Enhancement by Interferon of the Specific Cytotoxicity of Sensitized Lymphocytes

Abstract

Mouse interferon preparations enhanced the specific cytotoxicity of sensitized lymphocytes for allogeneic target tumor cells. The factor responsible for the enhancement of cytotoxicity could not be dissociated from the antiviral activity of interferon by standard physicochemical means. Thus, in addition to its well-known antiviral activity, and its effect on cell division, interferon also appears to enhance a specialized cellular function. It is suggested that a common mechanism of action underlies these seemingly different biologic phenomena, and that interferon may play a role in the regulation of fundamental cellular processes.In addition to its well-known antiviral activity, interferon has been shown to inhibit the multiplication of tumor and normal'mammalian cells in culture (1-4). It seems likely, therefore, that the antiviral action of interferon is only one expression of the effect of interferon on cells (3, 4). In the course of our studies on interferon-cell interactions, we observed that prior treatment of sensitized splenic lymphocytes with interferon resulted in an enhancement of the specific cytotoxicity of these cells for target tumor cells. Thus, interferon appears to enhance a specialized cellular function. The results of these experiments and the evidence suggesting that interferon was the factor responsible for enhancement of cytotoxicity of sensitized lymphocytes for target tumor cells are presented herein. MATERIALS AND METHODSImmunization of Mice with L 1210 Cells. Mouse lymphoid leukemia L 1210 cells (5) were maintained by serial passage in ascitic form in DBA/2 mice. For immunization, C 57 BL/6 mice were injected intraperitoneally with 5 X 107 L 1210 cells. The spleens of immunized mice were usually harvested 10 days after injection.Lymphocytes. Suspensions of splenic lymphocytes from immunized or normal C 57 BL/6 mice were obtained according to the method of Brunner et al. (6). The washed lymphocytes were suspended in Eagle's medium containing 10% heatinactivated calf serum -at a density of 20 X 106 viable' cells per ml.Target Cells. L 1210 cells, an interferon resistant subline of L 1210 cells (7) (L 1210-R) and Ehrlich ascites cells (7) were grown in nonagitated suspension cultures in nutrient medium RPMI 1640 (Gibco), supplemented with 10% heatAbbreviation: NDV, Newcastle Disease Virus. 721 inactivated horse serum, 1% iL-glutamine (10 mM/ml), penicillin (200 U/ml), and streptomycin (40 pg/ml). For labeling with radioactive chromium (51Cr), 1 ml of a cell suspension (5 X 106 viable cells per ml) was incubated for 30 min at 37°with 0.1 ml of Na251CrO4 (200 uCi/ml, specific activity 400 mCi/mg of chromium, Centre d'Energie Atomique, France), according to the method of Brunner et al. (6,8). The cell suspensions were washed three times and readjusted to a density of 2 X 106 viable cells per ml.Interferon and Control Preparations. Mouse interferon preparations were obtained from the nutrient medium of monolayer cultures of MSV-Ia (9), L-929 (10), and L cells (11,12) that were inocula...

Treatment of hepatocellular carcinoma with major portal vein thrombosis by combined therapy with subcutaneous interferon-α and intra-arterial 5-fluorouracil; role of type 1 interferon receptor expression

“…In vitro experiments showed that IFN-a induces cyclin-dependent kinase inhibitors involved in G1/G0 arrest (Sangfelt et al, 1999). Interferon-a may also exert its antitumour effect indirectly via the immune system since IFN-a is known to augment T-cell cytotoxicity (Lindahl et al, 1972;Trinchieri et al, 1978). Recently, we reported that the modulation of tumour necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-mediated cytotoxic pathway could partially contribute to the anti-HCC effect of IFN-a/5-FU combination therapy (Yamamoto et al, 2004).…”

Enhancement by Interferon of the Expression of Surface Antigens on Murine Leukemia L 1210 Cells

“…Control preparations consisted of the medium of uninoculated cell cultures or tissues of uninoculated animals. Preparation and semipurification of murine interferon have been described (15 (L 1210 and EL4 cells were maintained by serial passage in ascitic form in DBA/2 and C57B1/6 mice, respectively). The mice were bled 1 week after the last injection.…”

“…In addition to the well-known antiviral action (1), interferon preparations also exert various biologic effects on cells (2)(3)(4)(5)(6)(7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17). The nature of some of these effects suggested the possibility that interferon treatment might be associated with modifications of the cell surface.…”

Electrophoretically pure mouse interferon exerts multiple biologic effects.

“…In addition to interferon's well-known antiviral action, preparations of it have been reported to exert multiple effects on cells [i.e., inhibition of the multiplication of bormal and tumor cells in culture (2)(3)(4)(5), inhibition of the growth of a variety of transplantable tumors in mice (6)(7)(8), modulation of the synthesis and release of specific cellular products (9)(10)(11)(12)(13)(14)(15)(16), modification of the cell surface (17)(18)(19)(20)(21), and modulation of both the humoral (22)(23)(24)(25)(26)(27) and cell-mediated immune responses (28)(29)(30)(31)(32)(33)(34)]. Although experimental results support the hypothesis that the antiviral action of interferon is only one manifestation of its effect on cells (35)(36)(37), it is important to emphasize that these experiments were undertaken using preparations in which interferon protein constituted at most only 1% of the total protein content.…”