Accumulation of IL-12-activated antitumor effector cells into lymph nodes of tumor-bearing mice

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Abstract

Simultaneous administration of high dose of IL-12 into tumor-inoculated mice resulted in a marked reduction of tumor growth in parallel with the augmented generation of cytotoxic T-cells, natural killer (NK) cells and IFN-γ-producing Th cells. We found that these IL-12-activated antitumor effector cells preferentially accumulated in peripheral lymph nodes concomitantly with lymphadenopathy. However, IL-12 rather induced disappearance of antitumor effector cells including CD4+ T, CD8+ T and NK cells from spleen in spite of inducing splenomegaly. Lymph node cells obtained from IL-12-treated B16F0-bearing mice showed a marked IFN-γ production in response to not only IL-2, IL-12, anti CD3 mAb but also B16F0 melanoma cells. Moreover, they could lyse B16F0 melanoma cells in a long-term cytotoxicity assay. It was also confirmed that IL-12-activated IFN-γ producing Th1 cells were accumulated in tumor local site. Thus, IL-12 appeared to have a capability of stimulating selective migration of antitumor cells into lymph nodes and tumor local sites.

Introduction

IL-12 consisting of p35 and p40 heterodimeric proteins has been demonstrated to show a therapeutic activity in various immune disease models 1, 2. In particular, it has been clearly demonstrated that IL-12 showed a potent antitumor activity against both primary and transplantable tumors 3, 4, 5, 6, 7. The evidence that IL-12 can stimulate the induction of human antitumor effector cells in vitro [8], indicates its rationale for the application to cancer immunotherapy.

Many investigators have demonstrated that IL-12 showed its therapeutic effect through the activation of both antitumor killer cells and Th1 cells 9, 10, 11. Because Th1 cells, which can produce IL-2 and IFN-γ, are considered as pivotal immunoregulatory cells in cellular immunity 2, 12, 13, the selective activation of Th1 cells by IL-12 may be a key mechanism for the induction of antitumor immunity in vivo. In addition to the activation of these antitimor effector cells, IL-12 has been demonstrated to show other multiple functions in vivo concerning angiogenesis, lymphocyte migration and hematopoiesis 14, 15, 16.

In this paper, we investigated the effect of IL-12 on the activation of antitumor effector cells and their distribution pattern in tumor-bearing mouse spleen, lymph nodes and tumor tissue. The present data clearly demonstrated that IL-12-activated antitumor effector cells selectively accumulated into lymph nodes and tumor local site, while they rather decreased in spleen.

Section snippets

Treatment of tumor-bearing mice with IL-12

C57BL/6 mice were purchased from Charles River Japan (Yokohama 222, Japan). All mice were female and 5–8 weeks old. Generally, C57BL/6 mice were subcutaneously (s.c.) injected with B16F0 melanoma cells (106/mouse) and the tumor-bearing mice were treated with 30 μg/kg recombinant mouse IL-12 (kindly donated by Genetics Institute, MA) three times at intervals of 2 days. At 7–10 days after IL-12 treatment, the mice were sacrificed and examined. Their immunological parameters are described in the

Induction of splenomegaly and lymphadenopathy by administration of IL-12

C57BL/6 mice bearing B16F0 melanoma cells were treated with i.p. injection of IL-12 (30 μg/kg) three times, at intervals of 2 days. Like previous results, IL-12 showed a marked antitumor effect in vivo and inhibited tumor growth (Fig. 1). A total of 8 days after IL-12 administration, the tumor-bearing mice were sacrificed to examine the effect of IL-12 on various lymphoid tissues (thymus, axillary and inguinal lymph nodes and spleen). As control, the tissues from saline-treated mice were used.

Discussion

It is now well accepted that IL-12 is a useful cytokine for the application to therapy of immune diseases including tumor, infectious diseases, allergy and autoimmune diseases 3, 4, 5, 6, 7, 8, 21. This multifunction of IL-12 is mediated by the activation of Th1-dominant immunity which is essential for the induction of cell-mediated immunity 2, 12, 13. The present paper further demonstrates an interesting effect of IL-12 administration in vivo on the distribution of antitumor effector cells in

Acknowledgements

The authors would like to thank Drs Michiko Kobayashi and Steven H. Herrmann for their kind gift of IL-12. This work was supported in part by a Grant-in-Aid for The Science Frontier Program of MESC (the Ministry of Education Science and Culture, Japan), a Grant-in-Aid for Scientific Research on Priority Areas from MESC, and a Grant-in-Aid from the Ministry of Health and Welfare for Cancer Control, and by a Grant-in-Aid for the IL-12 project of Tokai University School of Medicine.

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