Long-Lasting Impact of Neonatal Exposure to Total Body Gamma Radiation on Secondary Lymphoid Organ Structure and Function

Abstract

The acute period after total body irradiation (TBI) is associated with an increased risk of infection, principally resulting from the loss of hematopoietic stem cells, as well as disruption of mucosal epithelial barriers. Although there is a return to baseline infection control coinciding with the apparent progressive recovery of hematopoietic cell populations, late susceptibility to infection in radiation-sensitive organs such as lung and kidney is known to occur. Indeed, pulmonary infections are particularly prevalent in hematopoietic cell transplant (HCT) survivors, in both adult and pediatric patient populations. Preclinical studies investigating late outcomes from localized thoracic irradiation have indicated that the mechanisms underlying pulmonary delayed effects are multifactorial, including exacerbated and persistent production of pro-inflammatory molecules and abnormal cross-talk among parenchymal and infiltrating immune and inflammatory cell populations. However, in the context of low-dose TBI, it is not clear whether the observed exacerbated response to infection remains contingent on these same mechanisms. It is possible instead, that after systemic radiation-induced injury, the susceptibility to infection may be independently related to defects in alternative organs that are revealed only through the challenge itself; indeed, we have hypothesized that this defect may be due to radiation-induced chronic effects in the structure and function of secondary lymphoid organs (SLO). In this study, we investigated the molecular and cellular alterations in SLO (i.e., spleen, mediastinal, inguinal and mesenteric lymph nodes) after TBI, and the time points when there appears to be immune competence. Furthermore, due to the high incidence of pulmonary infections in the late post-transplantation period of bone marrow transplant survivors, particularly in children, we focused on outcomes in mice irradiated as neonates, which served as a model for a pediatric population, and used the induction of adaptive immunity against influenza virus as a functional end point. We demonstrated that, in adult animals irradiated as neonates, high endothelial venule (HEV) expansion, generation of follicular helper T cells (TFH) and formation of splenic germinal centers (GC) were rapidly and, more importantly, persistently impaired in SLO, suggesting that the early-life exposure to sublethal radiation had long-lasting effects on the induction of humoral immunity. Although the neonatal TBI did not affect the overall outcome from influenza infection in the adults at the earlier time points assessed, we believe that they nonetheless contribute significantly to the increased mortality observed at subsequent late time points. Furthermore, we speculate that the detrimental and persistent impact on the induction of CD4 T- and B-cell responses in the mediastinal lymph nodes will decrease the animals’ ability to respond to other aerial pathogens. Since many of these pathogens are normally cleared by antibodies, our findings provide an expla...

NK Cells and Other Innate Lymphoid Cells in Hematopoietic Stem Cell Transplantation

“…These data are further supported by the finding that treatment with IL-22, in mice receiving bone marrow transplantation, resulted in increased intestinal stem cell recovery, in enhanced epithelial cell regeneration, and in reduction of intestinal GvHD ( 36 ). Given the role of ILC3 in lymphoid organogenesis and in lymphoid tissue remodeling, a role for these cells could also be envisaged in the regeneration of lymphoid tissues damaged by radiations ( 38 , 40 ). Of note, ILC3-derived IL-22 can also favor the recovery of thymic epithelial cells, thus allowing a more efficient and rapid reconstitution of T-cell compartment (Table 1 ) ( 41 ).…”

“…Conversely, it remains to be determined whether ILC3 also contribute to the regeneration of secondary lymphoid organs. In this context, it is recently shown that gamma irradiation used in conditioning regimen before HSCT may exert a long-lasting effect on secondary lymphoid organ structure and function ( 40 ). Also, ILC2 appear to be involved in epithelial tissue repair, particularly in lung tissues; however, no data are available to support an actual protection exerted by these cells in GvHD-induced tissue damages ( 42 ).…”

Addressing the Symptoms or Fixing the Problem? Developing Countermeasures against Normal Tissue Radiation Injury

“…Our group has demonstrated, in both adult and neonate models of lung irradiation, that low-dose irradiation leads to late susceptibility to pulmonary infections (54–56). However, further investigations have indicated these altered immune responses are subsequent to effects on different cell populations dependent on the age at the time of irradiation, i.e., loss of epithelial (club) cells (54) in the adult animals versus alterations in secondary lymph organs in the neonates (172), indicating that age and/or development status may also inform mitigation strategies. It is therefore likely that combination approaches will need to be tailored to the most critically affected organs or those most at risk, depending on the affected volume.…”

Harnessing Unconventional T Cells and Innate Lymphoid Cells to Prevent and Treat Hematological Malignancies: Prospects for New Immunotherapy

“…These harms can worsen with allo-HSCT following the occurrence of GVHD due to donor T lymphocytes [ 66 ]. An animal experimental model of aGVHD demonstrated that host-originated IL-22 could avoid the onset of GVHD, and that gut ILC3 cells are the principal makers of IL-22 after total body irradiation therapy [ 67 , 68 , 69 ]. Furthermore, ILC3-originated IL-22 can also promote thymic epithelial cell recovery, thus permitting a prompter re-formation of the T cell subset [ 70 ].…”