Effect of selenium on the immunocompetence of patients with head and neck cancer and on adoptive immunotherapy of early and established lesions.

Supplementation with 200 microg/day of sodium selenite during therapy for squamous cell carcinoma (SQCC) of the head and neck, e.g., surgery, radiation, or surgery and radiation, resulted in a significantly enhanced cell-mediated immune responsiveness. The enhanced responsiveness was evident during therapy and following conclusion of therapy. In contrast, patients in the placebo arm of the study showed a decline in immune responsiveness during therapy. The results from studies on mice inoculated with SQCC cells expressing the receptor for interleukin-2 (IL-2) and supplemented with Se (2.00 ppm) indicated that Se significantly retards the clinical appearance of tumors; peritumoral injections of 2,000 IU of IL-2 resulted in 50% reduction in the size of established tumors and 72% of early tumors. The combined data suggested that local immunotherapy with IL-2 in hosts supplemented with Se may represent an effective modality of treatment for the prevention of recurrences at the site of conventionally treated primary tumors.

Effect of interleukin-2 and selenium on the growth of squamous cell carcinoma cells.

OBJECTIVES: The objectives of this study were to determine whether the expression of the interleukin-2 (IL-2) receptors on squamous cell carcinoma cells can be enhanced in the presence of selenium (Se) and contribute to a greater retardation of tumor growth after locoregional therapy with IL-2. STUDY DESIGN: The growth of the cells was studied after in vitro or dietary supplementation with Se in a murine model. RESULTS: Treatment of established tumors in hosts supplemented with Se with peritumoral injections of IL-2 resulted in 50% reduction of tumor size, whereas treatment of early tumors resulted in 72.4% reduction. The effect was most likely related to a combination of enhanced immune responsiveness and enhanced IL-2 receptor expression on the tumor cells. CONCLUSIONS AND SIGNIFICANCE: The data suggested that local immunotherapy with IL-2 in hosts supplemented with Se may represent an effective modality of treatment for the prevention of recurrences at the site of conventionally treated primary tumors, including tumors that do not express IL-2 receptors.

Selenium and immunocompetence in patients with head and neck cancer.

This randomized double-blind placebo-controlled study aimed to determine whether oral intake of 200 microg/d of sodium selenite, a dose within the safe and adequate daily intake (50-200 microg/d) recommended by the U.S. Food and Nutrition Board, will abrogate depressed or enhance normal-level immune functions of patients receiving therapy for squamous cell carcinoma of the head and neck. Subjects were given one selenium/placebo tablet/d for 8 wk, beginning on the day of their first treatment for the disease (e.g., surgery, radiation, or surgery and radiation) and their immune functions were monitored. Supplementation with selenium (Se) during therapy resulted in a significantly enhanced cell-mediated immunue responsiveness, as reflected in the ability of the patient's lymphocytes to respond to stimulation with mitogen, to generate cytotoxic lymphocytes, and to destroy tumor cells. The enhanced responsiveness was evident during therapy and following conclusion of therapy. In contrast, patients in the placebo arm of the study showed a decline in immune responsiveness during therapy, which was followed, in some patients, by an enhancement, but the responses of the group remained significantly lower than baseline values. The data also show that at baseline, patients entered in the study had significantly lower plasma Se levels than healthy individuals, and patients in stage I or II of disease had significantly higher plasma selenium levels than patients in stage III or IV of disease.

Effect of combined adoptive immunotherapy and radiotherapy on tumor growth.

Advanced squamous cell carcinomas of the head and neck are difficult to control despite optimal surgery, radiotherapy and/or chemotherapy, and the tumors are usually not immunogenic. Because of the anatomic accessibility of the tumors, local adoptive immunotherapy of these tumors is feasible and may interact with radiotherapy to retard tumor growth. It is hypothesized that antigens released from tumor cells injured by radiation may stimulate, in the presence of interleukin-2, an enhanced immunocytodestruction of live tumor cells by adoptively transferred lymphokine activated killer cells and recruited tumor cytotoxic cells. DBA/2 mice were injected subcutaneously with 5 x 10(5) syngeneic squamous cell carcinoma cells in the thigh and the resulting tumors were treated for two weeks with daily peritumoral injections of interleukin-2 (1,000 International Units) or saline, four radiation treatments of 625 cGy each, and four peritumoral injections of 10(7) lymphokine activated killer cells. The results suggested that radiotherapy combined with peritumoral injection of lymphokine activated killer cells and interleukin-2 resulted in a significant reduction (P < 0.01) of tumor size whereas radiation alone, at the same dose, failed to produce a significant effect. Such results may have direct clinical application in enhancing the response of tumors to radiotherapy and in reducing the incidence of tumor recurrence.

Selenium and immune function.

Selenium (Se), an essential nutrient required for optimal growth of mammalian cells, affects the immune functions of a host in vivo. Utilizing a mouse model system and healthy human volunteers, we have shown that Se enhances the capacity of lymphocytes to respond to stimulation with mitogen or alloantigen, to proliferate, and to differentiate into cytotoxic effector cells. Supplementation with Se resulted in a significant increase in the tumor cytotoxicity of mouse cytotoxic lymphocytes, lymphokine activated killer cells and macrophages, and human cytotoxic lymphocytes and natural killer (NK) cells. Se also appears to abrogate the age-related deficiency of lymphocytes from an aged host to respond to stimulation by proliferation and differentiation into cytotoxic effector cells. These effects occurred in the absence of changes in the endogenous levels of interleukin-1, interleukin-2, or interferon-gamma, and were related to the ability of Se to enhance the expression of the alpha (p55) and/or beta (p70/75) subunits of the interleukin-2 receptor (IL-2R) on the surface of activated lymphocytes and NK cells. This resulted in a greater number of functional IL-2R/cell and in enhanced proliferation and clonal expansion of cytotoxic precursor cells. The molecular mechanism that mediates the effects of Se on immune cell function does not appear to be related to the function of Se as an antioxidant or to gene activation.

Supplementation with selenium augments the functions of natural killer and lymphokine-activated killer cells.

This study examined the effects of dietary (2.0 ppm for 8 wk) and in vitro (1 x 10(-7)M) supplementation with selenium (Se, as sodium selenite) on the activity of spleen natural killer (NK) cells and plastic-adherent lymphokine-activated killer (A-LAK) cells from C57B1/6J male mice. Dietary supplementation with Se resulted in a significant increase in the lytic activity of activated NK cells, and cells from these highly lytic effector cell populations expressed significantly higher numbers of intermediate affinity interleukin-2 receptors (II-2R)/cell. In the presence of high concentrations of II-2 and 1 x 10(-7)M Se, resting populations of spleen NK cells developed into A-LAK cells that had a significantly enhanced ability to proliferate, as indicated by the significantly higher amounts of nuclear 3H-thymidine incorporation, and a significantly augmented cytolytic activity against both NK-sensitive and NK-resistant target cells. Se appears to enhance the lytic activity of activated NK cells and to augment the proliferation, expansion, and lytic activity of A-LAK cells in the presence of high concentrations of II-2 through its ability to enhance the expression of intermediate affinity II-2R on these cells.

Supplementation with selenium restores age-related decline in immune cell function.

This study examined the effect of dietary (2.00 ppm for 8 weeks) supplementation with selenium (as sodium selenite) on the ability of lymphocytes from aged (24-month-old), male, C57BL/6JNIA mice to respond to: (i) stimulation with mitogen (phytohemagglutinin) or alloantigen; (ii) develop into cytotoxic effector cells; and (iii) destroy tumor cells. Supplementation with selenium resulted in a significant increase in the ability of spleen lymphocytes from aged animals to undergo blastogenesis, as indicated by significantly higher amounts of nuclear incorporation of 3H-thymidine after stimulation with mitogen. The dietary regimen restored the age-related deficiency of the cells to respond to stimulation by nuclear DNA synthesis and cell proliferation, at least, to the level of cells from unsupplemented young adult animals. Furthermore, populations of in vivo, alloantigen-activated lymphocytes from Se-supplemented aged animals contained significantly higher numbers of cytotoxic lymphocytes than those from Se-normal aged animals, which resulted in an enhanced capacity to destroy tumor cells. The significant increase in the number of cytotoxic effector cells within these activated T-lymphocyte populations was probably the result of an enhanced clonal proliferation of cytotoxic precursors cells, followed by the differentiation of greater numbers of cytotoxic effector cells. This effect occurred in the absence of changes in the ability of the cells to produce IL-2, which confirmed our earlier observation that dietary supplementation with selenium does not affect the production of IL-2. The data suggested that selenium restores the age-related defect in cell proliferation through an increase in the number of high-affinity IL-2 receptors.

Supplementation with selenium and human immune cell functions. I. Effect on lymphocyte proliferation and interleukin 2 receptor expression.

Selenium (Se) is an essential nutritional factor that was shown by us to alter the expression of the high affinity interleukin 2 receptor (Il2-R) and its subunits, cell proliferation, and clonal expansion of cytotoxic T-lymphocytes in mice. This study shows that dietary supplementation of Se-replete humans with 200 micrograms/d of sodium selenite for 8 wk, or in vitro supplementation with 1 x 10(-7) M Se (as sodium selenite), result in a significant augmentation of the ability of peripheral blood lymphocytes to respond to stimulation with 1 microgram/mL of phytohemagglutinin or alloantigen (mixed lymphocyte reaction) and to express high affinity Il2-R on their surface. There was a clear correlation between supplementation with Se and enhanced 3H-thymidine incorporation into nuclear DNA, preceded by enhanced expression of high affinity Il2-R. Supplementation with Se can apparently modulate T-lymphocyte mediated immune responses in humans that depend on signals generated by the interaction of interleukin 2 with Il2-R.

Supplementation with selenium and human immune cell functions. II. Effect on cytotoxic lymphocytes and natural killer cells.

This study examined the effect of dietary (200 micrograms/d for 8 wk) supplementation with selenium (as sodium selenite) on the ability of human peripheral blood lymphocytes to respond to stimulation with alloantigen, develop into cytotoxic lymphocytes, and to destroy tumor cells, and on the activity of natural killer cells. The participants in the study were randomized for age, sex, weight, height, and nutritional habits and given selenite or placebo tablets; all participants had a selenium replete status as indicated by their plasma Se levels prior to supplementation. The data indicated that the supplementation regimen resulted in 118% increase in cytotoxic lymphocyte-mediated tumor cytotoxicity and 82.3% increase in natural killer cell activity as compared to baseline values. This apparently was related to the ability of the nutrient to enhance the expression of receptors for the growth regulatory lymphokine interleukin-2, and consequently, the rate of cell proliferation and differentiation into cytotoxic cells. The supplementation regimen did not produce significant changes in the plasma Se levels of the participants. The results indicated that the immunoenhancing effects of selenium in humans require supplementation above the replete levels produced by normal dietary intake.

Selenium supplementation enhances the expression of interleukin 2 receptor subunits and internalization of interleukin 2.

Selenium (Se) is an essential nutritional factor that was shown previously by us to alter the kinetics of expression of high affinity (p55/p75) interleukin 2 receptors (IL-2R). This study shows that dietary (2 ppm for 8 weeks) or in vitro (1 x 10(-7) M) supplementation with Se (as sodium selenite) results in a significant upregulation of the expression of both the p55 and p70/75 IL-2 binding sites on the surface of concanavalin A-stimulated lymphocytes from C57BL/6J mice. This resulted in the formation of significantly higher numbers of high affinity IL-2R/cell with preservation of the normal ratio of high affinity to total IL-2 binding sites/cell. The high affinity IL-2R on cells from Se-supplemented animals functioned normally in terms of ligand binding and kinetics of IL-2 internalization, but their greater numbers/cell resulted in the internalization of significantly larger amounts of IL-2/cell. As Se supplementation results in an earlier expression of greater numbers of high affinity IL-2R, the presence of Se in the cell environment can result in an accelerated clonal expansion of activated lymphocytes.

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Effect of selenium on the expression of high affinity interleukin 2 receptors.

Selenium (Se) is an essential nutritional factor that has been shown to affect the development and expression of cell-mediated immune responses. This study shows that dietary (2 ppm for 8 weeks) or in vitro (1 x 10(-7) M) supplementation with Se results in a significant increase in the number of high affinity interleukin (IL) 2-binding sites (Kd of 10(-11) M) on the surface of concanavalin A-stimulated lymphocytes from C57BL/6J mice, whereas Se deficiency (0.02 ppm for 8 weeks) has the opposite effect. Se supplementation or deficiency apparently alters the kinetics of IL-2 receptor expression. Supplementation with Se in vivo or in vitro resulted in an earlier expression of high affinity IL-2 receptors, whereas Se deficiency resulted in a delayed expression of lower numbers of receptors. To exert its effect on IL-2 receptor expression, Se must be present or absent in the cell environment 8-24 hr after stimulation, and it most likely affects processes in the cytoplasmic and/or nuclear compartments of activated lymphocytes. Thus, in the presence of continuous immunologic stimulation, the presence or absence of Se in the cell environment can result in an accelerated or delayed clonal expansion of immunocompetent lymphocytes, respectively.

Regulation of cellular immune responses by selenium.

Selenium (Se) is an essential nutritional factor that affects the development and expression of cell-mediated immune responses directed toward malignant cells. These studies have shown that dietary (2 ppm for 8 wk) or in in vitro (1 x 10(-7)M) supplementation with Se (as sodium selenite) results in a significant enhancement of the proliferative responses of spleen lymphocytes from C57Bl/6J mice in response to stimulation with mitogen or antigen. Se deficiency (0.02 ppm for 8 wk) had the opposite effect. The alterations in the ability of the cells to proliferate, which occurred in the absence of changes in the endogenous levels of interleukin-2 (Il2) or interleukin 1, were apparently related to the ability of Se to alter the kinetics of expression of high-affinity Il2 receptors on the surface of activated lymphocytes. This resulted in an enhanced or delayed clonal expansion of the cells, and in an increased or decreased frequency of cytotoxic cells within a given cell population. The changes in tumor cytotoxicity were paralleled by changes in the amounts of lymphotoxin produced by the activated cells. Dietary Se modulations had a comparable effect on macrophage-mediated tumor cytodestruction. The results also suggested that Se exerts its effect 8-24 h after stimulation, and that it most likely affects processes in the cytoplasmic and/or nuclear compartments of activated lymphocytes.

Selenium and immune cell functions. I. Effect on lymphocyte proliferation and production of interleukin 1 and interleukin 2.

The dietary intake of selenium (Se) has been shown to influence the development and expression of various biologic processes. This study examined the immunologic competence of lymphocytes from C57BL/6J mice maintained for 8 weeks on Se-deficient (0.02 ppm Se), normal (0.20 ppm Se, as sodium selenite), or Se-supplemented (2.00 ppm Se) Torula yeast-based diets. The ability of the cells to recognize alloantigens, to proliferate in response to stimuli, and to produce interleukin 2 (IL-2) was determined. Se deficiency significantly inhibited the ability of the lymphocytes to proliferate in response to allogeneic stimulation in the mixed lymphocyte reaction or to mitogen stimulation by phytohemagglutinin, whereas Se supplementation significantly enhanced both responses. In contrast, the amounts of IL-2 and interleukin 1 (IL-1) produced by lymphocytes and macrophages, respectively, removed from Se-deficient or Se-supplemented animals did not differ significantly from the amounts of IL-2 and IL-1 produced by cells removed from animals maintained on the control diet. These results suggest that the mechanism(s) responsible for the observed effects of Se on lymphocyte proliferation are independent of the levels of IL-2 or IL-1.

Selenium and immune cell functions. II. Effect on lymphocyte-mediated cytotoxicity.

Selenium (Se) is an essential nutritional factor with a chemopreventive potential. This study examined the ability of C57BL/6J mice, maintained for 8 weeks on Se-deficient (0.02 ppm Se), normal (0.20 ppm Se), or Se-supplemented (2.00 ppm Se) Torula yeast-based diets, to generate cytotoxic lymphocytes (CTL) and to destroy tumor cells. CTL were generated in vivo by intraperitoneal immunization with P815 cells and in vitro by allogeneic stimulation of cells from animals maintained on a normal diet in media supplemented with 1 x 10(-9) to 1 x 10(-6) M Se (as selenite). Lymphocytes from animals maintained on the Se-supplemented diet had a greater ability to destroy tumor cells than lymphocytes from animals maintained on the normal diet, whereas Se deficiency reduced the cytotoxicity. The effects on cytotoxicity were accompanied by parallel changes in the levels of lymphotoxin produced. The greatest enhancement of tumor cytodestruction occurred with supplementation of 1 x 10(-7) M Se, whereas with 1 x 10(-6) M there was inhibition of the cytotoxic responses. The stimulatory effect of Se occurred during the phase of CTL generation rather than during the lytic phase of cytotoxicity. These results indicated that Se supplementation enhances CTL generation and the ability of a host to destroy malignant cells, whereas Se deficiency has the opposite effect.

Selenium and immune responses.

Selenium (Se) affects all components of the immune system, i.e., the development and expression of nonspecific, humoral, and cell-mediated responses. In general, a deficiency in Se appears to result in immunosuppression, whereas supplementation with low doses of Se appears to result in augmentation and/or restoration of immunologic functions. A deficiency of Se has been shown to inhibit resistance to microbial and viral infections, neutrophil function, antibody production, proliferation of T and B lymphocytes in response to mitogens, and cytodestruction by T lymphocytes and NK cells. Supplementation with Se has been shown to stimulate the function of neutrophils, production of antibodies, proliferation of T and B lymphocytes in response to mitogens, production of lymphokines, NK cell-mediated cytodestruction, delayed-type hypersensitivity reactions and allograft rejection, and the ability of a host to reject transplanted malignant tumors. The mechanism(s) whereby Se affects the immune system is speculative. The effects of Se on the function of glutathione peroxidase and on the cellular levels of reduced glutathione and H2Se, as well as the ability of Se to interact with cell membranes, probably represent only a few of many regulatory mechanisms. The manipulation of cellular levels of Se may be significant for the maintenance of general health and for the control of immunodeficiency disorders and the chemoprevention of cancer.

Effect of lidocaine on the function of immunocompetent cells. II. Chronic in vivo exposure and its effects on mouse lymphocyte activation and expression of immunity.

In vivo exposure of mice to lidocaine (0.25 mg/10 g body weight 4 times a day for 7 days) resulted in impairment of immunocompetent cell function. Spleen lymphocytes removed from animals immediately and 3 days after lidocaine exposure showed changes in their surface charge properties, inhibition of blastogenesis in response to concanavalin A and lipopolysaccharide, and inhibition of antigen-stimulated activation as measured by the mixed lymphocyte reaction. Lymphocytes from animals sensitized to keyhole limpet hemocyanin showed a significantly lower capacity to produce macrophage migration inhibitory factor 8 days after termination of exposure to lidocaine. Animals exposed to the drug were unable to accumulate an adequate number of immunocompetent cells at the site of challenge with a foreign substance (i.e. dextran), and the ability of the animals to destroy tumor cells nonspecifically and specifically was also impaired. The results indicated that chronic exposure to lidocaine resulted in impairment of lymphocyte function, even in the subsequent absence of the drug, and in significant changes in the expression of the immune response.

Effects of lidocaine on the function of immunocompetent cells. I. In vitro exposure of mouse spleen lymphocytes and peritoneal macrophages.

In vitro exposure of mouse lymphocytes and macrophages for 24 h to noncytotoxic doses of lidocaine (10(-4) to 10(-6)M) resulted in inhibition of random macrophage motility and in an interference with the production of macrophage migration inhibitory factor or with its interaction with the cell surface. The effects of lidocaine, membrane-stabilizing local anesthetic, were related to its concentration in the medium and to its ability to interact with the cell surface and cause changes in the ionic configuration of the plasma membrane. The drug conferred permanent changes on the surface of lymphocytes at all concentrations tested, but changes in the surface of macrophages induced by 10(-5) and 10(-6)M lidocaine were reversible. The presence of noncytotoxic doses of lidocaine in the cellular environment resulted in significant changes in cellular functions that appeared to be related to the ability of the drug to interact with cell membranes in a manner determined by the specific properties of the cell.

Effect of lidocaine on production of migration inhibitory factor and on macrophage motility: in vitro exposure of guinea pig lymphocytes and macrophages.

Exposure of lymphocytes from guinea pigs sensitized to keyhole limpet hemocyanin and of macrophages from nonsensitized animals to noncytotoxic doses of lidocaine (10(-4) to 10(-6) M) resulted in the inhibition of the production of macrophage migration inhibitory factor and of macrophage motility. The inhibition of both processes was related to the concentration of lidocaine in the medium. The effects of lidocaine, a membrane-stabilizing drug, were apparently related to its ability to interact with the cell surface and cause changes in the surface ionic configuration of the cells, as determined by cell electrophoresis. The drug conferred permanent changes in the surface of lymphocytes at all concentrations tested, but the changes in the surface of macrophages induced in the presence of 10(-5) and 10(-6) M of the drug were reversible. The presence of noncytotoxic doses of lidocaine in the cellular environment resulted in significant changes in cellular functions that appeared to be related to the ability of the drug to interact with cell membranes in a manner determined by the specific surface properties of the cell.