Alcohol, cancer, and immunomodulation.

There is a great deal of epidemiological evidence indicating that chronic, excessive alcohol consumption is a major risk factor for cancers in humans. However, the experimental basis for the increased cancer risk associated with alcohol intake is not clear. Since it appears that ethanol alone is not carcinogenic, ethanol effects must be explained in terms of its modifying the actions of other causal agents. Current studies indicate that ethanol and its congeners may act as tumor promoters, thereby enhancing the effect of initiating carcinogens from the environment. Available evidence also shows that ethanol is immunosuppressive. Clearly, cirrhosis due to high, prolonged alcohol intake is an indicator of the immunosuppressive effects of ethanol. It is less clear that more moderate intakes of alcohol could have as profound an effect on immune systems. However, changes do occur yielding alterations in lymphocyte sensitivity to alcohol in vitro and in cell development, as shown by increased NK cell function at low concentrations. Since other conditions, such as cytotoxic drugs which suppress cellular immune functions, are clearly associated with increased cancer risk. It is intriguing to think that prolonged exposure to ethanol-induced immunosuppression may be a cofactor in the promotion of cancer. The tumor promotion may take place via a variety of mechanisms as discussed in this paper, including reduced host defenses by direct effects of ethanol, its metabolites, and/or malnutrition. It may be beneficial to test methods for immunostimulation in prolonged alcohol abusers, where cessation of use is unsuccessful or residual immunosuppression remains, to reduce the risk of development or growth of initiated tumors.

Changes in lymphocyte and macrophage subsets due to morphine and ethanol treatment during a retrovirus infection causing murine AIDS.

Infection by LP-BM5 murine leukemia virus (MuLV) suppressed significantly the percentage of peripheral blood cells showing surface markers for macrophages, lymphocytes and activated lymphoid cells. Chronic administration of a 7% (36% calories) ethanol diet or injection of 1.9 mg/mouse/day of morphine for a 7 day period were followed by 3 week periods of abstinence and then 1 week periods of consumption of 5% ethanol diets or morphine injection to female C57BL/6 mice resulted in changes in the numbers of macrophages and lymphocyte subsets. The number of lymphocytes of various subsets were not significantly changed by the ethanol exposure except those showing activation markers which were reduced. The percentage of peripheral blood cells showing markers for macrophage functions and their activation were significantly reduced after "binge" use of ethanol. Ethanol retarded suppression of cells by retroviral infection. However by 25 weeks of infection there was a 8.6% survival in the ethanol fed mice infected with retrovirus which was much less than virally infected controls (45.0%). Morphine treatment also increased the percentage of cells with markers for macrophages and activated macrophages in virally infected mice, while suppressing them in uninfected mice. The second and third morphine injection series suppressed lymphocyte T-helper and T-suppressor cells, but not total T cells. However, suppression by morphine was significantly less during retroviral disease than suppression caused by the virus only. At 25 weeks of infection 44.8% of morphine treated, infected mice survived. Morphine treatment also caused deaths such that the survival in morphine treated, retrovirally infected was higher than would have been expected if the death rate in virally infected, and morphine injected animals were combined during combined treatment. Thus these drugs of abuse can modulate peripheral blood lymphoid subsets, suppression caused by retroviral infection, and survival.

Enhanced survival by vitamin A supplementation during a retrovirus infection causing murine AIDS.

Infection by LP-BM5 murine leukemia virus (MuLV) produces an AIDS-like condition in mice. The viral infection suppressed the percentage of peripheral blood cells showing surface markers for macrophages, activated macrophages, T lymphocytes and activated lymphoid cells. High dietary vitamin A (retinyl palmitate) caused increased numbers of activated macrophages. It also increased the percentage of cells with markers for Ia+ cells and macrophages in the retrovirally infected mice compared to infected controls. In uninfected mice retinyl palmitate stimulated the percentage of cells with activated lymphocytes bearing IL-2R, and T cytotoxic cells. These were associated with a retarded death rate during infection with LP-BM5 murine leukemia in C57BL/6 mice. By 25 weeks of infection and 20 weeks of retinyl palmitate supplementation 71.3% survived, while 45.0% virally infected controls survived. The mice also had elevated numbers of B cells measured in the blood after 4 and 8 weeks of dietary treatment. Vitamin A stimulation may play a role in the slower death rate for retrovirally infected mice.

Modification of lymphoid subsets by chronic ethanol consumption in C57Bl/6 mice infected with LP-BM5 murine leukemia virus.

The relatively high incidence of infectious disease in alcoholics is attributed to the immunosuppressive effects of alcohol. The potential role of alcohol as cofactor in HIV infection and in the development and expression of AIDS is suggested but unknown. In order to understand better the contribution of alcohol to immune dysfunction following HIV infection, we assessed the presence of specific markers on thymus and spleen cells in C57B1/6 mice infected with LP-BM5 murine leukemia virus and fed ethanol-containing diets. In the first experiments, mice were fed diets containing 0, 4.5, 5.5, and 6% (v/v) ethanol for 14 weeks. High ethanol exposure (6%) resulted in severe dehydration and death after 7 weeks. Although moderately low intakes of ethanol did not significantly modify percentages of T and B cells, they increased the absolute number of mature T, B, and CD4+ cells and decreased percentages of Thy 1.2+ cells. In the second experiment, mice were infected with LP-BM5 murine leukemia retrovirus and fed diets containing 5% ethanol in a regimen of 5 days of ethanol diet and 2 days of diet without alcohol for 12 weeks. Ethanol exposure in the retrovirally infected mice showed a marked decrease in Thy 1.2+ (P < 0.05). Moderate decreases in percentages of CD4+, CD8+, CD5+ cells and an increase in Ia+ cells were also observed in the retrovirus/infected ethanol-treated mice. Moderate ethanol consumption during retroviral infection induced mild/moderate changes on lymphoid cells. Ethanol consumption may accelerate the progression of murine AIDS through such changes in the lymphoid cells of the spleen.

Influence of the level of dietary ethanol in mice with murine AIDS on resistance to Streptococcus pneumoniae.

Chronic ethanol consumption impairs cellular immune functions. This may explain the increased occurrence of various opportunistic infections in heavy ethanol users. Immunological alterations associated with Acquired Immune Deficiency Syndrome (AIDS) also permit more opportunistic infections. In this study, we used a murine model of retrovirus infection induced by LP-BM5 murine leukemia virus. The combined effects of ethanol use and early retroviral infection (prior to the development of AIDS) on resistance to Streptococcus pneumoniae were investigated. Consumption of ethanol by non-retrovirus-infected mice resulted in decreased resistance to S. pneumoniae. However, retrovirus-infected mice fed a diet containing high concentrations of ethanol (6 and 7% v/v) exhibited a greater resistance to S. pneumoniae infection than retrovirus-infected mice fed diets with lower concentrations (5%) or no ethanol. The total number of white blood cells also decreased as serum ethanol levels increased. There were also fewer lymphocytes and more neutrophils and monocytes in retrovirus-infected mice fed ethanol. Diet consumption decreased as the concentration of ethanol increased in the diet. Consumption was dependent upon the dark-light cycle. The highest diet consumption was observed during the first 4 hr of the dark period. The level of ethanol in serum was influenced by the amount of the diet consumed and its ethanol concentration. Both retrovirus infection and ethanol consumption effected survival after S. pneumoniae infection.

Spleen and thymus cell subsets modified by long-term morphine administration in protein-undernourished mice--I.

Severe infections in intravenous drug abusers could be the consequence of morphine-induced damage on the immune system. To evaluate the long-term effect of in vivo morphine administration on the immune system we developed an experimental model where we studied the combined effects of morphine treatment and protein malnutrition. We treated protein-undernourished mice daily for 11 weeks with increasing doses of morphine. Morphine treatment produced a decrease in body weight and spleen cell number. The changes observed were partially independent of the nutritional status of the host. Saline-injected mice showed a decrease in the percentage of Thy 1+ cells in the spleen. Morphine treatment induced a decrease in the total number of cells and therefore in the absolute number of T-(Thy 1, CD4, CD8), B- and Mac 1+ (macrophages) cells in protein-undernourished mice. Saline-injected mice showed a decrease in the percentage of Thy 1+ cells and an increase in the percentage of B- and Ia(+)-cells in the spleen. We conclude that morphine altered the immune system by down-regulating splenocyte proliferation. We also studied the effects of i.p. administered morphine on expression of thymocyte phenotype in well-nourished and protein-undernourished mice. In well-nourished mice, morphine treatment reduced the number of Thy 1+, CD4+ and CD8+ cells per thymus to 30% of that found in untreated mice and to 40% of the cells in those saline-treated controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Spleen and thymus cell subsets modified by long-term morphine administration and murine AIDS--II.

Intravenous heroin abusers suffer a great variety of infections, including AIDS (acquired immune deficiency syndrome). We developed an experimental mouse model to evaluate the long-term effect of in vivo morphine administration during retrovirus-induced immune dysfunction. Mice were treated daily for 11 weeks with increasing doses of morphine. Morphine treatment produced a decrease in body weight and spleen cell number. Murine retrovirus infection provoked an increase in body weight due to enlargement of lymphoid organs, and an increase in the percentage and absolute number of CD4+ and Mac 1+ cells. Interestingly, retrovirus-infected mice that were also morphine-treated did not show the increase in the relative proportion of Mac 1+ cells. Moreover, under the experimental conditions of protein-malnutrition and morphine treatment potentiation of immune dysfunction by murine retrovirus infection was investigated. Retrovirus infection-induced splenocyte proliferation was partially regulated by morphine treatment. Splenocytes from retrovirus-infected mice presented a higher percentage of IL-2R+ cells and, lower levels of sIL-2R in splenocyte supernatants. Mitogen-stimulated splenocytes had a lower production of interferon-gamma as well as an increase in the secretion of tumor necrosis factor-alpha. Thus morphine altered the immune system by down-regulating splenocyte proliferation, because retrovirus infection-induced splenocyte proliferation was partially regulated by morphine treatment. We also evaluated the effects of joint murine retrovirus infection and protein undernutrition on the thymus cell subsets. Retrovirus infection was associated with a decrease in the absolute number of Thy 1+, CD4+ and CD8+ cells per thymus with the CD8+ cell subset being the most affected. Moreover, retrovirus-infected mice presented a dramatic decrease in the percentage of double-positive (CD4+ CD8+) cells in the thymus as well as changes in its immunoarchitecture. While protein undernutrition alone did not produce further differences between infected versus non-infected, protein-undernourished, morphine treatment induced a greater decrease in thymocyte number than that seen in retrovirus- or morphine-treated animals alone.