 初步研究发现 SUSD2 对白细胞介素 2 受体 (IL-2R) 信号传导具有抑制作用，这是一种良好的 建立了 T 细胞存活和效应功能所必需的途径。该提案的目标是审查 SUSD2 对微生物脓毒症中细胞死亡和 T 淋巴细胞功能障碍的因果影响。我们 假设 1) SUSD2 表达升高导致 IL-2 依赖性细胞存活和效应器减少 T 淋巴细胞的功能，导致持续的免疫抑制状态和更糟糕的疾病结果 败血症; 2）增强STAT5（信号转导子和转录激活子5）和BATF（基本 亮氨酸拉链 ATF 样转录因子）信号传导维持 Susd2−/− T 中的细胞存活和效应器功能 脓毒症后的细胞； 3) SUSD2 阻断可逆转脓毒症诱导的细胞死亡和 T 淋巴细胞功能障碍。 将进行循环免疫细胞的单细胞 RNA 测序分析，以检查抑制作用 SUSD2 在单细胞水平上对脓毒症后 T 细胞反应的影响。我们将测试是否使用 中和抗 SUSD2 抗体可逆转从脓毒症患者中分离出的功能失调的 T 细胞。这些结果 研究将提供实验和临床证据来支持 SUSD2 对 脓毒症引起的免疫抑制，这可能会导致脓毒症新方法的开发 治疗。