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The role of spleen for OK-432 immunotherapy in murine fibrosarcoma
349
THE EFFECTS OF ORAL ADMINISTRATION OF STREPTOCOCCAL PREPARATION OK-432(PICIBANIL) ON THE IMMUNITY OF MICE WITH TRANSPLANTED CECAL TUMORS
92
Y. Nio, T. Tsuchitani, N. Kan and T. Tobe Department of Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan. We studied the effects of oral administration of 0K-432 on the immunity of mice with transplanted cecal tumors. After the transplantation of tumor cells into the cecal patch lymphproliferative responses(LPR) of spleen cells to PHA and LPS were remarkably suppressed from day 7, but NK cell activity and mixed lymphocyte tumor cell reaction(MLTR) increased between day 7 and day 14, but decreased on day 21. In mesenteric lymph-node (b~N) cells, moderate suppression of LPR from day 7 and decrease of NK cell activity from day 14 were observed, but MLTR was enhanced between day 7 and day 14. In Peyer's patch (PP) cells, these parameters were slightly influenced by transplanted cecal tumor. In order to augment the anti-tumor immunity of mice with cecal tumors, we administered 0K-432 orally twice a week. OK-432 augmented LPR, NK cell activity and MLTR of MLN cells, but not of spleen and PP cells. In addition, inhibition of tumor growth and a life-prolonging effect were observed. These results demonstrate that orally ad~inistered OK-432 augments the local anti-tumor immunity of gut-associated lymphoid tissue in gastrointestinal malignancy and may have favorable therapeutic effects in cancer immunotherapy. THE ROLE OF SPLEEN FOR OK-432 IMMUNOTHERAPY IN MURINE FIBROSARCOMA H. Yamagishi, H. Konosu, Y. Kanki, H. Nomura, K. Naito, T. Tanaka and T. Oka Department of Surgery, Kyoto Prefectural University of Medicine, Medical Center Hospital at Yosanoumi, Kyoto, Japan. The mechanism of anti-tumor effect of OK-432 for tumor growth and lung metastasis was studied in C3H/He mice transplanted with methylcholanthrene induced fibrosarcoma. Both the tumor growth and the number of pulmonary metastatic colonies were significantly reduced in mice treated with streptococcal preparation, OK-432. On the other hand, splenectomized mice failed to respond to OK-432 immunotherapy. For the purpose of the characterization of effector cells augmented by 0K-432, the spleen cells were treated with i) anti-Thyl.2 serum plus complement, 2)irradiation of 700 rads, and 3)the depletion of adherent cells to plastic dish and carbonyl iron phagostic cells before Winn assay. The effector cells were eliminated by the treatment with anti-Thyl.2 serum + complement, and by the 700 rads irradiation, but not by the depletion of the adherent & phagocytic cells. Furthermore, in vitro cytostatic activity of both spleen cells and pulmonary macrophages from mice treated with OK-432 were activated, whereas in splenectomized mice 0K-432 little activated the pulmonary macrophages. The results suggest that the spleen is an essential organ in the host responsiveness to OK-432 immunotherapy, and T cells in the spleen and macrophages in the lung were activated by 0K-432. For the activation of the pulmonary macrophages by OK-432, T cell activation of the spleen may initially be necessary.
93
AUGMENTATION OF THERAPEUTIC EFFECT OF ADOPTIVE CANCER IMMUNOTHERAPY USING TUMOR-BEARERSPLEEN CELLS CULTURED WITH INTER-LEUKIN-2 BY STREPTOCOCCAL PREPARATION OK432 AS IL-2 INDUCER N. Kan, T. Hori, Y. Nio, H. Kodama, Dept. of Surg., Fac. of Med., Kyoto Univ.,Kyoto,Japan. We attempted to augment the therapeutic effect of adoptive cancer-immunotherapy (AIT) by using a streptococcal preparation, 0K432, as an interleukin-2 (IL-2) inducer. BALB/c mice and syngeneic plasmacytoma MOPCIO4E were used. For the therapy model, cultured lymphocytes (CL, 2x10 ? cells) were transferred IP into 5-days tumor-bearing mice that had been inoculated IP with Ixl0 s MOPC-tumor cells. CL were obtained by culturing tumor-bearer-spleen cells for Ii days with IL-2 and solubilized tumor extract, and were transferred IP. Cumulative results of 13 experiments (n=84) revealed a statistically significant (p<0.01), though marginal, life prolonging effect in the AIT group. Therapeutic efficacy was remarkably augmented when mice were injected with 1 liE of OK432 on days 3 and 4 after the tumor inoculation and 20% of mice were cured. The mechanism by which 0K432 augments the therapeutic effect of AIT appears to involve in vivo IL-2 inducer activity because (i) OK432 does not augment the effect of AIT using fresh, IL-2 independent, immune spleen cells, (2) sera from normal or tumor-bearing mice that were administered OK432 showed significantly low IL-2 inhibitor activity, and (3) the life span of 51Cr labelled CL injected IP was prolonged in the OK432 treated mice. This AIT system using 0K432 and cultured tumor-bearer-lymphocytes may be applicable clinically for several kinds of solid cancer.
94
THE EFFECTS OF ORAL ADMINISTRATION OF STREPTOCOCCAL PREPARATION OK-432(PICIBANIL) ON THE IMMUNITY OF MICE WITH TRANSPLANTED CECAL TUMORS
92
Y. Nio, T. Tsuchitani, N. Kan and T. Tobe Department of Surgery, Faculty of Medicine, Kyoto University, Kyoto, Japan. We studied the effects of oral administration of 0K-432 on the immunity of mice with transplanted cecal tumors. After the transplantation of tumor cells into the cecal patch lymphproliferative responses(LPR) of spleen cells to PHA and LPS were remarkably suppressed from day 7, but NK cell activity and mixed lymphocyte tumor cell reaction(MLTR) increased between day 7 and day 14, but decreased on day 21. In mesenteric lymph-node (b~N) cells, moderate suppression of LPR from day 7 and decrease of NK cell activity from day 14 were observed, but MLTR was enhanced between day 7 and day 14. In Peyer's patch (PP) cells, these parameters were slightly influenced by transplanted cecal tumor. In order to augment the anti-tumor immunity of mice with cecal tumors, we administered 0K-432 orally twice a week. OK-432 augmented LPR, NK cell activity and MLTR of MLN cells, but not of spleen and PP cells. In addition, inhibition of tumor growth and a life-prolonging effect were observed. These results demonstrate that orally ad~inistered OK-432 augments the local anti-tumor immunity of gut-associated lymphoid tissue in gastrointestinal malignancy and may have favorable therapeutic effects in cancer immunotherapy. THE ROLE OF SPLEEN FOR OK-432 IMMUNOTHERAPY IN MURINE FIBROSARCOMA H. Yamagishi, H. Konosu, Y. Kanki, H. Nomura, K. Naito, T. Tanaka and T. Oka Department of Surgery, Kyoto Prefectural University of Medicine, Medical Center Hospital at Yosanoumi, Kyoto, Japan. The mechanism of anti-tumor effect of OK-432 for tumor growth and lung metastasis was studied in C3H/He mice transplanted with methylcholanthrene induced fibrosarcoma. Both the tumor growth and the number of pulmonary metastatic colonies were significantly reduced in mice treated with streptococcal preparation, OK-432. On the other hand, splenectomized mice failed to respond to OK-432 immunotherapy. For the purpose of the characterization of effector cells augmented by 0K-432, the spleen cells were treated with i) anti-Thyl.2 serum plus complement, 2)irradiation of 700 rads, and 3)the depletion of adherent cells to plastic dish and carbonyl iron phagostic cells before Winn assay. The effector cells were eliminated by the treatment with anti-Thyl.2 serum + complement, and by the 700 rads irradiation, but not by the depletion of the adherent & phagocytic cells. Furthermore, in vitro cytostatic activity of both spleen cells and pulmonary macrophages from mice treated with OK-432 were activated, whereas in splenectomized mice 0K-432 little activated the pulmonary macrophages. The results suggest that the spleen is an essential organ in the host responsiveness to OK-432 immunotherapy, and T cells in the spleen and macrophages in the lung were activated by 0K-432. For the activation of the pulmonary macrophages by OK-432, T cell activation of the spleen may initially be necessary.
93
AUGMENTATION OF THERAPEUTIC EFFECT OF ADOPTIVE CANCER IMMUNOTHERAPY USING TUMOR-BEARERSPLEEN CELLS CULTURED WITH INTER-LEUKIN-2 BY STREPTOCOCCAL PREPARATION OK432 AS IL-2 INDUCER N. Kan, T. Hori, Y. Nio, H. Kodama, Dept. of Surg., Fac. of Med., Kyoto Univ.,Kyoto,Japan. We attempted to augment the therapeutic effect of adoptive cancer-immunotherapy (AIT) by using a streptococcal preparation, 0K432, as an interleukin-2 (IL-2) inducer. BALB/c mice and syngeneic plasmacytoma MOPCIO4E were used. For the therapy model, cultured lymphocytes (CL, 2x10 ? cells) were transferred IP into 5-days tumor-bearing mice that had been inoculated IP with Ixl0 s MOPC-tumor cells. CL were obtained by culturing tumor-bearer-spleen cells for Ii days with IL-2 and solubilized tumor extract, and were transferred IP. Cumulative results of 13 experiments (n=84) revealed a statistically significant (p<0.01), though marginal, life prolonging effect in the AIT group. Therapeutic efficacy was remarkably augmented when mice were injected with 1 liE of OK432 on days 3 and 4 after the tumor inoculation and 20% of mice were cured. The mechanism by which 0K432 augments the therapeutic effect of AIT appears to involve in vivo IL-2 inducer activity because (i) OK432 does not augment the effect of AIT using fresh, IL-2 independent, immune spleen cells, (2) sera from normal or tumor-bearing mice that were administered OK432 showed significantly low IL-2 inhibitor activity, and (3) the life span of 51Cr labelled CL injected IP was prolonged in the OK432 treated mice. This AIT system using 0K432 and cultured tumor-bearer-lymphocytes may be applicable clinically for several kinds of solid cancer.
94