Immune-modulation by 7, 8-diacetoxy-4-methylthiocoumarin in total body-irradiated mice: Implications for the mitigation of radiation-induced hematopoietic injury

Abstract

Aims: Development of novel medical countermeasures (MCMs) against acute radiation syndrome (ARS) and the associated lethality involves protection from and/or mitigation of radiation-induced hematopoietic injury, a critical clinical component of ARS. We earlier identified the molecule 7,8-diacetoxy-4-methylthiocoumarin (DAMTC) as a potent mitigator of hematopoietic injury and mortality in C57BL/6 mice when administered 24 h following total body irradiation (TBI). In the present study, we investigated mechanisms and functional relevance of immune modulation by DAMTC during the mitigation of hematopoietic injury.

Main methods: C57BL/6 mice were subjected to TBI doses of 3 and 7.6Gy; administered DAMTC intra-peritoneally 24 h post TBI. Isolation, characterization, intra-cellular cytokine analysis of myeloid cells from bone marrow and spleen accompanied by flow cytometric determination and characterization of B-lymphocytes, serum isolation from peripheral blood and cytokine analysis.

Key findings: Results showed that DAMTC induced stimulation of pro-inflammatory myeloid subsets in the bone marrow and spleen of TBI mice. Further, it promoted a favorable transition from Th2 to Th1 immunity, triggered humoral immunity, and activated an intricately balanced inflammatory response that appear to contribute to immune-modulation.

Significance: Thus, the present study shows that immune-modulation maybe one of the contributing factors for the mitigation of hematopoietic injury by DAMTC and underscores its efficacy as a potent mitigator of hematopoietic injury that merits to be developed further as a novel MCM to combat H-ARS.

Keywords: Acute radiation syndrome; DAMTC; Hematopoietic injury; Immune modulation; Macrophages; Medical countermeasures; Mitigation; Total-body irradiation.