Rabbit xenoantisera produced against diethyl-nitrosamine-induced strain-2 guinea-pig hepatoma line-10 cells (L-10) according to various immunization schedules were compared for their cytotoxicity on L-10 cells in the presence of guinea-pig complement. The highest activity was obtained with antisera (Cx-1) produced by repeated intravenous injections of living L-10 cells at high cell dosage, whereas intramuscular injections of living or glutaraldehyde-treated L-10 cells at similar frequency and cell dosage were less effective for the production of cytotoxic antibodies against L-10 cells. Intravenous injections of smaller cell doses were less effective. The cytotoxic antibody in Cx-1 antiserum was shown to be IgG by various methods including gel filtration on Sephadex G-200, ion exchange chromatography and immunoelectrophoresis of purified tumor-specific antibodies. It was concluded that L-10 cells can be lysed by guinea-pig complement and tumor-specific antibodies (IgG). Some antisera contained IgM antibodies which were not cytotoxic. A decrease in susceptibility of L-10 cells to complement-mediated lysis was observed when the cells were maintained in vivo for a long period (more than 20 passage generations). This was due to a lower density of tumor antigens on the cell surface. When tumor cells were treated with a second antibody directed against rabbit IgG or F(ab')2, cytotoxicity of Cx-1 antisera was completely abolished.
The mechanisms of tumor cell susceptibility and resistance to cytotoxic antibodies were investigated in the guinea-pig ascites hepatoma (line-1 and line-10) system. Treatment of line-specific rabbit antibody-coated tumor cells by ascitic fluid, by serum of tumor bearers or by tumor extract inhibited subsequent complement-mediated lysis. Inhibition by ascitic fluid and serum was not line-specific, but inhibition by tumor extract was line-specific. Treatment of tumor cells with ascitic fluid or tumor extract prior to exposure to specific cytotoxic antibody and complement did not inhibit lysis. Incubation of cytotoxic rabbit antisera with ascitic fluid, tumor-bearer serum or tumor extract neutralized their complement-dependent cytotoxic activity on tumor cells. Tumor-immune guinea-pigs exhibited line-specific delayed cutaneous reactions after injection with ascitic fluid or tumor extract. Studies with indrect immunofluorescence revealed that exposure to ascites fluid or tumor extract caused a rapid shedding of rabbit antibodies from the tumor cell surface. Evidence is presented indicating that the active fraction of ascites fluid was associated with immune complexes consisting of IgG and tumor antigen in excess. The relevance of these findings to tumor escape from immune destruction in vivo is discussed.
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