Regeneration of the Immune System after Radiation Exposure

辐射暴露后免疫系统的再生

基本信息

批准号：
10686385
负责人：
Chandan Guha
金额：
$ 68.23万
依托单位：
ALBERT EINSTEIN COLLEGE OF MEDICINE
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-08-18 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10686385
关键词：
Acceleration Acute Agonist Anemia Animals Antibody titer measurement Antigen Presentation Antigen-Presenting Cells Antigens Autophagocytosis B-Lymphocytes Bacteremia Biological Assay Bone Marrow Bone Regeneration CD28 gene CD3 Antigens CD8-Positive T-Lymphocytes CSF3 gene CXCL10 gene CXCR3 gene Cellular Immunity Clinical Defect Dose Effector Cell Elderly Event Exhibits Exposure to Extravasation FDA approved FLT3 ligand Failure Functional disorder Granulocyte-Macrophage Colony-Stimulating Factor Helper-Inducer T-Lymphocyte Hematopoietic Cell Growth Factors Homeostasis IL17 gene IL7 gene Immune Immune System Diseases Immune system Immunization Immunobiology Immunocompromised Host Immunoglobulin G Immunoglobulin M Immunologics Immunology procedure Immunophenotyping Impairment Inflammation Inflammatory Injury Interferon Type II Interleukin-2 Interleukin-6 Intestines Ionizing radiation Japan Lethal Dose 50 Listeria Longitudinal Studies Lung Lymphocyte Lymphocyte Count Lymphocyte Depletion Lymphocyte Function Lymphopenia MPL gene Marrow Measures Mediating Memory Metformin Mitogen-Activated Protein Kinase Inhibitor Modeling Molecular Chaperones Multiple Organ Failure Mus Myelogenous Natural regeneration Neutropenia Nuclear Power Plants Outcome Outcome Measure Ovalbumin Oxygen Consumption Peptides Peritoneal Phagocytosis Phase Phenotype Population Production Proliferating Proteins Protocols documentation RNA vaccine Radiation Radiation Injuries Radiation Toxicity Radiation exposure Radio Radiobiology Recombinants Regimen Residual state Roentgen Rays SARS-CoV-2 spike protein Septic Shock Serum Spleen Survivors Syndrome T cell receptor repertoire sequencing T-Cell Proliferation T-Lymphocyte TNF gene Terrorism Therapeutic Agents Thrombocytopenia Thrombopoietin Thymus Gland Time Tissues Transgenic Mice Vaccination Whole-Body Irradiation atomic bomb cell regeneration conditioning cytokine dirty bomb exhaust exhaustion functional restoration ghrelin immunosenescence inhibition of autophagy intestinal epithelium lymph nodes lymphoid organ mimetics mitochondrial dysfunction mucosa-associated lymphoid tissue neutrophil novel p38 Mitogen Activated Protein Kinase peripheral lymphoid organ prevent programmed cell death protein 1 programs radiation countermeasure radiation effect radiation mitigation radiation mitigator regenerative response senescence subcutaneous systemic inflammatory response transcriptomics

Acceleration Acute Agonist Anemia Animals Antibody titer measurement Antigen Presentation Antigen-Presenting Cells Antigens Autophagocytosis B-Lymphocytes Bacteremia Biological Assay Bone Marrow Bone Regeneration CD28 gene CD3 Antigens CD8-Positive T-Lymphocytes CSF3 gene CXCL10 gene CXCR3 gene Cellular Immunity Clinical Defect Dose Effector Cell Elderly Event Exhibits Exposure to Extravasation FDA approved FLT3 ligand Failure Functional disorder Granulocyte-Macrophage Colony-Stimulating Factor Helper-Inducer T-Lymphocyte Hematopoietic Cell Growth Factors Homeostasis IL17 gene IL7 gene Immune Immune System Diseases Immune system Immunization Immunobiology Immunocompromised Host Immunoglobulin G Immunoglobulin M Immunologics Immunology procedure Immunophenotyping Impairment Inflammation Inflammatory Injury Interferon Type II Interleukin-2 Interleukin-6 Intestines Ionizing radiation Japan Lethal Dose 50 Listeria Longitudinal Studies Lung Lymphocyte Lymphocyte Count Lymphocyte Depletion Lymphocyte Function Lymphopenia MPL gene Marrow Measures Mediating Memory Metformin Mitogen-Activated Protein Kinase Inhibitor Modeling Molecular Chaperones Multiple Organ Failure Mus Myelogenous Natural regeneration Neutropenia Nuclear Power Plants Outcome Outcome Measure Ovalbumin Oxygen Consumption Peptides Peritoneal Phagocytosis Phase Phenotype Population Production Proliferating Proteins Protocols documentation RNA vaccine Radiation Radiation Injuries Radiation Toxicity Radiation exposure Radio Radiobiology Recombinants Regimen Residual state Roentgen Rays SARS-CoV-2 spike protein Septic Shock Serum Spleen Survivors Syndrome T cell receptor repertoire sequencing T-Cell Proliferation T-Lymphocyte TNF gene Terrorism Therapeutic Agents Thrombocytopenia Thrombopoietin Thymus Gland Time Tissues Transgenic Mice Vaccination Whole-Body Irradiation atomic bomb cell regeneration conditioning cytokine dirty bomb exhaust exhaustion functional restoration ghrelin immunosenescence inhibition of autophagy intestinal epithelium lymph nodes lymphoid organ mimetics mitochondrial dysfunction mucosa-associated lymphoid tissue neutrophil novel p38 Mitogen Activated Protein Kinase peripheral lymphoid organ prevent programmed cell death protein 1 programs radiation countermeasure radiation effect radiation mitigation radiation mitigator regenerative response senescence subcutaneous systemic inflammatory response transcriptomics

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项目摘要

Abstract Radiation-Induced Immune Dysfunction (RIID) is a critical component of both acute and delayed effects of radiation exposure, which causes a multi-organ failure (MOF) syndrome, operationally divided based upon timing of clinical manifestations, as acute radiation syndrome (ARS) and delayed effects of acute radiation exposure (DEARE). The immediate lethality of ARS is caused by bone marrow and intestinal failure, with subsequent neutropenia, anemia, thrombocytopenia, lymphopenia, and loss of intestinal epithelial barrier, resulting in bacteremia, septic shock, and systemic inflammatory response. To date, FDA-approved radiation countermeasures are hematopoietic growth factors, such as, G-CSF, GM-CSF and Romiplostim that promote myeloid regeneration in the marrow. Ionizing radiation (IR) can cause reversible and irreversible damage to the immune system. Atomic bomb (A-bomb) survivors from Japan exhibited reduction in T helper cell subsets, alterations in naïve and memory T and B lymphocyte numbers and function, increased levels of serum pro- inflammatory cytokines, indicating significant residual injury and impairment of lymphocyte homeostasis in the lymphoid organs. We will investigate the immune landscape of regeneration in bone marrow, peripheral lymphoid organs (spleen, thymus, and peritoneal lymph nodes) and mucosa-associated lymphoid tissue (MALT) of the intestine and lungs, determine the functionality of antigen presenting cells, and whether IR induces mitochondrial dysfunction, inhibits macro- and chaperone-mediated autophagy, and accelerates T cell immunosenescence and inflammation following WBI under aim 1. We will also examine the regeneration of immune effector cells for mitochondrial dysfunction, inhibition of autophagy, accelerated immunosenescence, T cell exhaustion and inflammation in lymphocytes from peripheral lymphoid organs in mice exposed to IR and treated with radio-mitigators, TPOm or Flt3L or G-CSF (as control), 1-day post-WBI in aim 2. Under aim 3 we will develop an immuno-conditioning regimen to restore functional immune deficit for immunization protocols in radiation survivors, treated with or without radio-mitigators. We will also examine the effects of metformin and p38/MAPK inhibitor to overcome T cell immunosenescence as conditioning regimens with immunological outcomes measured by antigen-specific IgM, IgG and Th1 and Th2 responses. Relevance. Our proposal will define the functional radio-immunobiology of the regenerative immune system after WBI in mice. Since the tissue targets of radiation injury are well studied, we can also correlate whether T cell immunosenescence and dysfunction of myeloid population contributes to DEARE. These studies will provide a blueprint for developing optimized immuno-conditioning regimens for immunization protocols in radiation survivors that can be extended to immunocompromised and elderly population.

抽象的辐射诱导的免疫功能障碍（RIID）是急性和延迟作用的关键成分导致多器官故障（MOF）综合征的辐射暴露在操作上根据时间分裂临床表现，作为急性辐射综合征（ARS）和急性辐射暴露的延迟作用（亲爱的）。 ARS的直接致死性是由骨髓和肠道衰竭引起的，随后中性粒细胞减少，贫血，血小板减少症，淋巴细胞减少症和肠上皮屏障的丧失，导致菌血症，败血性休克和全身性炎症反应。迄今为止，FDA批准的辐射对策是造血生长因素，例如G-CSF，GM-CSF和Romiplostim 骨髓中的髓样再生。电离辐射（IR）可能会对免疫系统。来自日本的原子弹（A-BOMB）表面暴露于T辅助细胞子集的减少，天真和记忆T和B淋巴细胞的数量和功能的改变，血清疗法水平提高炎性细胞因子，表明严重的残留损伤和淋巴细胞稳态损害淋巴器官。我们将研究骨髓再生的免疫景观，外周淋巴器官（脾脏，，胸腺和肺淋巴结淋巴结淋巴结和腹膜淋巴结淋巴结（麦芽）和肺的淋巴组织（麦芽），确定抗原呈现细胞的功能，以及IR是否诱导线粒体功能障碍，抑制宏观和伴侣介导的自噬，并加速T细胞免疫和注射在AIM 1下进行WBI。我们还将检查线粒体免疫效应细胞的再生功能障碍，抑制自噬，加速免疫，T细胞耗尽和炎症暴露于IR的小鼠外周淋巴器官的淋巴细胞，并用射频降低剂，TPOM或 FLT3L或G-CSF（作为对照），AIM 2中的1天后。在AIM 3下，我们将开发免疫条件恢复用于辐射存活中免疫方案的功能免疫防御方案，并用或没有无线电降低器。我们还将检查二甲双胍和p38/MAPK抑制剂的影响细胞免疫吸收作为条件方案，具有免疫结局，以抗原特异性测量 IgM，IgG和Th1和Th2响应。关联。我们的建议将定义再生免疫系统的功能无线电生物学 WBI在小鼠中。由于辐射损伤的组织靶标很好地研究了，我们还可以相关髓样群体的细胞免疫和功能障碍有助于Deare。这些研究将提供用于开发优化的免疫条件方案的蓝图，用于辐射中的免疫条件方案可以扩展到免疫功能低下和老年人口的幸存者。