Bailin Liang

Prevention of immune dysfunction and vitamin E loss by dehydroepiandrosterone and melatonin supplementation during murine retrovirus infection

Female C57BL/6 mice infected with the LP‐BM5 leukaemia retrovirus developed murine acquired immune‐deficiency syndrome (AIDS). Dehydroepiandrosterone (DHEA) and melatonin (MLT) modify immune dysfunction and prevent lipid peroxidation. We investigated whether DHEA and MLT could prevent immune dysfunction, excessive lipid peroxidation, and tissue vitamin E loss induced by retrovirus infection. Retrovirus infection inhibited the release of T helper 1 (Th1) cytokines, stimulated secretion of Th2 cytokines, increased hepatic lipid peroxidation, and induced vitamin E deficiency. Treatment with DHEA or MLT alone, as well as together, largely prevented the reduction of B‐ and T‐cell proliferation as well as of Th1 cytokine secretion caused by retrovirus infection. Supplementation also suppressed the elevated production of Th2 cytokines stimulated by retrovirus infection. DHEA and MLT simultaneously reduced hepatic lipid peroxidation and prevented vitamin E loss. The use of DHEA plus MLT was more effective in preventing retrovirus‐induced immune dysfunction than either DHEA or MLT alone. These results suggest that supplementation with DHEA and MLT may prevent cytokine dysregulation, lipid oxidation and tissue vitamin E loss induced by retrovirus infection. Similarly, hormone supplementation also modified immune function and increased tissue vitamin E levels in uninfected mice.

MODULATION OF IMMUNE DYSFUNCTION DURING MURINE LEUKAEMIA RETROVIRUS INFECTION OF OLD MICE BY DEHYROEPIANDROSTERONE SULPHATE (DHEAS)

Ageing, leukaemia and acquired immune deficiency syndrome (AIDS) are conditions with dysregulated cytokine production. As dehydroepiandrosterone sulphate (DHEAS) restored normal cytokine production in old mice its effects on retrovirally infected old mice were investigated. Retrovirus infection and ageing‐induced immune dysfunction. Murine retrovirus‐infected old C57BL/6 female mice consumed 0·22 or 0·44 μg of DHEAS/mouse/day beginning 2 weeks postinfection for 10 weeks. DHEAS largely prevented the retrovirus‐induced reduction in T‐cell and B‐cell mitogenesis. DHEAS supplement prevented loss of cytokines [interleukin‐2 (IL‐2) and interferon‐γ] secretion by mitogen‐stimulated splenocytes representing T helper 1 (Th1) cell phenotypes. It also suppressed the retrovirus‐induced, excessive production of cytokines (IL‐6 and IL‐10) by Th2 cells. The highest dose of DHEAS reduced IL‐6 production by splenocytes from uninfected old mice by 75% while increasing their IL‐2 secretion by nearly 50%. Thus immune dysfunction induced by ageing, even when exacerbated by murine retrovirus infection, was largely prevented by DHEAS.

Modulation of Cytokine Production by Dehydroepiandrosterone (DHEA) Plus Melatonin (MLT) Supplementation of Old Mice

Abstract Tissue levels of the antioxidants melatonin (MLT) and dehydroepiandrosterone (DHEA) decline with age, and this decline is correlated with immune dysfunction. The aim of the current study is to determine whether hormone supplementation with MLT and DHEA together would synergize to reverse immune senescence. Old (16.5 months) female C57BL/6 mice were treated with DHEA, MLT, or DHEA + MLT. As expected, splenocytes were significantly (P < 0.05) higher in old mice as compared to young mice. DHEA, MLT, and DHEA + MLT significantly (P < 0.005) increased B cell proliferation in young mice. However, only MLT and DHEA + MLT significantly (P < 0.05) increased B cell proliferation in old mice. DHEA, MLT, and DHEA + MLT help to regulate immune function in aged female C57BL/6 mice by significantly (P < 0.05) increasing Th1 cytokines, IL-2, and IFN-γ or significantly (P < 0.05) decreasing Th2 cytokines, IL-6, and IL-10, thus regulating cytokine production. DHEA and MLT effectively modulate suppressed Th1 cytokine and elevated Th2 cytokine production; however, their combined use produced only a limited additive effect.

Vitamins and immunomodulation in AIDS

Acquired immune deficiency syndrome (AIDS) is a clinical disorder caused by a retrovirus infection and represents the end point in a progressive sequence of immunosuppressive changes. Vitamins can enhance disease resistance in animals and humans. As such they are important co-factors in optimal functioning of the immune systems. In this article, the immunological and nutritional modifications caused by AIDS are summarized. The effects of murine and human retrovirus infection on vitamin status are analyzed as co-factors in the development of severe immune dysfunction, AIDS. The properties of immunoenhancing antioxidative vitamins, vitamin A, B6, B12, C, E, and beta-carotene, which are frequently low in AIDS patients, are evaluated relative to the development of immunodeficiency during retrovirus infection. Vitamin A, E, and B12 deficiency accelerated the development of AIDS with low T cells, whereas their normalization retarded the development of immune dysfunction. The interactions between these vitamins and the immune system in human AIDS patients and animal models of AIDS are reviewed. Our purpose is to provide data on how retrovirus infection can cause nutritional deficiencies that accentuate immune damage and to evaluate the potential therapeutic role of vitamins in the treatment of immune dysfunctions in AIDS patients.

Alcohol Consumption Alters Cytokine Release During Murine AIDS

Acquired immune deficiency syndrome (AIDS) is a clinical disorder caused by a human immunodeficiency virus (HIV), representing the end point in a progressive sequence of immunosuppressive changes. HIV, the key causative agent of AIDS, induces immunosuppression that render the body highly susceptible to opportunistic infections and neoplasm. However, the onset of clinical symptoms of AIDS (e.g., low CD4+ T cells count, opportunistic infections, and tumors) is quite variable among HIV+ individuals with a mean incubation times 3-10 years following seroconversion. Because of the deleterious effects of chronic alcohol (EtOH) consumption on cytokine release, immune response, host defense, nutritional status, and oxidative stress, it has been believed to be a possible cofactor that could enhance the hosts susceptibility to HIV infection, and subsequently accelerate the development of AIDS. The purpose of this review is to present evidence of EtOH-induced cytokine dysregulation during murine AIDS. Our results done in murine AIDS indicate the EtOH consumption may accelerate the development of AIDS by disrupting cytokine production. These EtOH-induced abnormalities in cytokine release may promote a more rapid development of AIDS as a cofactor, which exacerbates the immune dysfunctions initiated by retrovirus infection.

Immunomodulation by pycnogenol® in retrovirus-infected or ethanol-fed mice

Pycnogenol is a commercial mixture of bioflavonoids that exhibits antioxidative activity. The effects of dietary pycnogenol on immune dysfunction in normal mice as well as those fed ethanol or infected with the LP-BM5 murine retrovirus were determined. The ethanol consumption and retrovirus infection caused abnormalities in the function and/or structure of a broad array of cells involved in humoral and cellular immunity. Pycnogenol enhanced in vitro IL-2 production by mitogen-stimulated splenocytes if its production was suppressed in ethanol-fed or retrovirus-infected mice. Mitogenesis of splenocytes did not show a significant change in mice treated with pycnogenol. It reduced the elevated levels of interleukin-6 produced in vitro by cells from retrovirus infected mice and IL-10 secreted by spleen cells from mice consuming ethanol. Natural killer cell cytotoxicity was increased with pycnogenol treatment.

T-cell-receptor dose and the time of treatment during murine retrovirus infection for maintenance of immune function

C57BL/6 mice were injected with different doses of human T‐cell receptor (TCR) Vβ8.1 CDR1 peptide at different times after murine retrovirus (LP‐BM5) infection. Injection with TCR Vβ8.1 CDR1 peptide largely prevented the retrovirus‐induced reduction in B‐ and T‐cell proliferation, and T‐helper 1 (Th1) cytokines [interleukin‐2 (IL‐2) and interferon‐γ (IFN‐γ)] secretion. It also suppressed T‐helper 2 (Th2) cytokines (IL‐6 and IL‐10) production, which was stimulated by retrovirus infection. These effects were accomplished using at least 100 μg of peptide per mouse and the most effective dose of peptide had to be given within 4 weeks after retrovirus infection. Immunization with doses above 100 μg/mouse as long as 4 weeks postinfection maintained natural killer (NK) cell activity during retrovirus infection. Reducing the dose of peptide or delaying it until the disease progressed towards early murine acquired immune deficiency syndrome (AIDS) allowed development of immune dysfunction. These studies provide data suggesting that immune dysfunction, induced by murine retrovirus infection, was largely prevented by TCR Vβ CDR1 peptide injection.

Melatonin, Immune Modulation and Aging

Melatonin is a hormone secreted by the pineal gland in response to photoperiods and influences many important biological processes. For one, Melatonin has been shown to produce resistance to cancer and infectious diseases in aged animals. Studies in animals have demonstrated melatonin-related mechanisms of action on immunoregulation. Additionally, melatonin has been successfully used in humans, along with interleukin-2, as a treatment of solid tumors. In vivo and in vitro studies show melatonin enhances both natural and acquired immunity in animals. Despite all of this intriguing evidence, melatonins mechanism of action on the immune system is only partially defined. It does, however, appear to act through lymphocyte receptors, and perhaps, receptors on other immune tissues, to modulate immune cells. In order to understand immunomodulation and anti-cancer effects, information on melatonin and its interactions with other endocrine hormones are summarized.

Vitamin E supplementation with interferon-gamma administration retards immune dysfunction during murine retrovirus infection.

Murine retrovirus infection induces loss of vitamin E and immune dysfunction with loss of cytokine production by T‐helper cells. Therefore interferon‐γ (IFN‐γ) was given during dietary vitamin E supplementation to effectively prevent murine retrovirus‐induced immunosuppression, cytokine dysregulation, and development of murine AIDS. Administration of IFN‐γ during vitamin E supplementation significantly prevented development of retrovirus‐induced suppression of splenic natural killer cell activity and T cell proliferation. It also significantly slowed retrovirus‐induced elevation of T helper (Th) 2 cytokine [interleukin (IL)‐4, IL‐5, and IL‐10] production and monokine (IL‐6 and tumor necrosis factor‐α) secretion by splenocytes. The treatment also prevented loss of Th1 cytokine (IL‐2 and IFN‐γ) secretion by splenocytes from retrovirus‐infected mice alleviating splenomegaly and hyper‐gammaglobulinemia. The combined therapy had an additive therapeutic impact. It was more effective than IFN‐γ treatment or vitamin E supplementation alone in delaying the development of retrovirus‐induced immunosuppression with its cytokine dysregulation.

Suppression of tissue levels of vitamin A, E, zinc and copper in murine aids*

Abstract Female C57BL/6 mice were infected with LP-BM5 retrovirus, causing murine acquired immune deficiency syndrome (MAIDS) which is functionally similar to human AIDS. Because human immunodeficiency virus may compromise nutritional status and nutritional disorders have been found in AIDS patients, the influence of murine retrovirus infection on levels of important immune-related nutrients (vitamin A, E, zinc and copper) in the serum, liver, small intestine, spleen and thymus was determined in MAIDS. The levels of vitamin A, E and copper in the liver in MAIDS were significantly reduced compared to controls, whereas the level of zinc in the liver was not affected. Intestinal level of vitamin A was significantly reduced by retrovirus infection, whereas copper level in the small intestine was significantly increased compared to controls. Intestinal levels of zinc and vitamin E were not affected. The levels of vitamin A, E and zinc in the spleen in murine AIDS were significantly rebared compared to controls, whereas the splenic level of copper was not influenced. The levels of vitamin A, E and copper in the thymus in MAIDS were significantly lessened by retrovirus infection compared to controls, whereas thymic level of zinc was significantly elevated. The levels of vitamin A and E in the serum in MAIDS were significantly decreased by retrovirus infection compared to controls. The data indicated that retrovirus infection can directly cause malnutrition, possible via damaging gastrointestinal cells, thereby leading to malabsorption. Such malnutrition has the theoretical potential to accelerate development of AIDS via immunosuppression secondary to nutritional deficiency.