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Principal Investigator: Chandan Guha
Organization: ALBERT EINSTEIN COLLEGE OF MEDICINE
Fiscal Year: 2022
Award: $582,293
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <(TNF)-α><19S Gamma Globulin><2019-nCoV S protein><2019-nCoV spike glycoprotein><2019-nCoV spike protein><7S Gamma Globulin><A-bomb><Acute><Acute Radiation Syndrome><Agonist><Anemia><Animals><Antibody titer measurement><Antigen-Presenting Cells><Antigens><Assay><Autophagocytosis><Autoregulation><B blood cells><B cell><B cell differentiation factor><B cell stimulating factor 2><B cells><B-Cell Differentiation Factor><B-Cell Differentiation Factor-2><B-Cell Stimulatory Factor-2><B-Cells><B-Lymphocytes><B-cell><BCDF><BSF-2><BSF2><Bacteremia><Bioassay><Biologic Assays><Biological Assay><Blood Neutrophil><Blood Polymorphonuclear Neutrophil><Blood Serum><Body Tissues><Bone Marrow><Bone Marrow Reticuloendothelial System><Bone Regeneration><Bone-Derived Transforming Growth Factor><CD183><CD28><CD28 gene><CD3><CD3 Antigens><CD3 Complex><CD3 molecule><CD8 Cell><CD8 T cells><CD8 lymphocyte><CD8+ T cell><CD8+ T-Lymphocyte><CD8-Positive Lymphocytes><CD8-Positive T-Lymphocytes><CKR-L2><CMKAR3><COVID-19 S protein><COVID-19 spike glycoprotein><COVID-19 spike protein><COVID19 S protein><COVID19 spike glycoprotein><COVID19 spike protein><CSAID-Binding Protein 1><CSAID-Binding Protein 2><CSBP2><CTLA-8 Gene><CTLA8 Gene><CXCR3><CXCR3 gene><Cachectin><Cell Mediated Immunology><Cell-Mediated Immunity><Cellular Immunity><Chaperone><Chemokine (C-X-C Motif) Receptor 3><Clinical><Co-Stimulator><Costimulator><Cytokine-Suppressive Antiinflammatory Drug-Binding Protein 1><Cytokine-Suppressive Antiinflammatory Drug-Binding protein 2><Cytotoxic T-Lymphocyte-Associated Antigen 8 Gene><Cytotoxic T-Lymphocyte-Associated Serine Esterase 8 Gene><Defect><Dimethylbiguanidine><Dimethylguanylguanidine><Dose><Dysfunction><Effector Cell><Elderly><Epidermal Thymocyte Activating Factor><Event><Exhibits><Exposure to><Extravasation><FDA approved><FLT 3 Ligand><FLT3 ligand><FLT3L><FLT3LG><FLT3LG gene><FMS-Related Tyrosine Kinase 3 Ligand Gene><FMS-Related Tyrosine Kinase-3 Ligand><Failure><Functional disorder><G Protein-Coupled Receptor 9><GPR9><Gamma interferon><HPGF><Helper Cells><Helper T-Cells><Helper T-Lymphocytes><Helper-Inducer T-Cells><Helper-Inducer T-Lymphocyte><Hematopoietic Cell Growth Factors><Hematopoietic-CGF><Hepatocyte-Stimulating Factor><Homeostasis><Hybridoma Growth Factor><IFN-Gamma><IFN-beta 2><IFN-g><IFN-γ><IFNB2><IFNG><IFNγ><IL-17 Gene><IL-17A Gene><IL-2><IL-6><IL-7><IL-7 Gene><IL17><IL17 gene><IL17A Gene><IL2 Protein><IL6 Protein><IL7><IL7 Protein><IL7 gene><IP10><IP10 Receptor><IP10-Mig receptor><IP10-R><IgG><IgM><Immune><Immune Diseases><Immune Disorders><Immune Dysfunction><Immune Interferon><Immune System Diseases><Immune System Disorder><Immune System Dysfunction><Immune System and Related Disorders><Immune system><Immunes><Immunization><Immunobiology><Immunochemical Immunologic><Immunocompromised><Immunocompromised Host><Immunocompromised Patient><Immunodeficiency and Immunosuppression Disorders><Immunoglobulin G><Immunoglobulin M><Immunologic><Immunologic Diseases><Immunologic Sensitization><Immunologic Stimulation><Immunologic Subtyping><Immunological><Immunological Diseases><Immunological Dysfunction><Immunological Sensitization><Immunological Stimulation><Immunological System Dysfunction><Immunologically><Immunologics><Immunology procedure><Immunophenotyping><Immunophysiology><Immunostimulation><Immunosuppressed Host><Impairment><Inducer Cells><Inducer T-Lymphocytes><Inflammation><Inflammatory><Injury><Interferon Gamma><Interferon Type II><Interferon-gamma><Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8) Gene><Interleukin 17 Precursor Gene><Interleukin 2><Interleukin 2 Precursor><Interleukin 7 Precursor><Interleukin 7 Precursor Gene><Interleukin II><Interleukin-2><Interleukin-6><Interleukin-7><Interleukin-7 Gene><Interleukine 2><Interleukine 2 Precursor><Interleukine II><Intestinal><Intestines><Ionizing Electromagnetic Radiation><Ionizing radiation><Japan><LD-50><LD50><Leakage><Lethal Dose 50><Listeria><Longitudinal Studies><Lung><Lung Respiratory System><Lymph Node Reticuloendothelial System><Lymph node proper><Lymphatic cell><Lymphatic nodes><Lymphocyte><Lymphocyte Count><Lymphocyte Depletion><Lymphocyte Function><Lymphocyte Mitogenic Factor><Lymphocyte Number><Lymphocytic><Lymphocytopenia><Lymphopenia><Lymphopoietin-1><MAPK Inhibitors><MAPK14><MAPK14 Mitogen-Activated Protein Kinase><MAPK14 gene><MGDF><MGDF Factor><MGI-2><MOF syndrome><MPL gene><MPLV><Macrophage-Derived TNF><Marrow><Marrow Neutrophil><Measures><Mediating><Megakaryocyte Colony Stimulating Factor><Megakaryocyte Growth and Development Factor><Metformin><Mice><Mice Mammals><Mig Receptor><Mig-R><MigR><Milk Growth Factor><Mitogen-Activated Protein Kinase 14><Mitogen-Activated Protein Kinase Inhibitor><Mitogenic Factor><Modeling><Molecular Chaperones><Monocyte-Derived TNF><Mouse Homolog of Myeloproliferative Leukemia Virus><Multiple Organ Dysfunction Syndrome><Multiple Organ Failure><Murine><Mus><Mxi2><Myelogenous><Myeloid><Myeloid Differentiation-Inducing Protein><Myeloproliferative Leukemia Virus Oncogene><Myeloproliferative Leukemia Virus Oncogene Ligand><N,N-dimethyl-imidodicarbonimidic diamide><Natural regeneration><Neutropenia><Neutrophilic Granulocyte><Neutrophilic Leukocyte><Nuclear Power Plants><OKT3 antigen><Outcome><Outcome Measure><Ovalbumin><Oxygen Consumption><PD 1><PD-1><PD1><Peptides><Peritoneal><Phagocytosis><Phase><Phenotype><Physiological Homeostasis><Physiopathology><Plasmacytoma Growth Factor><Platelet Transforming Growth Factor><Polymorphonuclear Cell><Polymorphonuclear Leukocytes><Polymorphonuclear Neutrophils><Population><Production><Proteins><Protocol><Protocols documentation><RNA vaccine><RNA-based vaccine><Radiation><Radiation Biology><Radiation Injuries><Radiation Toxicity><Radiation exposure><Radiation-Ionizing Total><Radio><Radiobiology><Radiotoxicity><Recombinants><Regeneration><Regimen><Residual><Residual state><Roentgen Rays><SAPK2A><SARS-CoV-2 S protein><SARS-CoV-2 spike glycoprotein><SARS-CoV-2 spike protein><SARS-CoV2 S protein><SARS-CoV2 spike glycoprotein><SARS-CoV2 spike protein><STK1-ligand><Septic Shock><Serum><Severe acute respiratory syndrome coronavirus 2 S protein><Severe acute respiratory syndrome coronavirus 2 spike glycoprotein><Severe acute respiratory syndrome coronavirus 2 spike protein><Spillage><Spleen><Spleen Reticuloendothelial System><Stress-Activated Protein Kinase 2A><Survivors><Syndrome><T cell growth factor><T cell receptor repertoire sequencing><T cell receptor sequencing><T memory cell><T-Cell Growth Factor><T-Cell Proliferation><T-Cell Stimulating Factor><T-Cells><T-Lymphocyte><T3 Antigens><T3 Complex><T3 molecule><T44><T8 Cells><T8 Lymphocytes><TCR repertoire sequencing><TCR sequencing><TCR-seq><TCRseq><TGF B><TGF-beta><TGF-β><TGFbeta><TGFβ><TNF><TNF A><TNF Alpha><TNF gene><TNF-α><TNFA><TNFα><TPOR><Terrorism><Therapeutic Agents><Thrombocytopenia><Thrombocytopoiesis-Stimulating Factor><Thrombocytopoietin><Thrombopenia><Thrombopoietin><Thrombopoietin Receptor><Thymocyte Stimulating Factor><Thymus><Thymus Gland><Thymus Proper><Thymus Reticuloendothelial System><Time><Tissues><Total Body Irradiation><Total Lymphocyte Count><Transforming Growth Factor beta><Transforming Growth Factor-Beta Family Gene><Transgenic Mice><Tumor Necrosis Factor><Tumor Necrosis Factor-alpha><Vaccination><Whole-Body Irradiation><Whole-Body Radiation><X-Radiation><X-Ray Radiation><X-ray><Xray><accessory cell><advanced age><allergic/immunologic body system><allergic/immunologic organ system><antibody titering><atom bomb><atomic bomb><autophagy><bacteraemia><bacterial sepsis><base><bowel><c-mpl Ligand><cell regeneration><cellular regeneration><conditioning><coronavirus disease 2019 S protein><coronavirus disease 2019 spike glycoprotein><coronavirus disease 2019 spike protein><cytokine><dirty bomb><elders><exhaust><exhaustion><flk2 ligand><flk2-flt3 ligand><flt3 ligand protein><geriatric><ghrelin><hematopoietic growth factor><immunogen><immunologic assay><immunologic assay/test><immunophenotype><immunosenescence><immunosuppressed patient><inhibition of autophagy><injuries><interferon beta 2><intestinal epithelium><ionizing output><irradiation injury><lFN-Gamma><late life><later life><long-term study><longitudinal outcome studies><longterm study><lymph cell><lymph gland><lymph nodes><lymph organ><lymphatic organ><lymphnodes><lymphocyte depletion therapy><lymphoid organ><mRNA vaccine><mRNA-based vaccine><memory T lymphocyte><mimetics><mitochondrial dysfunction><mpl Ligand><mucosa associated lymphoid tissue><mucosa associated lymphoid-tissue><mucosa-associated lymphoid tissue><multiorgan failure><multiple organ system failure><neutrophil><novel><older adult><older person><p38><p38 MAP Kinase><p38 MAPK Gene><p38 Mitogen Activated Protein Kinase><p38 Protein Kinase><p38 SAPK><p38-Alpha><p38Alpha><pathophysiology><peripheral lymph organ><peripheral lymphoid organ><prevent><preventing><programmed cell death 1><programmed cell death protein 1><programmed death 1><pulmonary><radiation countermeasure><radiation effect><radiation mitigation><radiation poisoning><radiological countermeasure><radiological mitigation><radiomitigation><regenerate><regenerate bone><regenerative><response><senescence><senescent><senior citizen><sle2><stem cell tyrosine kinase 1 ligand><subcutaneous><subdermal><systemic inflammation><systemic inflammatory response><systemic lupus erythematosus susceptibility 2><terrorist attack><thymus derived lymphocyte><transcriptomics>