title: alpha-Galactosylceramide (AGL-517) treatment protects mice from lethal irradiation.
abstract: AGL-517 (AGL) has an alpha-galactosylceramide structure and is a derivative of agelasphin-9b, which in turn is isolated from Agelas mauritianus and has immunomodulating activity. When administered before irradiation, AGL has been found to increase survival rates in lethally irradiated mice. In this study, we found that a single injection of AGL administered within 2 hours of lethal irradiation resulted in the long-term survival of mice without bone marrow transplantation. Peripheral blood hematology showed that AGL administration accelerated the recovery of hematopoietic parameters, including reticulocytes and red and white blood cells. Recovery of platelets was moderate. In addition, AGL significantly increased the number of endogenous colony forming units-spleen (E-CFU-S). AGL itself displayed no colony-stimulating activity, but AGL-stimulated spleen cell-conditioned medium (AGL-SCM) promoted the proliferation and differentiation of bone marrow mononuclear cells from normal mice and Lin marrow cells from 5-fluorouracil (5-FU)-treated mice. Using suitable assay systems, we analyzed cytokines in AGL-SCM and found significant increases in stem cell factor (SCF), interleukin-3 (IL-3), granulocyte-macrophage colony-stimulating factor (GM-CSF), and IL-6 levels compared with control SCM. Additionally, using immunoenzymetric assays, we assessed serum levels of these factors in AGL-treated mice after lethal irradiation. The serum concentrations of IL-3, GM-CSF, and IL-6 were substantially elevated, the maximum levels being reached within 2 hours of injection. Despite inducing the in vitro increase in SCF, AGL did not elevate serum SCF levels. However, certain levels of SCF (approximately 5 ng/mL) were detected in mouse serum regardless of irradiation or AGL treatment. When irradiated mice were given a cytokine cocktail composed of recombinant murine (rm) IL-3, rmGM-CSF, and recombinant human (rh) IL-6 three times a day for 6 days (1 microg of each factor per mouse per day) starting 2 hours after irradiation, 60% of the mice achieved 50-day survival. The radioprotective effect of AGL can be attributed, in part, to the cooperative effect of the cytokines induced by AGL in vivo. These findings suggest that AGL may be a useful in treating radiation-induced hematopoietic damage.
authors.affiliation: Pharmaceutical Research Laboratory, Kirin Brewery Co., Takasaki, Gunma, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Inoue
authors.forename: Y
authors.initials: Y
authors.lastname: Koezuka
authors.forename: N
authors.initials: N
authors.lastname: Nishi
authors.forename: M
authors.initials: M
authors.lastname: Osawa
authors.forename: K
authors.initials: K
authors.lastname: Motoki
authors.forename: E
authors.initials: E
authors.lastname: Kobayashi
authors.forename: K
authors.initials: K
authors.lastname: Kabaya
authors.forename: M
authors.initials: M
authors.lastname: Obuchi
authors.forename: H
authors.initials: H
authors.lastname: Fukushima
authors.forename: K J
authors.initials: KJ
authors.lastname: Mori
mesh_terms: D000818:Animals; D005699:Galactosylceramides / Q000494:pharmacology*; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000097:blood / Q000494:pharmacology; D006410:Hematopoiesis / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007377:Interleukin-3 / Q000097:blood / Q000494:pharmacology; D015850:Interleukin-6 / Q000097:blood; D007700:Kinetics; D008297:Male; D051379:Mice; D011833:Radiation Injuries, Experimental / Q000401:mortality / Q000517:prevention & control; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D011994:Recombinant Proteins; D019089:Stem Cell Factor / Q000097:blood; D015996:Survival Rate; D014916:Whole-Body Irradiation
chemical_list: C107484:AGL 517; D005699:Galactosylceramides; D007377:Interleukin-3; D015850:Interleukin-6; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; D019089:Stem Cell Factor; D016178:Granulocyte-Macrophage Colony-Stimulating Factor