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Endogenous production of tumor necrosis factor by a combination of interferon and BRM of bacterial origin
364 ENDOGENOUS PRODUCTION OF TUMOR NECROSIS FACTOR BY A COMBINATION OF INTERFERON AND BRM OF BACTERIAL ORIGIN
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M.Satoh, H.Inagawa, H.Minagawa, T.Kajikawa, H.Oshima, S.Abe~ M.Yamazaki # alld D.Mizuno Res. Dev. Corp., Japan * and Fac. Pharm. Sci., Teikyo Univ., # Japan. We have established a model to induce endogenous production of tumor necrosis factor (TNF) in cancer patients. We reported previously that tuberculin allergy elicited by PPD could enhance the TNF-triggering by LPS in mice at a long time after the first BCGsensitization, implying a participation of some lymphokines like macrophage activating factor. Mice were iv administered by interferon (IFN) followed by iv injection of LPS or a streptococcal preparation OK-432 and activity of TNF in the serum 2 hrs after the injection was measured by in Vi/O%0 cytocidal assay using L-929 cells. When various IFNs including rec.huIFN-e(A/D), rec.muIFN-8 and rec.muIFN-y was iv administered, a remarkable enhancement of TNF production was triggered either by LPS or by OK-432. The possible effect of residual IFN in serum on in ui/0%0 assay was negligible. PPD-challenge followed by administration of LPS caused reggression of MM46 carcinoma in mice sensitized with BCG 14 weeks before, but not in non-sensitized mice. A combination of IFN and OK-432 was effective in non-sensitized mice. The results suggest that a combination of IFN and BRM of bacterial origin can be applied efficiently to cancer patients for the endogenous production of huTNF.
BACTERIA, BACTERIAL F R A C T I O N S AND PRODUCTS AS IMMUNOMODULATORS III MECHANISMS OF IMMUNOSTIMULATING ACTIVITIES OF RO 41740, A BACTERIAL GLYCOPROTEIN EXTRACT FROM K. PNEUMONIAE.
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M. Guenounou, F. Vacheron, P. Smets and J. Agneray. Laboratoire de Miorobiologie, UER de M~decine de Paris-Ouest, ERA-CNRS n ° 396, Universit# Paris Sud and CRI, Roussel Uclaf, Cassenne, Paris, France. RU 41740, a glycoprotein extracted from K. pneumoniae K201 strain, is an immunostimulating compound which has been shown to reduce infectious episodes in pantients ~rone to reccurent infections. In vivo, RU 41740 stimulates anti-SRBC response in mice, when given by oral or parenteral route. In vitro, RU 41740 is found mitogenic for murine spleen cells. It acts as a polyclonal B c@ll activator and does not induce blastogenesis in T cell enriched population. However, when given (at i and lO ug/ml) in conjonction with Con A, it potentiates the Con A-induced proliferation. This effect is dependent on the presence of adherent cells in the T cell preparation. In additional experiments, RU 41740 is shown to induce interleukin 1 (IL l) production by adherent peritoneal or splenic cells. RU 41740 also enhances in vitro anti-SRBC antibody response in mouse spleen cell cultures. These findings suggest that B cell activation and the stimulation of the ILl -IL2 cascade could constitute two additive mechanisms involved in the immunomodulating activities of RU 41740.
RU 41740, A BACTERIAL IMMUNOMODULATOR, INDUCES THE RELEASE OF A CYTOTOXIC FACTOR FROM MOUSE MACROPHAGES. M. Guenounou, F. Vacheron, P. Smets and C. N a u e i e l . Laboratoire de Microbiologie, UER de M~decine Paris-Ouest, ERA-CNRS n ° 396, Universit@ Paris Sud and CRI, Roussel Uclaf, Cassenne, Paris, France. RU 41740, a glycoprotein extracted from K. pneumoniae K201 strain, is an immunomodufating compound which has been shown to reduce infectious episodes in patients prone to reecurent infections. In vivo, RU 41740 stimulates resistance to viral and bacterial infections in mice. RU 41740 induces a variety macrophage function including the production of interleukin i. We report here that RU 41740 induces the release by mouse peritoneal macrophages of a cytotoxic factor which is active on L-929 cells and a methylcholanthrene induced tumor cell line, but inactive on normal fibroblasts. The cytotoxic factor was released within 2 hours of contact with RU 41740 either in serumfree or in serum containing media. It was, stable for 30 min at 56 ° C, but inactivated after lO min at 80 ° C. After gel filtratio~ a single peak of activity at 50-60 000 daltons was found.
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M.Satoh, H.Inagawa, H.Minagawa, T.Kajikawa, H.Oshima, S.Abe~ M.Yamazaki # alld D.Mizuno Res. Dev. Corp., Japan * and Fac. Pharm. Sci., Teikyo Univ., # Japan. We have established a model to induce endogenous production of tumor necrosis factor (TNF) in cancer patients. We reported previously that tuberculin allergy elicited by PPD could enhance the TNF-triggering by LPS in mice at a long time after the first BCGsensitization, implying a participation of some lymphokines like macrophage activating factor. Mice were iv administered by interferon (IFN) followed by iv injection of LPS or a streptococcal preparation OK-432 and activity of TNF in the serum 2 hrs after the injection was measured by in Vi/O%0 cytocidal assay using L-929 cells. When various IFNs including rec.huIFN-e(A/D), rec.muIFN-8 and rec.muIFN-y was iv administered, a remarkable enhancement of TNF production was triggered either by LPS or by OK-432. The possible effect of residual IFN in serum on in ui/0%0 assay was negligible. PPD-challenge followed by administration of LPS caused reggression of MM46 carcinoma in mice sensitized with BCG 14 weeks before, but not in non-sensitized mice. A combination of IFN and OK-432 was effective in non-sensitized mice. The results suggest that a combination of IFN and BRM of bacterial origin can be applied efficiently to cancer patients for the endogenous production of huTNF.
BACTERIA, BACTERIAL F R A C T I O N S AND PRODUCTS AS IMMUNOMODULATORS III MECHANISMS OF IMMUNOSTIMULATING ACTIVITIES OF RO 41740, A BACTERIAL GLYCOPROTEIN EXTRACT FROM K. PNEUMONIAE.
34
M. Guenounou, F. Vacheron, P. Smets and J. Agneray. Laboratoire de Miorobiologie, UER de M~decine de Paris-Ouest, ERA-CNRS n ° 396, Universit# Paris Sud and CRI, Roussel Uclaf, Cassenne, Paris, France. RU 41740, a glycoprotein extracted from K. pneumoniae K201 strain, is an immunostimulating compound which has been shown to reduce infectious episodes in pantients ~rone to reccurent infections. In vivo, RU 41740 stimulates anti-SRBC response in mice, when given by oral or parenteral route. In vitro, RU 41740 is found mitogenic for murine spleen cells. It acts as a polyclonal B c@ll activator and does not induce blastogenesis in T cell enriched population. However, when given (at i and lO ug/ml) in conjonction with Con A, it potentiates the Con A-induced proliferation. This effect is dependent on the presence of adherent cells in the T cell preparation. In additional experiments, RU 41740 is shown to induce interleukin 1 (IL l) production by adherent peritoneal or splenic cells. RU 41740 also enhances in vitro anti-SRBC antibody response in mouse spleen cell cultures. These findings suggest that B cell activation and the stimulation of the ILl -IL2 cascade could constitute two additive mechanisms involved in the immunomodulating activities of RU 41740.
RU 41740, A BACTERIAL IMMUNOMODULATOR, INDUCES THE RELEASE OF A CYTOTOXIC FACTOR FROM MOUSE MACROPHAGES. M. Guenounou, F. Vacheron, P. Smets and C. N a u e i e l . Laboratoire de Microbiologie, UER de M~decine Paris-Ouest, ERA-CNRS n ° 396, Universit@ Paris Sud and CRI, Roussel Uclaf, Cassenne, Paris, France. RU 41740, a glycoprotein extracted from K. pneumoniae K201 strain, is an immunomodufating compound which has been shown to reduce infectious episodes in patients prone to reecurent infections. In vivo, RU 41740 stimulates resistance to viral and bacterial infections in mice. RU 41740 induces a variety macrophage function including the production of interleukin i. We report here that RU 41740 induces the release by mouse peritoneal macrophages of a cytotoxic factor which is active on L-929 cells and a methylcholanthrene induced tumor cell line, but inactive on normal fibroblasts. The cytotoxic factor was released within 2 hours of contact with RU 41740 either in serumfree or in serum containing media. It was, stable for 30 min at 56 ° C, but inactivated after lO min at 80 ° C. After gel filtratio~ a single peak of activity at 50-60 000 daltons was found.
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