A role for tumor necrosis factor in poly(I:C)-induced hemorrhagic necrosis and T-cell-dependent regression of a murine sarcoma.
It was found that intravenous injection of the synthetic double-stranded ribonucleic acid, polyinosinic-polycytidylic acid [poly(I:C)], which is a well-studied interferon (IFN)-inducing agent, can result in extensive hemorrhagic necrosis of the center of an established murine sarcoma and in subsequent complete regression of the surviving rim of the tumor. The poly(I:C)-induced intratumor hemorrhagic reaction was associated with production of appreciable quantities of tumor necrosis factor (TNF) by the host. Neutralization of TNF by treatment with anti-rTNF immunoglobulin G (IgG) caused substantial inhibition of hemorrhagic necrosis and prevented tumor regression from proceeding. Tumor regression was prevented in all mice by depleting them of CD8+ T cells 1 day before poly(I:C) was given. Taken as a whole, the results indicate that the antitumor action of poly(I:C), like that of endotoxin, is based on its capacity to induce the host to make enough TNF to cause a hemorrhagic reaction extensive enough to reduce the tumor burden to a size capable of being dealt with by an underlying host antitumor immune response.
North
R J
RJ
Trudeau Institute, Inc., Saranac Lake, NY 12983.
Dunn
P L
PL
Havell
E A
EA
D000818:Animals; D004731:Endotoxins / Q000008:administration & dosage; D005260:Female; D006470:Hemorrhage / Q000473:pathology*; D007074:Immunoglobulin G / Q000276:immunology; D007275:Injections, Intravenous; D051379:Mice; D008805:Mice, Inbred A; D008810:Mice, Inbred C57BL; D009336:Necrosis; D011070:Poly I-C / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins; D012074:Remission Induction; D012477:Salmonella enteritidis; D012513:Sarcoma, Experimental / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013601:T-Lymphocytes / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000276:immunology
D004731:Endotoxins; D007074:Immunoglobulin G; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D011070:Poly I-C