Oral WGP Beta Glucan Treatment Accelerates Myeloid Recovery after Radiation Exposure

The threat of nuclear radiation terrorism has prompted a widespread search for defenses against this menace. Radiation destroys the bone marrow (BM) and depletes the body of white blood cells (WBC or leukocytes) that defend against infection and disease. In this immune-weakened state, the body is more susceptible to infection and may become overwhelmed before the immune system has time to recover. I.V. treatment with β-glucan, β(1,3) linked polymers of D-glucose isolated from the cell wall of baker’s yeast, has previously been shown in mice to accelerate BM recovery and increase survival after lethal irradiation. Oral yeast β-glucan administration offers many practical and financial benefits as an alternative treatment, but has not been previously examined for a similar benefit in post-radiation myeloid recovery and survival. To test this hypothesis, mice were exposed to a sublethal dose of radiation (500 cGy) and treated daily with 80 μg of whole glucan particles (WGP Beta Glucan) by gastric gavage. This treatment with WGP Beta Glucan gave rise a to significantly faster recovery of leukocyte counts, as early as 7 days post-irradiation compared to control mice treated with PBS. A role for CR3 in mediating this hematopoietic recovery was established as oral WGP treatment in sublethally irradiated CR3 (i.e. CD11b) mice failed to enhance myeloid recovery. Complement receptor 3 (CR3, Mac-1, or CD11b/CD18) is a β2-integrin found on monocytes, macrophages, and neutrophils that functions as a major leukocyte receptor for β-glucan, as well as for iC3b and ICAM-1. Subsequent investigation of mice that had been fed fluorescein-labeled WGP Beta Glucan revealed intestinal macrophages that had ingested WGP Beta Glucan and had migrated to the spleen and BM. Further experiments showed that wild-type, but not CR3 macrophages, stimulated by WGP Beta Glucan synthesized IL-12 and several other inflammatory cytokines including GM-CSF. IL-12 is known to stimulate T lymphocyte production of oncostatin-M, a potent hematopoietic cytokine. In addition, the damaged BM removed from irradiated mice showed evidence for deposition of the serum complement protein C3 (iC3b-fragment) that was shown in vitro to serve as a co-stimulator of hematopoietic stem cell CR3 when added in combination with fragments of the β-glucan that are probably released by macrophages that convey WGP Beta Glucan to the BM. A role for serum complement C3 was further suggested because both C3-deficient (C3) and CR3 mice exhibited a similar defect in recovery of blood leukocytes following sublethal radiation injury. While the exact mechanism of WGP Beta Glucan-enhanced myeloid recovery remains to be established, these data indicate that orally administered WGP Beta Glucan stimulates myeloid recovery following irradiation in a CR3-dependent manner. Consequently, oral treatment with WGP Beta Glucan may be a useful therapeutic intervention following radiation exposure to accelerate myeloid recovery after radiation exposure.