A Novel Warming Strategy For Improving Neutrophil Recovery Following Total Body Irradiation

Total body irradiation (TBI) exposure damages not only the hematopoietic compartment but also at least two other important immunological barriers to infection: the gut mucosa and the skin. This leaves those exposed to sufficient doses of radiation highly susceptible to infection. In order to prevent illness or death from microbial invaders, new strategies are needed that can safely and rapidly boost leukocyte numbers. We hypothesized that mildly elevating core temperature, which we and others have shown previously to alter leukocyte numbers and migration patterns, following a non-myeloablative dose of TBI, will enhance immune reconstitution through a thermally sensitive, cytokine driven bone marrow release of granulocytes to the peripheral blood. This hypothesis was generated from the following initial observations: C57BL/6 mice were given TBI (3Gy) followed 2 hours later by a mild heating (where core body temperature was elevated to 39.5°C). In mice that were heated following TBI, a significant increase in recovery rate of peripheral blood granulocytes was observed by day 8 compared to mice that received radiation alone or heating alone. In addition, G-CSF concentration was increased two fold in the serum of radiated/heated mice correlating with the increased granulocyte recovery. G-CSF production was driven by IL-17 production in the intestine seen only when radiation was followed by heat treatment. IL-17 was later confirmed to be necessary for the thermal enhancement of neutrophil recovery when the effect of heating after radiation was lost in the IL-17R knockout mouse model. Flow analysis of the bone marrow from wild type mice revealed comparable percentages of hematopoietic stem cells in the control (63.3±2.8% of LSK were CD34-) and the radiation/heat-treated groups (62.0±1.2% of LSK were CD34-); however, there was a significantly lower percentage of hematopoietic stem cells in the bone marrow of the radiation-alone group (43.4±1.7%; p Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 575. doi:10.1158/1538-7445.AM2011-575