Ionizing radiation and immune system: low and high dose effects

Exposure to ionizing radiation at low and high doses can exert varying responses on the immune system. Radiation exposures to doses <100 mSv is important since it contributes to our understanding of biological effects of low dose radiation. Low dose ionizing radiation (LDIR) induced transient adaptive response (AR) in BALB/c mice which was due to hyper activation of MAPK signaling. Similar experiments in C57BL/6 mice indicated absence of AR despite low dose induced MAPK activation. Evaluation of upstream MAPK activators indicated that differential induction of Ca²⁺ and NO signaling in BALB/c and C57BL/6 mice was responsible for these effects. On the other hand, localised radiation exposures can play a crucial role in affecting the tumor induced immunosuppression. Select doses of ionizing radiation increased immune activating potential of dendritic cells (DC) through STAT5/Zbtb46 signalling mediated by irradiation induced apoptotic bodies (AB). Splenic and bone marrow derived DC from tumour bearing mice exposed to localised irradiation showed abrogation of tumour induced immunosuppression. This phenomenon was also recapitulated in DC derived from normal mice exposed to whole body irradiation or those differentiated from in vitro irradiated progenitor cells. Further, these DCs derived from irradiated progenitors could resist the suppressive effects of tumour conditioned medium and had increased immune activating potential. Exposure to higher doses of localized radiation increases immunosuppressive molecules like PD-1. COX-2 inhibitor NS-398 decreases tumor induced expression of PD-1 and hence was used in combination therapy along with localized radiation and anti- PD1 antibody. There was a significant reduction in tumor burden with NS-398/radiation combination or NS-398/radiation/anti-PD-1 combination when compared to either NS-398 or radiation alone. These results thus demonstrate that though localized irradiation can activate DC, it can also induce immunosuppressive molecules and use of anti-PD-1 or agents like NS-398 can decrease PD-1 expression and can potentiate radiotherapy. (author)