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Selection for High Immunogenicity in Drug-resistant Sublines of Murine Lymphomas Demonstrated by Plaque Assay¹

Department of Experimental Therapeutics and Grace Cancer Drug Center, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14203

The immunogenicity of lymphoma L1210 and three L1210 sublines, resistant to methylglyoxal bis(guanylhydrazone), 4,4'-diacetyldiphenylurea bis(guanylhydrazone), or guanazole (L1210/GZL), respectively, was evaluated. Syngeneic DBA/2J mice were given a single i.p. injection of serially diluted suspension of irradiated cells from L1210 or L1210 sublines. Five days later spleen cells from the immunized mice were tested for the presence of plaqueforming cells using the immunizing lymphoma cell lines as target. Sera collected from the animals were examined for cytolytic antibody activity by lysis in gel using the same target cells. For comparison, the H-2 immunogenicity of L1210 and its sublines was investigated in H-2-incompatible allogeneic mice. The following results were obtained. (a) All the sublines showed increased immunogenicity and susceptibility to lysis as compared to L1210 cells. The number of plaque-forming cells/spleen ranged from 100 for L1210 to 4450 for L1210/GZL, the most immunogenic subline, and the antibody titer ranged from 1/8 for L1210 to 1/128 for L1210/GZL. (b) All the sublines carried common tumor-associated antigens that apparently made primary contributions to the increased immunogenicity. (c) The common tumor-associated antigens were also expressed on L1210 cells, although in a lesser degree, as evidenced by the definite, albeit low, capacity of L1210 cells to absorb DBA/2J anti-L1210/ GZL antibodies. (d) Spleen and thymus cells of DBA/2J mice as well as unrelated murine ascites tumor cells did not cause significant absorption of these antibodies. (e) Only a partial inverse relationship could be demonstrated between tumor-associated antigens and H-2 immunogenicity. L1210/GZL showed the highest immunogenicity for tumor-associated antigens but the lowest for H-2.

The above results would seem compatible with the hypothesis that the increased immunogenicity of drug-resistant L1210 sublines is attributable to the selection of preexisting highly immunogenic cells during immunosuppression by treatments selecting for drug resistance.

¹ This investigation was supported in part by Project Grant CA 15142 and Core Program Grant 13038 from the National Cancer Institute, USPHS.

² Present address: Department of Immunology Research, Roswell Park Memorial Institute.

Received 10/11/74. Accepted 12/16/74.