Regeneration of the Immune System after Radiation Exposure

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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.