Depression of early protection against influenza virus infection by cyclophosphamide and its restoration by Y-19995 [2,4'-bis(1-methyl-2-dimethyl-aminoethoxyl)-3-benzoylpyridine dimaleate].
The relationship between depression of early protection against influenza virus infection and the decrease in the number of peripheral polymorphonuclear leukocytes in cyclophosphamide-treated mice was investigated by means of a novel synthetic compound, Y-19995 [2,4'-bis(1-methyl-2-dimethyl-aminoethoxyl)-3-benzoylpyridine dimaleate], which had been shown to exert a potent restorative effect on leukocytopenia in immunocompromised hosts. Following intranasal inoculation with influenza virus (1.5 x 10(3) plaque-forming units) into untreated mice, the pulmonary virus titer progressively increased during 3 days and decreased gradually from day 7 after infection. The treatment with cyclophosphamide 2 days before infection markedly enhanced the pulmonary virus multiplication from the early phase of infection, and the higher virus titer was maintained thereafter. When mice were given Y-19995 after cyclophosphamide treatment, virus titers from the early to late phases of infection were lower than those in untreated mice. The number of peripheral polymorphonuclear leukocytes in cyclophosphamide-treated mice rapidly decreased and returned to normal levels only 9 days after the treatment, while such leukocytopenia was prevented to some extent and the leukocyte count was restored completely up to 7 days by postcyclophosphamide treatment with Y-19995. Furthermore, the treatment with Y-19995 augmented the inactivation of virus by the polymorphonuclear leukocytes. However, the virus inactivation by alveolar macrophages was modified only slightly by Y-19995 treatment. In addition, Y-19995 treatment could potentiate antibody-dependent cell-mediated cytotoxicity of polymorphonuclear leukocytes against the virus-infected target cells, and the production of serum neutralizing antibody to influenza virus in untreated and cyclophosphamide-treated mice. Y-19995 revealed neither antiviral nor interferon-inducing activities.(ABSTRACT TRUNCATED AT 250 WORDS)
Tsuru
S
S
Department of Microbiology, National Defense Medical College, Saitama, Japan.
Shinomiya
N
N
Nomoto
K
K
D000818:Animals; D000914:Antibodies, Viral / Q000096:biosynthesis; D003520:Cyclophosphamide / Q000633:toxicity*; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D005260:Female; D007970:Leukopenia / Q000139:chemically induced / Q000188:drug therapy; D008264:Macrophages / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D009504:Neutrophils / Q000187:drug effects / Q000276:immunology; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000209:etiology / Q000276:immunology; D011725:Pyridines / Q000627:therapeutic use*; D014779:Virus Replication / Q000187:drug effects
D000914:Antibodies, Viral; D011725:Pyridines; C054098:Y 19995; D003520:Cyclophosphamide