Pathophysiological effects of human TNF-alpha-producing tumor xenografts in immunosuppressed mice.

Groups of CBA mice immunosuppressed with anti-thymocyte serum (ATS) treatment were xeno-transplanted with either HeLa human cervical carcinoma cells or genetically modified cells expressing the human tumor necrosis factor-alpha (TNF) gene (All cells). Both cell lines were highly resistant to the cytotoxic effects of TNF. If 3 x 10(6) tumor cells were inoculated s.c. into female mice, HeLa cells grew progressively into large tumors and killed 74% of the recipients, while TNF-expressing All cells caused fatal tumor growth only in 22% of the mice. 3 x 10(6) or 1.5 x 10(7). All cells produced progressive tumor growth and lethality in all male recipients. In sera of all the A11-cell-transplanted mice, biologically active TNF was detected shortly (4.5 h) after tumor inoculation (6 39 U/ml), decreasing to below detection level in the circulation by day 3. In recipients of 15 million A11 cells, circulating TNF reappeared and reached high levels (12-1000 U/ml) 3 to 7 weeks later, when the animals bore large tumors (14-23 mm). Generally, such mice became cachectic, severely anemic, hypothermic, and soon died. On account of calcium mobilization from bones, their serum Ca levels were high. Electron microscopy revealed severe liver damage, but there were no signs of chronic arthritis. These results suggest that ATS-treated mice xenotransplanted with TNF-gene-transfected A11 human tumor cells provide a new model for studying the pathophysiological and anti-tumor effects of TNF.

[Comparative study of 2 transplantable lines of murine L cells]. / Sravnitel'noe issledovanie dvukh perevivaemykh linii myshinykh kletok L.

A continuous line of mouse L cells chronically infected with SV5 paramyxovirus differs from mouse L0 cells free from this virus in the mitotic activity and karyologic features. The LSV5 line is characterized by inhibition of the mitotic activity, a decrease in the number of chromosomes and the presence of the marker chromosome. LSV5 and L0 cell cultures do not differ in the number of pathological mitoses, structural aberrations of chromosomes and the cytomorphological picture. The persisting SV5 virus can be detected in LSV5 line cultures by a number of methods (immunofluorescence, virological methods, etc.).

[Immunologic properties of malignant and non-malignant L cell sublines. II. Immunogenicity, sensitivity to complement and T-lymphocytes, cell secretions modifying immune reactions]. / Immunologicheskie svoistva zlokachestvennoi i nezlokachestvennoi sublinii kletok L. Soobshchenie II. Immunogennost', chuvstvitel'nost' k komplementu i T-limfotsitam, kletochnye vydeleniia, modifitsiruiushchie immunnye reaktsii.

The malignant subline of L cells did not differ from the initial benign subline in such immunological parameters as immunogenicity, ability for modigying immunological reactions by their metabolic products, sensitivity to the lyzing action of the complement, ability for surface adsorption of lymphocytes. The cells of the malignant subline were somewhat less sensitive to the lyzing action of T lymphocytes than the cells of the initial subline.

[Immunological properties of malignant and nonmalignant L-cell sublines. I. Obtaining a malignant L-cell subline and its immunological cross reactivity with nonmalignant cells]. / Immunologicheskie svoistva zlokachestvennoi i nezlokachestvennoi sublinii kletok L. Soobshchenie I. Poluchenie zlokachestvennoi sublinii kletok L, immunologicheskaia kross-reactivnost' s nezlokachestvennymi kletkami.

LS cells, the malignant subline of benign L cells, were obtained from L cells by selection carried out by means of their cultivation in the abdominal cavity of allogenic mice. When inoculated subcutaneously in a dose of 1 x 10(6) into the back, LS cells took and progressively grew in 70% of syngeneic animals. The preliminary immunization with L cells protected 30% of mice inoculated subsequently with L cells.

[Immunologic properties of malignant and benign L cell sublines. IV. Immune response of C3Hf mice]. / Immunologicheskie svoistva zlokachestvennoi i nezlokachestvennoi sublinii kletok L. Soobshchenie IV. Immunyi otvet u myshei C3Hf.

Malignant LS cells obtained from benign L cells by selection retained their immunogenicity in syngeneic recipients. Nevertheless, such selection resulted in a partial change in their antigenic structure, which was manifested by the fact that only partial cross reactivity existed between L and LS cells on the level of both humoral and cellular immunity. The preliminary inoculation of L cells induced statistically significant lymphocytic reaction in the animals against LS cells, sufficient to protect 30% of mice inoculated with these cells.

Involvement of tumor necrosis factor-related apoptosis-inducing ligand in NK cell-mediated and IFN-gamma-dependent suppression of subcutaneous tumor growth.

Natural killer (NK) cells and interferon- (IFN) gamma have been implicated in immune surveillance against tumor development. Here we show tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), which is a type II membrane protein belonging to the TNF family and plays a critical role in the NK cell-mediated and IFN-gamma-dependent suppression of subcutaneous growth of TRAIL-sensitive tumors. Administration of a neutralizing monoclonal antibody against TRAIL promoted outgrowth of subcutaneously inoculated TRAIL-sensitive tumors (L929, LB27.4, and Renca) but not TRAIL-resistant tumors (P815 and B16). Such a protective effect of TRAIL against TRAIL-sensitive tumors was abrogated in NK cell-depleted or IFN-gamma-deficient mice. These results suggested a substantial role of TRAIL as the effector molecule that eliminates subcutaneously developing TRAIL-sensitive tumors.