Metazoan organisms may discriminate between self and non-self not only by the presence of foreign antigens but also by the absence of normal self markers. Mammalian adaptive immune responses use the first strategy, with the additional requirement that foreign antigens are recognized in the context of self-major histocompatibility complex (MHC) products at the cell surface. Aberrant cells which fail to express MHC products adequately can therefore avoid detection. A more primitive but complementary defence system, eliminating such cells on the basis of absent self-markers, is suggested by a re-interpretation of phenomena associated with metastasis and natural resistance. We now show that murine lymphoma cells selected for loss of H-2 expression are less malignant after low-dose inoculation in syngeneic hosts than are wild-type cells, and that the rejection of such cells is non-adaptive. On the basis of our data, we suggest that natural killer cells are effector cells in a defence system geared to detect the deleted or reduced expression of self-MHC.
Two peptides which have previously been shown to induce chemotactic motility in a number of tumor cells were tested for their ability to alter the adhesiveness of Walker Carcinosarcoma cells (A chemotactically-responsive rat tumor) and normal rat fibroblasts (which have previously been shown to be chemotactically nonresponsive). Adherence of the tumor cells to nylon fibers was increased in a dose-dependent manner by the two active peptides. Adherence of the fibroblasts was not increased. Nonchemotactic peptide analogues of the two active peptides did not alter the adherence of either cell type. The increased adhesiveness to foreign surfaces may contribute to the chemotactic response.
Two variant subpopulations of murine fibrosarcoma cells that differ significantly in their malignant potential and normal mouse fibroblasts were compared with regard to ability to respond chemotactically to collagen, collagen-derived peptides and the C5-derived tumor cell chemotactic peptide. Two distinct patterns of responsiveness were observed. The normal fibroblasts and non-metastasizing fibrosarcoma cells responded to the collagen products but not the C5 peptide. The metastasizing fibrosarcoma cells responded to the C5 peptide but not to the collagen products. These findings emphasize the similarities between the normal fibroblasts and the non-metastasizing fibrosarcoma cells.
After several years of intense interest in technique has been described (7,9). Labeled hyperthermia as a potential treatment for [ U-'4C]glucose (NEC-042) and [ 1-l4C]pyrucancer, little is known about the mechanisms vate (NEC-255) were obtained from New of heat-dependent tumor cell destruction. En-England Nuclear (Boston, Mass.). The convironmental or extracellular factors, particu-centration of ascorbic acid in the flasks was larly nutritional state and degree of oxygen-either 0 or 1 mM. A proportional temperature ation, have been shown to influence the sus-controller (Yellow Springs Instruments ceptibility of tumor cells to destruction by Model 72) was used to precisely control hyperthermic treatment (1-3). Overgaard has shaker bath water temperature (+O. 1 "). postulated that hyperthermia inhibits respi-Following the incubation period, the reacration, but not glycolysis, resulting in in-tions were stopped by injecting 1 ml of 2 N creased lactate levels and a decreased pH (4, HC104 through the serum caps. The flasks 5). An increase in cellular acidity has been were then shaken an additional hour to reshown to enhance hyperthermic lethality (6). cover l4COn. Blanks were prepared by adding This communication examines the effect of PCA before addition of the cell suspension. hyperthermia on glucose, pyruvate, and lac-After shaking with PCA, the paper and vial tate metabolism in Ehrlich ascites tumor cells were removed and placed in a scintillation (EATC). The role of ascorbic acid, which has vial containing 15 ml of cocktail (7) before been shown to greatly increase respiration in counting in a Packard Tri-Carb scintillation EATC suspensions (7) was also examined.spectrometer. Quench correction was done Materials and methods. EATC were serially using the channels ratio method. transplanted intraperitoneally at regular in-All in vitro tumor cell experiments were in tervals in male Swiss mice.2 Cells were har-the presence of glucose as the substrate. Colvested 6-14 days after transplantation. The orimetric analysis of lactic acid was perprotein content was determined by a biuret formed enzymatically with a Gilford 240 digmethod using bovine serum albumin as the ital spectrometer (10). standard (8). Experimental hyperthermia and EATC metabolism of [ 1 -14C]pyruvate with the effect of supplemental ascorbic acid were supplemental combinations of ascorbic acid examined simultaneously.(1 mM), theophylline (1 mM), and dibutyryl Metabolic studies were performed in 25-ml cyclic AMP (1 mM) was studied in vitro at stoppered siliconized glass Erlenmeyer flasks 37.5" and 42.5". These experiments were conwith specially constructed center wells for ducted to study whether ascorbic acid may COn collection. All incubations were per-alter metabolism by potentiating intracellular formed in Krebs Ringers phosphate buffer CAMP levels. without calcium (1 8). The 14C02 collection In a separate preliminary study the effect of dietary supplementation of 5% ascorbate This work was supported by grants from the Keating on tumor cell metabolis...
Previous studies demonstrated that NK-cell-enriched spleen cells bind to sensitive but not to resistant mouse lymphoma targets, measured by a single-cell target binding assay. In the present report we further analyzed this "NK-patterned" binding using effector cells with high, low or no NK activity. In agreement with previous results, nylon-wool-passed spleen cells as well as a cloned cytotoxic cell line with NK activity bound tumor targets largely according to their NK sensitivity; NK-sensitive tumors had a higher frequency of binders than the more resistant ones. The correlation coefficient relating the percentage target binding cells (TBC) for each tumor with the ability of the same tumor to inhibit lysis in cold target competition assays was consistently higher than that relating percentage TBC with direct NK lysis. A non-lytic variant of the cloned cytotoxic cell line had a binding pattern identical to that of the lytic line, demonstrating that "NK-patterned" binding occurred in the absence of lysis. Thymocytes, which are totally devoid of NK activity, also bound preferentially NK-sensitive targets, and their binding was decreased after trypsin treatment or in the presence of EDTA. Peritoneal macrophages also showed "NK-patterned" binding, thus demonstrating that this was not restricted to cells in the T-cell lineage. Variants from a mouse lymphoma selected for decreased NK sensitivity bound a lower frequency of NK-active (nylon-wool-passed spleen cells) and inactive cells (thymocytes, peritoneal macrophages). This study therefore showed that the membrane property conferring NK-binding selectivity exists on several types of non-NK leukocytes.
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