16,16 dimethyl-prostaglandin E2 Administration Prior to Lethal Irradiation Ameliorates Long-term Immune Suppression.

Abstract

Survivors of the hematopoietic acute radiation syndrome (H-ARS) face delayed effects of acute radiation exposure (DEARE), including chronic immune suppression and thymic involution, for which no effective countermeasures exist. We previously demonstrated that 16,16-dimethyl prostaglandin E2 (dmPGE2) enhances H-ARS survival when administered prior to irradiation. Here, we investigated its long-term radiation protective effects on immune reconstitution at 6 and 12 months after exposure in a lethal total-body irradiation (TBI) mouse model. C57BL/6J mice received dmPGE2 30 min prior to TBI (PGE-pre-irradiation), 24 h after TBI [prostaglandin E (PGE)-postirradiation], or vehicle (Veh), with non-irradiated mice included as controls. Surviving mice treated with Veh prior to TBI exhibited persistent thymic involution, decreased thymocyte subsets, and diminished splenic T and B cells, alongside elevated bone marrow (BM) and serum IL-6, KC, MCP-1, and G-CSF levels with reduced MIP-1β, reflecting systemic immune dysregulation. Treatment of mice with dmPGE2 pre-irradiation significantly prevented these effects with mice exhibiting enhanced thymocyte maturation, increased splenic lymphocytes, preservation of the thymic cortex/medulla ratio, attenuated BM/serum cytokine disturbance, and generation of functional lymphocytes in vitro. Administration of dmPGE2 at 24 h postirradiation had minimal effect. Competitive BM transplantation and in vitro co-culture studies in mice receiving dmPGE2 pre-irradiation revealed that dmPGE2 enhanced BM lymphoid progenitor cell differentiation and function. RNA sequencing of phenotypically defined hematopoietic stem cells (HSC) at 24 h after TBI from mice treated with dmPGE2 30 min prior to TBI showed upregulation of genes associated with lymphopoiesis, notably Flt3, involved in hematopoietic cell proliferation and survival, and Dntt, involved in the development of T and B cells. These findings demonstrate that dmPGE2 can prevent radiation-induced long-term immune suppression by protecting lymphoid progenitors, suggesting its potential as a radioprotectant for radiation accident victims and radiotherapy patients.