Mucosal cytokine therapy: marked antiviral and antitumor activity.
Mucosal administration of the Th1 stimulatory cytokines interleukin-2 (IL-2), IL-12, IL-15, IL-18, or granulocyte-macrophage colony-stimulating factor (GM-CSF) induced antiviral activity in mice challenged systemically with a lethal dose of encephalomyocarditis virus (EMCV) similar to that observed following parenteral administration. In contrast, mucosal administration of the Th2 stimulatory cytokines IL-4, IL-5, IL-10, or IL-13 did not affect significantly the survival of EMCV-infected animals. Mucosal administration of IL-2 or IL-12 also exerted a marked antitumor activity in mice inoculated intravenously with Friend erythroleukemia cells. Recombinant IL-2 and IL-18, but none of the other recombinant cytokines tested, induced low levels of IFN in vitro. Polyclonal antibodies to both mouse and human interferon-alpha/beta (IFN-alpha/beta) abrogated the antiviral activity of IL-2 in vivo, even though the anti-human IFN-alpha/beta antibody did not neutralize mouse IFN-alpha/beta, and neither antibody bound to IL-2. IL-15 did not exhibit antiviral activity in IFN-alpha/beta R-/- mice, which are deficient in natural killer (NK) cell activity. These results suggest that mucosal Th1 cytokine therapy induces a soluble factor or activates a specific cell population in the lymphoid or epithelial tissue of the oropharyngeal cavity, which potentiates elimination of virus-infected or neoplasic cells systemically.
Tovey
M G
MG
Laboratory of Viral Oncology, UPR 9045 CNRS, Institut de Recherches sur le Cancer/IFR Y1221, Villejuif, France. tovey@infobiogen.fr
Meritet
J F
JF
Guymarho
J
J
Maury
C
C
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D000998:Antiviral Agents / Q000627:therapeutic use*; D005622:Friend murine leukemia virus / Q000187:drug effects; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000627:therapeutic use*; D006801:Humans; D007372:Interferons / Q000627:therapeutic use*; D007378:Interleukins / Q000627:therapeutic use*; D007928:Lethal Dose 50; D007942:Leukemia, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D009092:Mucous Membrane / Q000187:drug effects; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000627:therapeutic use; D015996:Survival Rate; D014777:Virus Diseases / Q000188:drug therapy; D014779:Virus Replication / Q000187:drug effects
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D007378:Interleukins; D011994:Recombinant Proteins; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D007372:Interferons