Regeneration of the Immune System after Radiation Exposure

辐射暴露后免疫系统的再生

• 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
• 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

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.

摘要 辐射诱导的免疫功能障碍(RIID)是急性和延迟效应的关键组成部分 导致多器官衰竭(MOF)综合征的辐射暴露，根据时间进行手术划分 临床表现，如急性辐射综合征(ARS)和急性辐射暴露的延迟效应 (Deare)。急性呼吸窘迫综合征的直接致死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、淋巴细胞减少和肠上皮屏障丧失，导致 菌血症、败血性休克和全身炎症反应。到目前为止，FDA批准的辐射 对策是造血生长因子，如G-CSF，GM-CSF和罗米普替丁，促进 骨髓中的髓样再生。电离辐射(IR)可对人体造成可逆和不可逆的损害。 免疫系统。来自日本的原子弹幸存者表现出T辅助细胞亚群的减少， 幼稚和记忆性T、B淋巴细胞数量和功能的改变，血清PRO水平升高 炎性细胞因子，表明存在显著的残留损伤和淋巴细胞稳态受损 淋巴器官。 我们将研究骨髓、外周淋巴器官(脾、 胸腺和腹膜淋巴结)以及肠和肺的粘膜相关淋巴组织(MALT)， 确定抗原提呈细胞的功能，以及IR是否导致线粒体功能障碍，抑制 巨噬细胞和伴侣蛋白介导的自噬，并加速T细胞免疫衰老和炎症 遵循目标1下的WBI。我们还将检查线粒体免疫效应细胞的再生 功能障碍、自噬抑制、加速免疫衰老、T细胞耗竭和炎症 放射缓释剂TPOm或TPOM对IR暴露小鼠外周淋巴器官淋巴细胞的影响 Flt3L或G-CSF(作为对照)，在目标2中，WBI后1天。在目标3下，我们将开发一种免疫调节 恢复放射幸存者免疫方案的功能性免疫缺陷的方案 没有无线电减震器。我们还将研究二甲双胍和p38/MAPK抑制剂对克服T 细胞免疫衰老作为以抗原特异性来衡量免疫学结果的预适应方案 免疫球蛋白、免疫球蛋白和Th1、Th2反应。 关联性。我们的提案将定义再生免疫系统的功能性放射免疫生物学 在小鼠的WBI之后。由于对辐射损伤的组织靶点进行了很好的研究，我们还可以关联T 细胞免疫衰老和髓系细胞功能障碍与DeARE的发生有关。这些研究将提供 为放射免疫方案开发优化的免疫调节方案的蓝图 幸存者可以扩大到免疫功能低下和老年人口。