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      Acute alcohol intoxication suppresses natural killer cell activity and promotes tumor metastasis.

      Nature medicine

      Alcohol Drinking, immunology, pathology, Animals, Killer Cells, Natural, drug effects, Lymphocyte Activation, Male, Neoplasm Metastasis, Neoplasms, Experimental, Rats, Rats, Inbred F344

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          Abstract

          Alcohol consumption is associated with increased morbidity and mortality related to infectious diseases and malignancy (1-5), although immune mediation of these relationships is controversial. Specifically, the activity of natural killer (NK) cells, which are involved in the resistance to infections and metastasis, can be suppressed in the presence of ethanol in vitro. However, acute consumption or infusion of ethanol in vivo exerts no effects on NK activity assessed in vitro thereafter. Therefore, we have developed and used a method to study the effects of ethanol on NK activity in living rats by using an NK-sensitive metastatic process and selective depletion of NK cells in vivo. Acute ethanol intoxication caused a marked suppression of NK activity in vivo and a tenfold increase in the number of MADB106 tumor metastases. Ethanol had no effect in rats selectively depleted of NK cells or when an NK-insensitive tumor (C4047) was used. These findings suggest that even acute ethanol intoxication markedly suppresses NK activity in the living organism. This suppression may underlie some aspects of the association between alcoholism, infectious disease and malignancies.

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          Most cited references 20

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          Role of NK cells in the control of metastatic spread and growth of tumor cells in mice.

          The ability of BALB/c nude and C57BL/6 mice to eliminate tumor cells from the blood stream was severely impaired after a single inoculation of 0.2 ml of anti-asialo BMI (asGMI) serum, diluted 1:40 to 1:320. The number of i.v.-inoculated YAC-I cells surviving in the lungs of BALB/c nude mice pretreated with anti-asGMI serum was 28 times higher than in the control nude mice. In this respect, nude mice treated with anti-asGMI behaved similarly to beige mice. The increase in the initial survival of tumor cells in the mice that was induced by pre-treatment with anti-asGMI resulted in a substantial increase in the number of artificial lung metastases that developed. In C57BL/6 +/+ mice treated with anti-asGMI and in C57BL/6 beige mice, i.v. inoculation of B16 melanoma cells induced 10 times more metastatic foci in the lungs than in the control C57BL/6 +/+ mice. In contrast, in nude mice which possess higher levels of NK reactivity, metastatic growth was suppressed 7-fold in comparison with intact C57BL/6 +/+ mice. In beige mice and in C57BL/6 +/+ mice treated with anti-asGMI, multiple metastatic foci developed in the liver, whereas in control C57BL/6 +/+ and nude mice, no extrapulmonary metastases were found. These data indicate that B16 melanoma cells are able to grow in the liver, but their growth is ordinarily prevented by NK cells. The antimetastatic defense of C57BL/6 mice treated by anti-asGMI could be restored by transplantation of 40 X 10(6) normal spleen cells. This antimetastatic effect of transplanted spleen cells was mediated by asGMI-bearing cells, since after in vitro pre-treatment of normal spleen cells with anti-asGMI and complement, they lost their ability to inhibit the development of artificial metastases in the lungs of C57BL/6 mice. Suppression of NK reactivity by multiple injections of anti-asGMI (every 4 to 5 days), in C57BL/6 mice inoculated intrafootpad (i.f.p.) with B16 melanoma or 3LL tumor cells, did not influence the growth of local tumors, but dramatically accelerated the development of spontaneous pulmonary metastases. These data demonstrate that NK cells may play an important role in resistance to the dissemination of tumor cells, and therefore contribute to the control of metastasis formation in mice.
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            Monoclonal antibody to a triggering structure expressed on rat natural killer cells and adherent lymphokine-activated killer cells

            To study the cellular structures involved in NK and lymphokine- activated killer (LAK) cell function, we have produced a panel of mAbs that modulate the cytolytic function of a population of cells with LAK activity that derive from large granular lymphocyte (LGL)/NK cells (adherent LAK [A-LAK] cells). In this report, we describe an mAb (3.2.3; IgG1k) that recognizes a triggering structure that is expressed on rat LGL/NK cells and A-LAK cells. This epitope is also expressed on polymorphonuclear leukocytes (PMN). The expression of the epitope identified by mAb 3.2.3 increased progressively on A-LAK cells after culture in the presence of rIL-2. mAb 3.2.3 enhanced the cytolytic activity of NK and A-LAK cells against FcR+ target cells, but not FcR- target cells. However, this effect was not induced by F(ab')2 fragments of 3.2.3. This antibody also induced the release of N-alpha- benzyloxycarbonyl-L-lysine thiobenzy esteresterase by A-LAK cells. These data suggest that the epitope identified by mAb 3.2.3 is on a triggering structure expressed on rat NK cells and A-LAK cells. The expression of the epitope recognized by mAb 3.2.3 on LGL/NK cells and PMN suggests that this structure may be analogous to that identified by the anti-CD16 (-FcR) mAbs. However, the molecule immunoprecipitated by mAb 3.2.3 was a 60-kD dimer composed of two 30-kD chains. These data suggest that mAb 3.2.3 recognizes a unique triggering structure. As mAb 3.2.3 is the first antibody recognizing a determinant with functional significance, selectively expressed on both rat NK cells and A-LAK cells, it will be a useful tool for the study of NK cell ontogeny and function, and the development of cells with LAK activity from the NK cell compartment.
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              Morphine attenuates surgery-induced enhancement of metastatic colonization in rats.

              Painful stressors such as surgery have been shown both to suppress immune function and to enhance tumor development. Whether the immune system mediates the tumor-enhancing effects of surgery remains unclear. Moreover, the role of postoperative pain has been largely ignored in such studies. To explore these issues, we used the MADB106 tumor, a mammary adenocarcinoma syngeneic to the subjects of this study (Fischer 344 rats) and known to be sensitive to natural killer (NK) cell activity. We found that surgery enhanced metastatic colonization and that this tumor-enhancing effect occurred only during the time in which the MADB106 tumor is sensitive to NK control. These results support the hypothesis that suppression of NK cell activity mediates the surgery-induced enhancement of metastatic colonization. Further, we found that an analgesic dose of morphine blocked the surgery-induced increase in metastasis without affecting metastasis in unoperated animals. These findings suggest that postoperative pain is a critical factor in promoting metastatic spread. If a similar relationship between pain and metastasis occurs in humans, then pain control must be considered a vital component of postoperative care.
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