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Targeting immune inhibitory molecule SUSD2 to reverse immunosuppression

靶向免疫抑制分子SUSD2逆转免疫抑制

基本信息

批准号：
10430219
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
项目类别：
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/10430219
关键词：
Ablation Animals Antibodies Antibody Therapy Apoptosis Attenuated Automobile Driving Biochemical Biological Assay Cancer Model Cause of Death Cell Death 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 Intensive Care Intensive Care Units Interleukin 2 Receptor Interleukin-2 Lead Life Lymphocyte Maps Mechanical Ventilators Mediating Modeling Mus Organ Pathway interactions Patients Pharmacology Phase Phenotype Prevention Proteins Receptor Signaling Regimen Role STAT protein Sepsis Signal Transduction Stat5 protein 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 base 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 polymicrobial sepsis programmed cell death protein 1 restoration septic septic patients single molecule single-cell RNA sequencing transcription factor tumor

项目摘要

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.

项目总结/文摘