Preclinical development of a bridging therapy for radiation causalities

Victims of a terrorist attack presenting with the hematopoietic syndrome resulting from exposure to excessive levels of ionizing radiation will succumb to sepsis if not adequately treated. The probability of survival is increased substantially if the victim's immune system is allowed to recover before sepsis sets in. We report here preclinical development of a new bridging therapy which will allow the victim's immune system to recover from damage caused by ionizing radiation. CD2F1 mice were irradiated with lethal, whole-body doses of cobalt-60 gamma-radiation and then transfused intravenously (retro-orbital sinus) with whole blood, peripheral blood mononuclear cells (PBMC) or plasma from tocopherol succinate (TS) and AMD3100-injected mice after irradiation. Survival was monitored for 30 days after transfusion of whole blood, PBMC or plasma. Intestinal and splenic tissues were harvested after irradiation and cells of those tissues were analyzed for markers of apoptosis and mitosis. Bacterial translocation from gut to heart, spleen, and liver in TS-mobilized PBMC-treated and irradiated mice was evaluated by bacterial culture. The infusion of PBMC from TS- and AMD3100-injected mice significantly enhanced survival after high radiation doses causing hematopoietic and gastrointestinal syndromes, inhibited apoptosis, increased cell proliferation in tissues, and inhibited bacterial translocation to various organs compared to mice receiving vehicle-mobilized cells. TS and AMD3100 mobilized progenitors into peripheral circulation and the infusion of mobilized progenitor-containing blood or PBMC acted as a bridging therapy for immune-system recovery in mice exposed to high, potentially fatal doses of ionizing radiation. The efficacy of TS-mobilized progenitors was comparable to granulocyte colony-stimulating factor (G-CSF)-mobilized progenitors, though only one injection of TS was required compared to four injections of G-CSF. We suggest this novel bridging therapeutic approach that involves the infusion of TS-mobilized hematopoietic progenitors following acute radiation injury might be applicable to humans as well. The views expressed do not necessarily represent the Armed Forces Radiobiology Research Institute, the Uniformed Services University of the Health Sciences, or the Department of Defense. (author)