Increase in liver-associated natural killer activity by polyribonucleotides

Several polyribonucleotides are currently in clinical trials for the treatment of cancer or viral diseases. The present report in mice demonstrates that polyinosinic-polycytidylic acid and poly-L-lysine which has been stabilized in carboxymethylcellulose (poly (ICLC) as well as polyadenosinic-polyuridylic acid (poly AU), both potently augment natural killer (NK) activity in the liver, which is often a target organ for the formation of metastases during the progression of human cancer. Following the administration of poly ICLC (10 micrograms/mouse), greater NK activity as measured by lytic units (LU), was observed in the liver (445 LU) than in blood (63 LU) or spleen (20 LU). The high level of NK activity in the liver was in contrast to the low levels observed in untreated mice, and was maintained for at least 9 days post injection. NK activity in the blood and spleen returned to normal levels by day 6. Similar results were obtained with poly AU except that approximately 10-fold more poly AU (100 micrograms/mouse) was required to induce optimal augmentation of NK activity. Further studies demonstrated that the increase in liver-associated NK activity induced by poly ICLC was associated with a 10- to 20-fold increase in liver-associated leukocytes, termed nonparenchymal cells (NPC). Fractionation of the NPC on discontinuous density gradients of Percoll demonstrated that the NK activity mediated by NPC was associated with cells morphologically characterized as large granular lymphocytes (LGL). Further studies demonstrated that the repeated administration of poly ICLC resulted in significantly higher levels of liver-associated NK activity and total liver-associated LGL as compared to a single injection.