In vivo augmentation of IFN-gamma with a rIL-12 human/mouse chimera: pleiotropic effects against infectious agents in mice and rats.
A heterodimer containing the mouse 35 kDa and human 40 kDa subunit of IL-12 was expressed in COS cells (cIL-12). Administration of 25-200 U of the cIL-12-COS supernatant to mice twice daily for 2 days augmented spleen cell IFN-gamma production in response to IL-2 and peritoneal macrophage activity (superoxide and nitrites) as compared to animals receiving mock transfected supernatants. cIL-12 also increased levels of IFN-gamma in serum but most dramatically following an LPS injection (50-fold over controls). Animals pretreated with cIL-12 suffered enhanced mortality following challenge with the Gram negative organism E. coli but enhanced survival or clearance following infection with the Gram positive organisms L. monocytogenes and S. aureus. Although daily treatment of mice with cIL-12 following an intranasal influenza A infection elevated levels of IFN-gamma in the bronchioalveolar lavage fluid three-fold over controls, neither prophylactic or therapeutic treatment with the same dose level decreased viral titres in the lung. In addition, no effect was observed in animals infected with encephalomyocarditis virus or respiratory syncytial virus. Therefore, cIL-12 is a potent in vivo augmentor of IFN-gamma production. It has differential effects on infectious disease depending on the invading organism and time of administration; being efficacious for intracellular bacteria but ineffective at the same dose levels against viral diseases.
Gladue
R P
RP
Central Research Division, Pfizer, Inc., Groton, CT 06340.
Laquerre
A M
AM
Magna
H A
HA
Carroll
L A
LA
O'Donnell
M
M
Changelian
P S
PS
Franke
A E
AE
D000818:Animals; D000906:Antibodies / Q000494:pharmacology; D002460:Cell Line; D004927:Escherichia coli Infections / Q000276:immunology*; D005260:Female; D006133:Growth Substances / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis* / Q000097:blood; D018664:Interleukin-12; D007378:Interleukins / Q000096:biosynthesis / Q000494:pharmacology* / Q000627:therapeutic use; D008070:Lipopolysaccharides / Q000633:toxicity*; D008089:Listeria monocytogenes / Q000187:drug effects / Q000254:growth & development; D008088:Listeriosis / Q000276:immunology* / Q000628:therapy; D008099:Liver / Q000187:drug effects / Q000382:microbiology; D008168:Lung / Q000187:drug effects / Q000382:microbiology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis / Q000494:pharmacology* / Q000627:therapeutic use; D013203:Staphylococcal Infections / Q000276:immunology* / Q000628:therapy; D014162:Transfection; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D014777:Virus Diseases / Q000276:immunology / Q000628:therapy
D000906:Antibodies; D006133:Growth Substances; D007378:Interleukins; D008070:Lipopolysaccharides; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D018664:Interleukin-12; D007371:Interferon-gamma