Synergistic effect of interleukin-15 and interleukin-12 on antitumor activity in a murine malignant pleurisy model.
Interleukin(IL)-15, which uses IL-2 receptor (R) beta and gamma chains for signal transduction, shares many of the biological activities of IL-2. We examined the effects of exogenous IL-15 on protection in a murine malignant pleurisy model using BALB/c mice and syngeneic MethA fibrosarcoma (MethA). Intrapleural administration of IL-15 significantly prolonged the survival time of mice after an intrapleural inoculation of MethA, whereas the same dose of IL-2 did not. The in vivo antitumor effect of IL-15 was synergistically enhanced by additive administration of IL-12. Combination therapy of IL-15 and IL-12 protected mice from death from bloody pleural fluid. Such treatment induced marked increases in the number of CD3-IL-2Rbeta+ cells corresponding to natural killer (NK) cells and the production of interferon gamma (IFNgamma) by T cells in the thoracic exudate cells (TEC). Administration of anti-IFNgamma mAb partly inhibited the protective effect of a combination of IL-15 and IL-12. A tumor-neutralizing (Winn) assay revealed that the antitumor activity of effector cells in the TEC was abrogated by treatment with anti-CD8 mAb or anti-asialoGM1 Ab plus complement. Thus, treatment with IL-15 in combination with IL-12 may enhance the activities of NK and CD8+ T cells in the TEC, providing strong antitumor activity against the malignant pleurisy. These results suggest that IL-15 together with IL-12 may have potential for the immunotherapy of some types of malignant pleurisy.
Kimura
K
K
Research Institute for Disease Mechanism and Control, 1st Department of Surgery, Nagoya University School of Medicine, Japan.
Nishimura
H
H
Matsuzaki
T
T
Yokokura
T
T
Nimura
Y
Y
Yoshikai
Y
Y
D000818:Animals; D004357:Drug Synergism; D005354:Fibrosarcoma / Q000188:drug therapy*; D007371:Interferon-gamma / Q000096:biosynthesis; D018664:Interleukin-12 / Q000008:administration & dosage*; D019409:Interleukin-15 / Q000008:administration & dosage*; D007694:Killer Cells, Natural / Q000187:drug effects; D008297:Male; D008748:Methylcholanthrene; D051379:Mice; D008807:Mice, Inbred BALB C; D010998:Pleurisy / Q000188:drug therapy*; D051381:Rats; D011994:Recombinant Proteins / Q000627:therapeutic use
D019409:Interleukin-15; D011994:Recombinant Proteins; D018664:Interleukin-12; D008748:Methylcholanthrene; D007371:Interferon-gamma