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Combination thymosin alpha 1 and lymphoblastoid interferon treatment in chronic hepatitis C
Rasi G; DiVirgilio D; Mutchnick MG; Colella F; Sinibaldi-Vallebona P; Pierimarchi P; Valli B; Garaci E
Istituto di Medicina Sperimentale, CNR-Roma, Italy.
Gut (England) Nov 1996, 39 (5) p679-83

BACKGROUND: Monotherapy for chronic hepatitis C using interferon (IFN) results in a very small proportion of patients exhibiting a sustained response. Clinical trials assessing the benefit of combination drug therapy may provide evidence of improved treatment response over that seen with single drug treatment. AIM: To assess the response in patients with chronic hepatitis C to one year of combination treatment: thymosin alpha 1 (T alpha 1), 1 mg twice weekly, and lymphoblastoid (L)-IFN, 3 MU thrice weekly.

PATIENTS AND METHODS: Fifteen patients with serum HCV RNA positive chronic hepatitis C were studied. Eleven patients were treatment naive and four had failed previous standard IFN therapy. Thirteen patients were HCV RNA serotype 1b. All patients were given combination T alpha 1 and L-IFN therapy for one year with a six month follow up period.

RESULTS: Six months after initiation of treatment seven patients (47%) were sera HCV RNA negative and at completion of the one year treatment 11 (73%), including two who had failed previous standard IFN treatment, had negative serum HCV RNA. Six months after treatment, six patients (40%), including five with HCV type 1b, showed a sustained response characterized by a negative serum HCV RNA.

CONCLUSIONS: The results of this open label trial suggest that there may be a potential benefit to combining an immune modulator (T alpha 1) with an antiviral (IFN) in the treatment of chronic hepatitis C. Verification of the observations in this study require completion of a randomised controlled study.

Effective immunization against neuroblastoma using double-transduced tumor cells secreting GM-CSF and interferon-gamma.
Bausero MA; Panoskaltsis-Mortari A; Blazar BR; Katsanis E
Department of Pediatrics, University of Minnesota, Minneapolis 55455, USA.
J Immunother Emphasis Tumor Immunol (United States) Mar 1996, 19 (2) p113-24

Murine neuroblastoma, neuro-2a, was transduced with the retroviral vector MFG-granulocyte-macrophage colony-stimulating factor (GM-CSF), to examine immune stimulation conferred by localized GM-CSF production. Expression of murine GM-CSF by neuro-2a (N-2a/GM) significantly reduced its tumorigenicity. Moreover, immunization of mice with irradiated N-2a/GM cells resulted in a significant protective effect against live tumor challenge 14 days later. Approximately 41% of mice immunized with irradiated N-2a/GM versus 0% of those vaccinated with irradiated parental tumor survived. Surviving mice were rechallenged after 50 days with wild-type neuro-2a or with the Sa1 syngeneic sarcoma to discern whether the generated immunity was durable and tumor specific. All mice survived wild-type neuro-2a challenge, whereas none survived inoculation with Sa1. Because both CD4+ and CD8+ T cells were necessary during priming to this MHC class Ilo, II-tumor, these data indicate that major histocompatibility complex (MHC) class I+, II+ antigen-presenting cells (APCs) were required for the T-cell antitumor response. Co-expression of GM-CSF and IFN-gamma, both of which have immunostimulatory activities on antigen-presenting cells, abrogated the tumorigenic potential of this tumor and increased immunogenicity over N-2a/IFN but not N-2a/GM. Vaccination of mice with preexisting retroperitoneal tumors with irradiated N-2a/GM and irradiated N-2a/IFN/GM improved survival. There was a trend for nonirradiated transduced cells to be more immunogenic than their irradiated counterparts. Immunohistochemistry of tissues from the vaccination site revealed a pronounced macrophage infiltration associated with nonirradiated N-2a/GM and N-2a/IFN/GM. These data suggest that vaccination involving nonirradiated neuroblastoma cells transduced with genes that stimulate APCs may be a useful approach in stimulating antitumor T-cell responses.

Improved sustained response following treatment of chronic hepatitis C by gradual reduction in the interferon dose.
Shiffman ML; Hofmann CM; Luketic VA; Sanyal AJ; Contos MJ; Mills AS
Hepatology Section, Medical College of Virginia, Richmond, Va 23298, USA.
Hepatology (United States) Jul 1996, 24 (1) p21-6

Interferon (IFN) treatment of chronic hepatitis C virus (HCV) is associated with a high rate of relapse. IFN is thought to exert its effect against HCV via direct viral inhibition and immune stimulation. We have hypothesized that relapse following termination of therapy results from the sudden withdrawal of this immune modulatory effect and that gradual reduction in the IFN dose may decrease the incidence of relapse. One hundred six patients with chronic HCV were enrolled into this 24-month controlled, randomized prospective trial. All were treated with 5 mU of interferon-alpha-2b three times a week for 6 months. Patients who achieved biochemical response were randomized to either stop or taper IFN gradually at monthly intervals as follows; 3 mu, 2 mU, 1 mU, and 0.5 mU (all three times a week). 0.5 mU twice weekly and then once weekly. Liver histology was assessed by Knodell index and HCV RNA was measured by a quantitative polymerase chain reaction (PCR) assay. Of the 92 patients who completed the initial 6 months of IFN treatment, 47 (51%) achieved biochemical response. Twenty-one of these patients were randomized to stop IFN treatment and 25 to taper (1 drop-out). At randomization patients were well matched with respect to age, sex, race, serum alanine transaminase (ALT), and liver histology. Biochemical relapse was observed in 19 of 21 (91%) patients who stopped IFN treatment compared with only 60% who tapered IFN (P= .04). Virological relapse occurred in 90% of patients who stopped and only 48% of persons who tapered IFN therapy. At completion of the 24-month study patients who achieved long-term sustained biochemical response had a significantly lower mean Knodell score (3.5 vs. 6.5) and a significantly greater number were HCV RNA negative in serum (85% vs. 18%) compared with relapsers. We conclude that gradual reduction in IFN dose is associated with a significant higher rate of sustained response and clearance of HCV RNA from serum compared with abruptly stopping treatment. This in turn is associated with a significant improvement in hepatic histology supporting the premise that response to IFN therapy can prevent progression to cirrhosis.

Improved immunotherapy of a recombinant carcinoembryonic antigen vaccinia vaccine when given in combination with interleukin-2.
McLaughlin JP; Schlom J; Kantor JA; Greiner JW
Laboratory of Tumor Immunology and Biology, National Cancer Institute, NIH, Bethesda, Maryland 20892, USA.
Cancer Res (United States) May 15 1996, 56 (10) p2361-7

Interleukin-2 (IL-2) has been an effective immune modulator in several active-specific immunotherapy experimental protocols using either viral or oncolysate-based vaccines. In this report, data indicate that IL-2 administration can appreciably augment the therapeutic effect of a single immunization of a recombinant vaccinia virus-carcinoembryonic antigen (rV-CEA) vaccine using a CEA-expressing syngeneic experimental murine model system. A single rV-CEA immunization of C57BL/6 mice bearing palpable CEA-positive colon adenocarcinoma tumors results in complete tumor regression in approximately 20% of the mice. The addition of a course of low-dose IL-2 results in complete tumor regression in 60-70% of the mice. Moreover, the combination of rV-CEA and IL-2 induces systemic immunity, which protects those tumor-free mice from subsequent rechallenge with the CEA-expressing tumor cells. No such tumor regression or protection was observed in those mice immunized with the wild-type vaccinia vaccine (V-Wyeth) alone or with IL-2 administration alone. Cellular immune assays revealed that the addition of IL-2 to rV-CEA immunization significantly increased the CEA-specific T-cell proliferative responses as well as the cytolytic T-cell responses when compared with rV-CEA immunization alone. The enhanced CEA-specific immune response, coupled with the improved experimental therapeutic outcome following IL-2 administration, suggests that treatment with that cytokine may effectively substitute for multiple rV-CEA immunizations in active-specific immunotherapy clinical protocols directed at CEA-expressing tumors.

Vitamins and immunity: II. Influenceof L-carnitine on the immune system.
De Simone C; Ferrari M; Lozzi A; Meli D; Ricca D; Sorice F
Acta Vitaminol Enzymol (Italy) 1982, 4 (1-2)

Vitamin A affects the antibody responses and may affect phagocytic function and properdin levels. Pyridoxine deficiency impairs nucleic acid synthesis and depresses antibody formation, delayed hypersensitivity reactions and the ability of phagocytes to kill bacteria. Pantothenic acid deficiency impairs antibody formation. Vitamin-C deficiency increases the incidence of infection, primary by a negative influence on reparative processes. Deficiencies of other vitamins either have not been sufficiently studied or have a variable effect. Moreover, even substances which for their biosynthesis require an adequate vitamin supplementation may exert immunomodulatory influences. With this respect the authors report their results on the influence of L-carnitine on the immune system. L-carnitine increases the proliferative responses of both murine and human lymphocyte following mitogenic stimulation and increase polymorphonuclear chemotaxis. Furthermore, L-carnitine, even at minimal concentrations, neutralizes the lipid induced immunosuppression.

Suppression of tumor growth and enhancement of immune status with high levels of dietary vitamin B6 in BALB/c mice.
Gridley DS; Stickney DR; Nutter RL; Slater JM; Shultz TD
J Natl Cancer Inst 1987 May;78(5):951-9

Effects of dietary vitamin B6 at levels ranging from deficiency to megadoses on the development of herpes simplex virus type 2-transformed (H238) cell-induced tumors and on in vitro responses relating to cell-mediated immunity were examined. Male BALB/cByJ mice (n = 260), 5 weeks of age, were fed 20% casein diets containing pyridoxine (PN) at 0.2, 1.2 for the control diet, 7.7, or 74.3 mg/kg diet for 4-11 weeks. After 4 weeks of dietary treatment, 120 of the mice received an injection of H238 cells; mice without H238 injection served as controls. At 4, 8, and 11 weeks, animals from each group were euthanized and blood and spleen samples obtained. Mice fed 0.2 mg PN developed mild deficiency symptoms and gained significantly less weight than those fed 1.2-, 7.7-, and 74.3-mg PN diets. Thirteen to 16 days after tumor cell injection, primary tumor incidence was lowest in mice fed 74.3 mg PN; later, incidence among groups was similar. Mice fed 1.2 mg PN had the largest primary tumor volume, the highest incidence of lung metastases, and the greatest number of metastatic nodules per animal at 7 weeks post injection. Overall, lower tumor volumes were found in animals fed 7.7 and 74.3 mg PN (14 and 32% less than the tumor volume for those fed 1.2 mg PN, respectively); mice fed 0.2 mg PN had the lowest tumor volume. Blood and spleen lymphoproliferative response to stimulation by phytohemagglutinin or concanavalin A generally tended to be higher in mice fed 7.7 and 74.3 mg PN as compared to that in animals fed either 0.2 or 1.2 mg PN. However, decreased mitogen-stimulated responsiveness was observed in all animals with progressive tumor growth. Tumor growth also resulted in splenomegaly and increased thymic atrophy. Significant negative relationships between tumor volume and tumor pyridoxal 5-phosphate (PLP) concentrations were observed for 1.2-, 7.7-, and 74.3-mg PN diet groups. These data suggest that high dietary intake of vitamin B6 may have suppressed tumor development by either immune enhancement or PLP growth regulation of this tumor.

The activities of coenzyme Q10 and vitamin B6 for immune responses.
Folkers K, Morita M, McRee J Jr
Institute for Biomedical Research, University of Texas, Austin 78712.
Biochem Biophys Res Commun 1993 May 28;193(1):88-92

Coenzyme Q10 (CoQ10) and vitamin B6 (pyridoxine) have been administered together and separately to three groups of human subjects. The blood levels of CoQ10 increased (p < 0.001) when CoQ10 and pyridoxine were administered together and when CoQ10 was given alone. The blood levels of IgG increased when CoQ10 and pyridoxine were administered together (p < 0.01) and when CoQ10 was administered alone (p < 0.05). The blood levels of T4-lymphocytes increased when CoQ10 and pyridoxine were administered together (p < 0.01) and separately (p < 0.001). The ratio of T4/T8 lymphocytes increased when CoQ10 and pyridoxine were administered together (p < 0.001) and separately (p < 0.05). These increases in IgG and T4-lymphocytes with CoQ10 and vitamin B6 are clinically important for trials on AIDS, other infectious diseases, and on cancer.

Research on coenzyme Q10 in clinical medicine and in immunomodulation.
Folkers K; Wolaniuk A
Drugs Exp Clin Res (Switzerland) 1985, 11 (8) p539-45

Coenzyme Q10 (CoQ10) is a redox component in the respiratory chain. CoQ10 is necessary for human life to exist; and a deficiency can be contributory to ill health and disease. A deficiency of CoQ10 in myocardial disease has been found and controlled therapeutic trials have established CoQ10 as a major advance in the therapy of resistant myocardial failure. The cardiotoxicity of adriamycin, used in treatment modalities of cancer, is significantly reduced by CoQ10, apparently because the side-effects of adriamycin include inhibition of mitochondrial CoQ10 enzymes. Models of the immune system including phagocytic rate, circulating antibody level, neoplasia, viral and parasitic infections were used to demonstrate that CoQ10 is an immunomodulating agent. It was concluded that CoQ10, at the mitochondrial level, is essential for the optimal function of the immune system.

Immunoenhancing effect of flavonoid compounds on lymphocyte proliferation and immunoglobulin synthesis.
Brattig NW; Diao GJ; Berg PA
Int J Immunopharmacol (England) 1984, 6 (3) p205-15

Flavonoid compounds are lipophilic agents which can interact with membrane lipids and may affect responsiveness of immune cells. We therefore studied whether cianidanol ((+)-catechin), the O-methyl-derivative (+)-3-methoxy-5,7,3',4'-tetrahydroxyflavan and palmitoyl-derivative (+)-3-palmitoyl-5,7,3',4'-tetrahydroxyflavan influence T and B cell functions. In addition, immunomodulatory property of ubiquinone 50 was also investigated. As controls were used cyclosporin A and inosine which are known to inhibit or enhance immune responses, respectively. The in vitro spontaneous, antigen and mitogen induced proliferation as well as immunoglobulin synthesis of peripheral blood mononuclear cells from healthy individuals was determined in the presence of different concentrations of the agents. All flavonoid compounds and ubiquinone 50 significantly increased (p less than 0.05 - less than 0.01) the spontaneous lymphocyte transformation but hardly affected antigen, alloantigen and mitogen induced proliferative response. Only cianidanol and O-methyl-derivative enhanced significantly (p less than 0.05 - less than 0.01) spontaneous, pokeweedmitogen and Staphylococcus aureus Cowan I induced immunoglobulin synthesis while the palmitoyl-derivative and ubiquinone 50 had only minor influence on B cell function. In contrast, Staphylococcus aureus induced immunoglobulin production was neither increased by inosine nor suppressed by cyclosporin A. These studies show that especially cianidanol and the O-methyl-derivative can exert an immunoenhancing effect on T and B cell functions.

Immunological senescence in mice and its reversal by coenzyme Q10.
Bliznakov EG
Mech Ageing Dev 1978 Mar;7(3):189-97

A pronounced suppression of the humoral, hemolytic, primary immune response in old (22 months) mice was demonstrated as compared with this response in young (10 weeks) mice. The suppression is associated with a lower thymus weight:body weight ratio. In contrast, the ratios spleen weight:body weight and liver weight:body weight in 10 weeks and 22 months old mice remain almost constant. A single administration of coenzyme Q10--a non-toxic, non-specific stimulant of the host defense system--partly compensates the age-determined suppression of the humoral, immune response. This suppression probably results from an age-dependent imbalance of T cells: B cells ratio and a decline of their immunological responsiveness which is compensated by the administration of coenzyme Q10.

Immune effects of preoperative immunotherapy with high-dose subcutaneous interleukin-2 versus neuroimmunotherapy with low-dose interleukin-2 plus the neurohormone melatonin in gastrointestinal tract tumor patients.
Lissoni P; Brivio F; Brivio O; Fumagalli L; Gramazio F; Rossi M
J Biol Regul Homeost Agents (Italy) Jan-Mar 1995, 9 (1) p31-3

Surgery-induced immunosuppression could influence tumor/host interactions in surgically treated cancer patients. Previous studies have shown that high-dose IL-2 preoperative therapy may neutralize surgery-induced lymphocytopenia. Moreover, experimental studies have demonstrated that the immunomodulating neurohormone melatonin (MLT) may amplify IL-2 activity and reduce its dose required to activate the immune system. On this basis, we have compared the immune effects of presurgical therapy with high-dose IL-2 with respect to those obtained with preoperative neuroimmunotherapy consisting of low-dose IL-2 plus MLT. The study included 30 patients with gastrointestinal tract tumors, who were randomized to undergo surgery alone, or surgery plus a preoperative biotherapy with high-dose IL-2 (18 million IU/day subcutaneously for 3 days) or low-dose IL-2 (6 million IU/day subcutaneously for 5 days) plus MLT (40 mg/day orally). Patients underwent surgery within 36 hours from IL-2 interruption. Both IL-2 plus MLT were able to prevent surgery-induced lymphocytopenia. However, mean number of lymphocytes, T lymphocytes and T helper lymphocytes observed on day 1 of postoperative period was significantly higher in patients treated with IL-2 plus MLT than in those receiving IL-2 alone. Moreover, toxicity was less in patients treated with IL-2 and MLT. This biological study shows that both immunotherapy with high-dose IL-2 or neuroimmunotherapy with low-dose IL-2 plus MLT preoperatively are tolerated biotherapies, capable of neutralizing surgery-induced lymphocytopenia in cancer patients. Moreover, the study would suggest that the neuroimmunotherapy may induce a more rapid effect on postoperative immune changes with respect to IL-2 alone.

Pineal-opioid system interactions in the control of immunoinflammatory responses.
Lissoni P, Barni S, Tancini G, Fossati V, Frigerio F
Division of Radiation Oncology, San Gerardo Hospital, Monza, Milan, Italy.
Ann N Y Acad Sci 1994 Nov 25;741:191-6

Several studies have demonstrated involvement of the pineal gland in the regulation of neuropeptide secretion and activity. In particular, the existence of links between the pineal gland and the brain opioid system has been documented. Both opioid peptides and melatonin (MLT), the most investigated pineal hormone, play an important role in neuromodulation of the immunity. Moreover, the immune effects of MLT are mediated by endogenous opioid peptides, which may be produced by both the endocrine system and the immune cells. In addition, the immune dysfunctions that characterize some human diseases, such as cancer, depend not only on the immune system per se, but also at least in part, on altered secretion of immunomodulating neurohormones, including MLT and opioid peptides. Therefore, the exogenous administration of neurohormones could potentially improve the immune status in humans. The present study evaluates the effects of MLT on changes in the number of T lymphocytes, natural killer cells, and eosinophils induced by exogenous administration of interleukin-2 (IL-2). Macrophage activity was also evaluated by determining serum levels of its specific marker, neopterin. The study was performed in 90 patients with advanced solid neoplasms, who received IL-2 at a dose of 3 million IU/day subcutaneously for 6 days a week for 4 weeks plus MLT at a daily dose of 40 mg. Both drugs were given in the evening. The results were compared to those in 40 cancer patients treated with IL-2 alone. The mean increase in T lymphocytes, natural killer cells, and eosinophils was significantly higher in patients treated with IL-2 plus MLT than in those who received IL-2 alone.

Evidence for a direct action of melatoninon the immune system.
Poon AM, Liu ZM, Pang CS, Brown GM, Pang SF
Department of Physiology, University of Hong Kong.
Biol Signals 1994 Mar-Apr;3(2):107-17

Pineal melatonin modulates the mammalian immune system. In vivo studies showed that melatonin enhanced the natural and acquired immunity while in vitro studies demonstrated its inhibitory influence. The mechanism of melatonin action on the immune system remains unknown. Actions through lymphokines or opioid release or via other endocrine changes have been proposed. In this paper, a direct action of melatonin on the lymphoid tissue is hypothesized. 2-[125I]Iodomelatonin binding sites have been identified in the membrane homogenates of thymus, bursa of Fabricius and spleens of a number of birds and mammals. The bindings were stable, saturable, reversible, specific and of high affinity. The Bmax ranged from 0.6 to 3.9 fmol/mg protein. The Kd was in the physiological range of circulating melatonin levels, about 30-70 pmol/l. The binding sites in the primary lymphoid organs demonstrated diurnal variation in density, with higher levels found at the middle of the light period. However, those in the spleen did not vary with the time of the day.An age-dependent decrease in the density was also found in the chicken bursa of Fabricius. In addition, when the nocturnal melatonin secretion was suppressed by constant light exposure, the density of the binding sites increased in the guinea pig spleen. Immunosuppression with cortisol injection in young ducks decreased the density of the melatonin binding sites in the thymus. The regulation of the binding characteristics by physiological variation in melatonin levels and/or immunological status of the animals provide evidence that these 2-[125I]iodomelatonin binding sites in the lymphoid tissues may be physiologically significant and represent true melatonin receptors. The melatonin receptors in the lymphoid organs may be coupled to a G protein as Guanosine 5'-0-(3-thiotriphosphate inhibited 2-[125I]iodomelatonin binding in the spleen by increasing the Kd and decreasing the Bmax.

The immuno-reconstituting effect of melatonin or pineal grafting and its relation to zinc pool in aging mice.
Mocchegiani E, Bulian D, Santarelli L, Tibaldi A, Muzzioli M, Pierpaoli W, Fabris N
Gerontology Research Department, Italian National Institute for Research on Aging (INRCA), Ancona.
J Neuroimmunol 1994 Sep;53(2):189-201

It has been demonstrated that melatonin, the main neuro-hormone of the pineal gland, affects thymic functions and the regulation of the immune system. In addition, experimental evidences indicate that melatonin can modulate zinc turnover. The knowledge that with advancing age both melatonin and zinc plasma levels decline, and that zinc supplementation in old mice is able to restore the reduced immunological functions, has prompted investigations on the effect of chronic melatonin treatment or pineal graft in old mice on the age-related decline of thymic endocrine activity, peripheral immune functions and zinc turnover. Both melatonin treatment in old mice and pineal graft into the thymus of old mice correct the reduced thymic endocrine activity and increase the weight of the thymus and its cellularity. A restoration of cortical thymic volume, as detected by the percentage of tissue in active proliferation, is also observed in old mice after both treatments. Thymocyte CD phenotype expression is also restored to young values. At peripheral level, recovery of peripheral blood lymphocyte number and of spleen cell subsets, with increased mitogen responsiveness also occurs. Melatonin treatment or pineal graft induce also a restoration of the altered zinc turnover in aged mice with an increment of the crude zinc balance from negative (-1.6 microgram/day/mouse) to positive value (+1.2 microgram/day/mouse), similar to that one of young mice (+1.4 microgram/day/mouse). The reduced zinc plasma level is restored to normal values. These findings support the idea that the effect of melatonin on thymic endocrine activity and peripheral immune functions may be mediated by the zinc pool.

The immunoneuroendocrine role of melatonin.
Maestroni GJ
J Pineal Res (Denmark) Jan 1993, 14 (1) p1-10

A tight, physiological link between the pineal gland and the immune system is emerging from a series of experimental studies. This link might reflect the evolutionary connection between self-recognition and reproduction. Pinealectomy or other experimental methods which inhibit melatonin synthesis and secretion induce a state of immunodepression which is counteracted by melatonin. In general, melatonin seems to have an immunoenhancing effect that is particularly apparent in immunodepressive states. The negative effect of acute stress or immunosuppressive pharmacological treatments on various immune parameters are counteracted by melatonin. It seems important to note that one of the main targets of melatonin is the thymus, i.e., the central organ of the immune system. The clinical use of melatonin as an immunotherapeutic agent seems promising in primary and secondary immunodeficiencies as well as in cancer immunotherapy. The immunoenhancing action of melatonin seems to be mediated by T-helper cell-derived opioid peptides as well as by lymphokines and, perhaps, by pituitary hormones. Melatonin-induced-immuno-opioids (MIIO) and lymphokines imply the presence of specific binding sites or melatonin receptors on cells of the immune system. On the other hand, lymphokines such as gamma-interferon and interleukin-2 as well as thymic hormones can modulate the synthesis of melatonin in the pineal gland. The pineal gland might thus be viewed as the crux of a sophisticated immunoneuroendocrine network which functions as an unconscious, diffuse sensory organ.

The pineal neurohormone melatonin stimulates activated CD4+, Thy-1+ cells to release opioid agonist(s) with immunoenhancing and anti-stress properties.
Maestroni GJ, Conti A
Laboratory for Experimental Pathology, Istituto Cantonale di Patologia, Locarno, Switzerland.
J Neuroimmunol 1990 Jul;28(2):167-76

In previous studies we showed that in mice the pineal gland modulates the immune response via the circadian synthesis and release of melatonin. Exogenous melatonin proved also to exert immunoenhancing effects and to counteract completely the immunologic effect of acute stress. Melatonin was active only in vivo, in mice primed with T-dependent antigens and its effects on the primary antibody response and thymus weight were abolished by the specific opioid antagonist naltrexone. Here we demonstrate that physiologic concentrations of melatonin stimulate, in vitro, activated L3T4+ (CD4+) cells to release opioid agonist(s) that can reproduce in vivo the immunoenhancing and anti-stress effects on thymus cellularity and antibody production of melatonin and compete with specific binding of [3H]naloxone to mouse brain membranes. Similar results were obtained when mitogen-activated human immunocompetent cells were incubated with melatonin. In the human model the results were, however, less consistent than those obtained with murine cells, in that only four out of ten blood donors provided cells that were responsive to melatonin. This finding elucidates the mechanism of a novel immuno-neuroendocrine connection with relevant implications for our understanding of the neuroendocrine factors that may influence the immune response in vivo in normal and stressful situations. In addition, it opens new perspectives in a wide range of research fields.

Endocrine and immune effects of melatonin therapy in metastatic cancer patients.
Lissoni P, Barni S, Crispino S, Tancini G, Fraschini F
Divisione di Radioterapia Oncologica, Ospedale San Gerardo, Milano, Italy.
Eur J Cancer Clin Oncol 1989 May;25(5):789-95

Melatonin, the most important indole hormone produced by the pineal gland, appears to inhibit tumor growth; moreover, altered melatonin secretion has been reported in cancer patients. Despite these data, the possible use of melatonin in human neoplasms remains to be established. The aim of this clinical trial was to evaluate the therapeutic, immunological and endocrine effects of melatonin in patients with metastatic solid tumor, who did not respond to standard therapies. The study was carried out on 14 cancer patients (colon, six; lung, three; pancreas, two; liver, two; stomach, one). Melatonin was given intramuscularly at a daily dose of 20 mg at 3.00 p.m., followed by a maintenance period in an oral dose of 10 mg daily in patients who had a remission, stable disease or an improvement in PS. Before and after the first 2 months of therapy, GH, somatomedin-C, beta-endorphin, melatonin blood levels and lymphocyte subpopulations were evaluated. A partial response was achieved in one case with cancer of the pancreas, with a duration of 18+ months; moreover, six patients had stable disease, while the other eight progressed. An evident improvement in PS was obtained in 8/14 patients. In patients who did not progress, T4/T8 mean ratio was significantly higher after than before melatonin therapy, while it decreased in patients who progressed. On the contrary, hormonal levels were not affected by melatonin administration. This study would suggest that melatonin may be of value in untreatable metastatic cancer patients, particularly in improving their PS and quality of life; moreover, based on its effects on the immune system, melatonin could be tested in association with other antitumor treatments.

Dehydroepiandrosterone (DHEA) treatment reverses the impaired immune response of old mice to influenza vaccination and protects from influenza infection.
Danenberg HD; Ben-Yehuda A; Zakay-Rones Z; Friedman G
Vaccine (England) 1995, 13 (15) p1445-8

Dehydroepiandrosterone (DHEA) is a native steroid with an immunomodulating activity. Recently it was suggested that its age-associated decline is related with immunosenescence. To examine whether DHEA administration could effectively reverse the age-associated decline of immunity against influenza vaccine, aged mice were simultaneously vaccinated and treated with DHEA. Reversal of the age-associated decline and a significant constant increase of humoral response was observed in treated mice. Increased resistance to post-vaccination intranasal challenge with live influenza virus was observed in DHEA-treated aged mice. Thus, DHEA treatment overcame the age-related defect in the immunity of old mice against influenza.

Dehydroepiandrosterone modulationof lipopolysaccharide-stimulated monocyte cytotoxicity.
McLachlan JA, Serkin CD, Bakouche O
Department of Molecular Pharmacology and Biologic Chemistry, Northwestern University Medical School, Chicago, IL 60611, USA.
J Immunol 1996 Jan 1;156(1):328-35

Dehydroepiandrosterone (DHEA), the predominant androgen secreted by the adrenal cortex, can be converted to both potent androgens and estrogens. In addition to its role as a precursor for other steroid hormones, DHEA has been proposed to play an important role in immunity. This study has investigated DHEA modulation of LPS-induced monocyte cytotoxicity. Cytotoxicity markers assessed include tumor cell killing, IL-1 secretion, reactive oxygen intermediate release, nitric oxide synthetase activity as measured by the release of reactive nitrogen intermediates, complement receptor-1 cell surface protein, and TNF-alpha protein presence. Monocytes stimulated with LPS concentrations of 1.0 micrograms/ml displayed the above cytotoxic markers, whereas monocytes stimulated with DHEA alone or with LPS at a lower concentration of 0.2 ng/ml did not. However, when used simultaneously, DHEA and LPS 0.2 ng/ml displayed a synergistic effect on monocyte cytotoxicity protein, and TNF-alpha cancerous cell lines, IL-1 secretion, reactive nitrogen intermediate release, complement receptor-1 cell-surface protein, and TNF-alpha protein to levels comparable with levels obtained using LPS 1.0 microgram/ml. Finally, Scatchard plot analysis demonstrated the presence of a DHEA receptor in monocytes, suggesting that DHEA effects on LPS-stimulated monocytes are mediated through a receptor-dependent process.

Administration of dehydroepiandrosterone reverses the immune suppression induced by high dose antigen in mice.
Kim HR, Ryu SY, Kim HS, Choi BM, Lee EJ, Kim HM, Chung HT
Department of Microbiology/Immunology, School of Medicine, College of Oriental Medicine, Wonkwang University, Iri, Chonbuk, Korea.
Immunol Invest 1995 May;24(4):583-93

Several factors including antigen concentration, the route of antigen administration, hormones and cytokines have shown to affect T cells to produce the distinct patterns of lymphokines which exert regulatory and effector functions of immune response. In this study, we asked whether administration of dehydroepiandrosterone (DHEA) to mice which were tolerized by high dose of antigen could modulate T cell functions to restore the suppressed cellular immune response and to produce the distinct lymphokines. An intravenous injection of high dose of sheep red blood cells induced suppression of delayed type hypersensitivity (DTH) and a single subcutaneous injection of the tolerant mice with DHEA restored the suppressed DTH response. Furthermore, in vitro treatment of spleen cells from tolerant mice with DHEA abolished the transfer of tolerance to naive recipients. Lymphocytes from the DHEA-treated tolerant mice produced more IFN-gamma and less IL-4 and IL-6 than the cells from tolerant animals without DHEA treatment. These findings indicate that DHEA could recover antigen-specific immune suppression by differentially affecting T cells to produce the distinct lymphokines.

Pregnenolone and dehydroepiandrosterone as precursors of native 7-hydroxylated metabolites which increase the immune response in mice.
Morfin R, Courchay G
Bio-industries, Laboratoire de Biologie, Conservatoire National des Arts et Metiers, Paris, France.
J Steroid Biochem Mol Biol 1994 Jul;50(1-2):91-100

Dehydroepiandrosterone (DHEA) and pregnenolone (PREG) were both metabolized by homogenates of brain, spleen, thymus, perianal skin, ventral skin, intestine, colon, coecum and muscle tissues from mice. The use of 2H-labeled substrates and of the twin ion technique of gas chromatography-mass spectrometry permitted identification of 7 alpha-hydroxy-DHEA and of 5-androstene-3 beta, 17 beta-diol as DHEA metabolites in digests of all tissues. The extent of PREG metabolism was much lower than for DHEA with all tissues but amounts of the main transformation product were sufficient in brain, spleen and ventral skin digests for identification with 7 alpha-hydroxy-PREG. Dimethylsulfoxide (DMSO) solutions of DHEA, PREG and of their 7-hydroxylated metabolites were injected at different doses and time intervals prior to proximal subcutaneous administration of a lysozyme antigen. Quantities of anti-lysozyme IgG were measured in the serum of treated mice and compared with that from sham-treated animals. Increase of anti-lysozyme IgG was obtained with DHEA and PREG (1 g/kg) when injected 2 h prior to lysozyme. Much lower doses (160 times less) of 7 alpha-hydroxy-DHEA and -PREG were also found to be significantly active when administered at the moment of lysozyme injection. A larger dose of 7 beta-hydroxy-DHEA (50 mg/kg) was necessary for a similar effect. These results suggest that in tissues where immune response takes place, the locally-produced 7-hydroxy metabolites of PREG and DHEA are involved in a process which may participate in the physiological regulation of the body's immune response.

The relationship of serum DHEA-S and cortisol levels to measures of immune function in human immunodeficiency virus-related illness.
Wisniewski TL, Hilton CW, Morse EV, Svec F
Department of Medicine, Louisiana State University Medical Center, New Orleans.
Am J Med Sci 1993 Feb;305(2):79-83

Human immunodeficiency virus (HIV) is a major cause of immunoincompetence. Whether the virus, itself, accounts for all the deficiency remains in question. Steroids can also influence immune function; glucocorticoids cause immunoincompetence while dehydroepiandrosterone (DHEA) enhances immune function. Changes in the levels of such hormones during the course of HIV illness might result in significant changes in immune competence. The purpose of this study is to investigate whether dehydroepiandrosterone-sulphate (DHEA-S) or cortisol levels correlate with absolute CD4 lymphocyte levels. Plasma for cortisol and DHEA-S was drawn from 98 adults with HIV. Of these, 67 had simultaneous CD4 levels. Cortisol levels were 12.4 +/- 4.6 micrograms/dl, DHEA-S 262 +/- 142 micrograms/dl, and CD4 levels were 308 +/- 217/mm3 (mean +/- SD). Correlational analysis revealed a significant relationship between DHEA-S and CD4 levels (r = 0.30; p = 0.01) but not between CD4 levels and cortisol (r = 0.11; p = 0.36) or cortisol/DHEA-S ratios (r = 0.17; p = 0.16). When analyzed by clinical subgroups, significant differences were also found with a decrease in DHEA-S levels seen in persons with more advanced illness. The data exhibit a positive relationship between the immune status of patients with HIV-related illness and DHEA, leading to the hypothesis that DHEA deficiency may worsen immune status.

Dehydroepiandrosterone enhances IL2 production and cytotoxic effector function of human T cells.
Suzuki T, Suzuki N, Daynes RA, Engleman EG
Department of Pathology, Stanford University School of Medicine, California 94305.
Clin Immunol Immunopathol 1991 Nov;61(2 Pt 1):202-11

Dehydroepiandrosterone (DHEA) is the most abundant adrenal steroid hormone in humans. Although it is well established that DHEA serves as an intermediate in sex steroid synthesis, recent studies in mice suggest that DHEA may also be a physiologic regulator of IL2 secretion. To explore the effect of DHEA on the human immune system, T lymphocytes from healthy adults were exposed to DHEA followed by stimulation with mitogens or antigen. Upon activation with a variety of stimuli, T cells pretreated with 10(-8) to 10(-11) M DHEA produced significantly greater amounts of IL2 and mediated more potent cytotoxicity than T cells activated in the absence of this steroid hormone. The peak effect of DHEA was observed at 10(-9) M, the concentration of hormone present in the blood of normal adults. In contrast to its effect on murine T cells, the IL2 enhancing effect of DHEA on human lymphocytes was limited to fresh CD4+ T cells and CD4+ clones; neither fresh CD8+ cells nor CD8+ clones were directly affected by DHEA treatment, although CD8+ cells stimulated in the presence of CD4+ cells and DHEA demonstrated enhanced cytotoxicity. The enhancing effect of DHEA was also detected at the level of IL2 mRNA, suggesting that DHEA may act as a transcriptional enhancer of the IL2 gene in CD4+ T cells. These results corroborate and extend earlier studies in mice and suggest a physiologic role for DHEA in regulating the human immune response.

Protection from glucocorticoid induced thymic involution by dehydroepiandrosterone.
May M, Holmes E, Rogers W, Poth M
Walter Reed Army Medical Center, Washington, D.C. 20307-5001.
Life Sci 1990;46(22):1627-31

Dehydroepiandrosterone (DHEA), the most abundantly secreted human adrenal steroid, has no known specific function. In spite of this fact there is an abundance of data associating DHEA with "health" in both man and experimental animals. Research in our laboratory has demonstrated evidence for an antagonistic interaction between DHEA and glucocorticoids (GC) in liver and brown adipose tissue. We hypothesized that DHEA also antagonized effects of GC on the immune system and that this "immune protective effect" might explain the diffuse positive effects of DHEA reported in the literature. Effects of GC on the immune system include involution of the thymus when given in animals in vivo and death of thymic lymphocytes in vivo with exposure to these steroids. We hypothesized that DHEA would block this GC mediated thymocyte destruction in vivo and in vitro. Pretreatment with DHEA for three days blocked approximately 50% of the thymic involution seen with dexamethasone. Results of in vitro experiments confirmed protective effects of DHEA in pretreated animals. (less than 50% of cell death in lymphocytes from pretreated mice compared with lymphocytes from control mice.) We conclude from these studies that DHEA protects against at least one GC anti-immune effect, thymic lymphocyte lysis.

Immune development in young-adult C.RF-hyt mice is affected by congenital and maternal hypothyroidism.
Erf GF
Department of Biological Sciences, Smith College, Northampton, Massachusetts 01063.
Proc Soc Exp Biol Med 1993 Oct;204(1):40-8

C.RF-hyt mice carry a mutation (hyt) that results in the phenotypic expression of congenital hypothyroidism in hyt/hyt mice due to a nonresponsiveness of the thyroid gland to thyroid-stimulating hormone. Heterozygotes of this strain are euthyroid. To further define thyroid-immune interactions, the effect of congenital hypothyroidism and maternal hypothyroidism on immune development were examined in 3- to 4-month-old hyt/+ and hyt/hyt progeny from hyt/+ and hyt/hyt dams. The state of immune development in these mice was compared on the basis of immune organ weights and the proliferation response of splenocytes stimulated with the T cell mitogens concanavalin A (Con A) and phytohemagglutinin and the B cell mitogen lipopolysaccharide. In addition, analysis of T cell subpopulations in thymus and spleen was conducted using direct and indirect immunofluorescence and flow cytometry. Data analyses for the main effects of congenital hypothyroidism on immune development revealed a significantly lower absolute thymus weight (P < 0.001), a lower (P = 0.022) percentage of thymocytes expressing CD8 (CD8+), a higher (P = 0.010) ratio between CD4+ and CD8+ thymocytes, a lower (P < 0.001) absolute and adjusted spleen weight, a lower (P = 0.001) Con A to phytohemagglutinin response ratio, a higher (P = 0.003) percentage of CD4+ splenocytes, and a marginally significant (P = 0.055) increase in the ratio between CD4+ and CD8+ splenocytes in hypothyroid compared with euthyroid mice. Data analyses for the main effects of maternal hypothyroidism revealed a significantly higher absolute (P = 0.025) and adjusted (P = 0.001) thymus weight, a higher (P = 0.006) ratio between CD4+ and CD8+ thymocytes, a lower Con A (P = 0.018) and lipopolysaccharides (P < 0.001) response, a marginally (P = 0.069) lower Con A to phytohemagglutinin response ratio, a lower (P = 0.001) percentage of CD4+ splenocytes, and a lower (P = 0.003) ratio between CD4+ and CD8+ splenocytes in progeny of hypothyroid compared with progeny of euthyroid mothers. These data provide further evidence for the importance of normal thyroid function in the development, maintenance, and function of the immune system. It was concluded that not only congenital hypothyroidism results in altered immune development in young-adult mice, but also long-term effects on immune development occur in progeny of hypothyroid mothers.

Binding and functional effects of thyroid stimulating hormone on human immune cells.
Coutelier JP, Kehrl JH, Bellur SS, Kohn LD, Notkins AL, Prabhakar BS
Laboratory of Oral Medicine, National Institute of Dental Research, National Institutes of Health, Bethesda, Maryland 20892.
J Clin Immunol 1990 Jul;10(4):204-10

The expression and functional relevance of thyroid stimulating hormone (TSH) receptors on human immune cells were studied. Flow cytometric analysis was used to study the binding of biotinylated TSH to human peripheral blood mononuclear cells (PBMC) and various purified lymphoid populations. Our results indicate that the hormone binds well to monocytes and natural killer (NK) cells and marginally to purified tonsillar T and B lymphocytes. There was a significant increase in the binding of TSH to purified B cells that were activated in vitro with Staphylococcus aureaus Cowan. In contrast, the binding of TSH to T cells was unaltered when they were stimulated with phytohemagglutinin (PHA). While TSH increases DNA synthesis and intracellular cAMP levels of FRTL-5 rat thyroid cells, it did not have such stimulatory effects on lymphocytes. However, there was a moderate increase in Ig production by activated B lymphocytes when they were cultured in the presence of the hormone. A possible function for TSH as a link between the immune system and the thyroid is discussed.

Immunorestoration in children with recurrent respiratory infections treated with isoprinosine.
Wiedermann D, Wiedermannova D, Lokaj J
Department of Pathological Physiology, Medical Faculty, J.E. Purkyne University, Brno, Czechoslovakia.
Int J Immunopharmacol 1987;9(8):947-9

In 27 children, 4-8 years old, with recurrent respiratory infections of the upper and lower respiratory tracts Isoprinosine (ISO) tablets were administered for 7-10 days at daily doses of 50-100 mg/kg. Clinical signs of acute respiratory disease, including temperature abnormalities and subjective complaints, subsided in a short time and the children showed no symptoms for periods ranging from several weeks to several months following the therapy. The children were selected for immunotherapy with ISO on the basis of their low levels of E-rosette forming cells in peripheral blood. Several immune function parameters assessed immediately after treatment with ISO and compared with those obtained before illness and ISO administration. Low levels of T-lymphocytes returned to normal after ISO therapy, B-lymphocyte relative and absolute numbers, however, were not affected by the treatment. Nor were any changes due to ISO found in immunoglobulins, complement components, beta 2-microglobulin and C-reactive protein. Moreover, ISO had no stimulative effect on spontaneous tetrazolium reductase activity of granulocytes but it showed a slight inhibition of their phagocytosis-associated metabolic activity.

Isoprinosine abolishes the blocking factor-mediated inhibition of lymphocyte responses to Epstein-Barr virus antigens and phytohemagglutinin.
Sundar SK; Menezes J
Int J Immunopharmacol 1986;8(1):101-6

Acute infectious mononucleosis (IM) is accompanied by measurable abnormalities of immune function, including a transient immunosuppression. The sera of patients with acute IM contain an IgG blocking factor which binds to T-lymphocytes and decreases their responses to antigens and mitogens. The experiments reported herein indicate that isoprinosine, an immunopotentiating agent, can reverse this inhibition of T cells by IM-associated IgG blocking factor. Isoprinosine may be a useful tool in understanding the interactions between blocking factors and lymphocytes; moreover, isoprinosine may be of value in patients with abnormal clinical responses to Epstein-Barr virus (EBV) such as chronic IM or persistent active EBV infections.

Isoprinosine as an immunopotentiator in an animal model of human osteosarcoma.
Tsang KY; Fudenberg HH
Int J Immunopharmacol 1981;3(4):383-9

The effects of isoprinosine (ISO) on the immune responses (Con A-induced lymphocyte proliferation, monocyte chemotactic responsiveness, and "natural killer" cytotoxicity) of normal hamsters and hamsters with human osteosarcoma (OS) were investigated. Human osteosarcoma was induced in newborn inbred hamsters (LHX/SsLAK) after induction of tolerance in utero. In vitro, ISO increased Con A-induced proliferation of peripheral blood lymphocytes (PBL) from normal hamsters by 23.4-48.9% and from OS-bearing hamsters by 58.1-107.4% over controls (Con A alone). When ISO was administered in vivo by intraperitoneal injection. Con A-induced proliferation of PBL from both normal and OS-bearing recipients in vitro was increased by 50-55% at 1, 3 and 5 days after injection. The chemotactic responsiveness of monocytes from OS-bearing hamsters was also significantly increased (59.1-97.4%) at 1, 3 and 5 days after injection of ISO. Natural killer cytotoxicity was augmented at 1, 3 and 5 days after injection of ISO by 31.7-83.6% in normal hamsters and 54.6-184% in OS-bearing hamsters. These results indicate that ISO can produce a generalized enhancement of immune function in hamsters with OS.

The effect of Biostim (RU-41740) onthe expression of cytokine mRNAs in murine peritoneal macrophages in vitro.
Meredith C, Scott MP, Pekelharing H, Miller K
Immunotoxicology Department, British Industrial Biological Research Association, Carshalton, Surrey, U.K.
Toxicol Lett 1990 Oct;53(3):327-37

The immunomodulatory agent Biostim (RU-41740) was investigated for its ability to induce the expression of cytokine mRNAs in murine peritoneal macrophages in vitro. Northern blot analysis showed that in quiescent macrophage populations, both IL-1 alpha and IL-1 beta mRNA levels were dramatically increased in response to 1 microgram/ml Biostim. Dot-blot analysis showed that in quiescent macrophage populations the expression of mRNAs for IL-1 alpha, IL-1 beta, IL-6 and TNF-alpha could be elevated by concentrations of Biostim as low as 1-10 pg/ml, detectable after 3 h exposure. In parallel experiments LPS was effective only at the higher concentration of 10 ng/ml. Time-course analysis showed that the expression of these cytokine mRNAs was transient, peaking after 1-3 h; only transcripts of IL-1 beta were detectable after 23 h exposure. No effects were seen on the expression of actin, a high-turnover housekeeping gene. We propose that this type of analysis represents a sensitive, specific and reproducible method for assessing the ability of drugs and chemicals to modulate the expression of cytokines that play a pivotal role in the induction of the immune response.

Isoprinosine (inosine pranobex BAN, INPX) in the treatment of AIDS and other acquired immunodeficiencies of clinical importance.
Glasky AJ; Gordon JF
Cancer Detect Prev Suppl 1987;1:597-609

The immunopharmacologic effects of Isoprinosine (INPX) have been associated with clinical benefit to the patient in a number of conditions characterized by immunodeficiency of diverse etiology. Immunodepressed homosexuals at risk of developing acquired immunodeficiency syndrome (AIDS) treated with placebo or INPX experienced an increase in the function and number of immunocompetent cells associated with clinical improvement. A multicenter trial designed to confirm these results has demonstrated that INPX produced an increase in natural killer (NK)-cell activity, total T cells, and T-helper cells, with certain effects persisting for months after completion of the 28-day treatment period. INPX-treated patients also experienced clinical improvement and decreased incidence of progression to AIDS. The administration of INPX for longer periods to patients with frank AIDS under a compassionate-use protocol has also proved useful. Clinical benefit associated with INPX treatment has been demonstrated in other patients with a depressed immune response, such as aged patients, cancer patients, severely burned patients, ill patients, and surgery patients. This program of clinical trials supports the therapeutic use of INPX in the treatment of AIDS and other acquired immunodeficiencies of clinical importance.

Immunological effests of Isoprinosine as a pulse immunotherapy in melanoma and ARC patients in melanoma and ARC patients
Pompidou A; Soubrane C; Cour V; Telvi L; Meunier C; Jacquillat C
Cancer Detect Prev Suppl; 1:457-62 1987

Immunomodulatory effect of Isoprinosine are presented in melanoma and HTLV-III/LAV infected patients. Isoprinosine (50 mg/kg) was used as a pulse immunotherapy according to two different schedules: A) 5 days every 15 days and B) 5 days every 15 days for 2 months, then 5 days every 2 months. The patients' immunological profiles were tested before and during the treatment in terms of T-cell subsets, cell number requirement for PHA-induced proliferation, and delayed hypersensitivity reaction to recall antigens. Primary malignant melanoma patients are randomized between surgery alone or associated to isotherapy (schedule A or B). Schedule A,after an initial improvement of surgery-induced immune deficiency, is responsible for an immunodepression, whereas schedule B determines a prolonged restoration in immune responses in melanoma and AIDS related complex or Kaposi sarcoma patients as well. In vitro effects of Isoprinosine on HTLV-III/LAV infection are presented. These data exhibit 1) the need of an immunological follow-up during isotherapy and 2) the immunological benefit of a pulse immunotherapy during acquired immunodeficiencies related to cancer surgery or to HTLV-III/LAV infection in man.

A modified determination of coenzyme Q10 in human blood and CoQ10 blood levels in diverse patients with allergies.
Ye CQ, Folkers K, Tamagawa H, Pfeiffer C
Institute for Biomedical Research, University of Texas, Austin.
Biofactors 1988 Dec;1(4):303-6

Two situations required a modified determination of coenzyme Q10 (CoQ10) in human blood and organ tissue. Blood from patients with AIDS and cancer raised apprehensions about safety to an analyst, and the number of specimens for analysis is increasing enormously. A modified determination replaces silica gel-TLC with disposable Florisil columns, and steps were simplified to allow more analyses per unit time. Data from the modified determination are quantitatively compatible with data from older and tedious procedures. This determination was used for blood from 36 diverse patients with allergies. The mean CoQ10 blood level of these patients is not different from the mean level of so-called normal individuals, but approximately 40% (14/36) of these allergic patients had levels up to 0.65 micrograms/ml, which is the level of dying class IV cardiac patients. The biosynthesis of CoQ10 in human tissues is a complex process that requires several vitamins and micronutrients, so that countless vitamin-unsupplemented Americans may be deficient in CoQ10. The relationship of allergies to autoimmune mechanisms and immunity, and the established relationship of CoQ10 to immune states, may be a rationale for therapeutic trials of administering CoQ10 to patients with allergies who have low CoQ10 blood levels and are very likely deficient.

Carnitine in human immunodeficiency virus type 1 infection/acquired immune deficiency syndrome.
Mintz M
University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School at Camden 08103, USA.
J Child Neurol 1995 Nov;10 Suppl 2:S40-4

There is an increasing body of evidence that subgroups of patients infected with human immunodeficiency virus type 1 possess carnitine deficiency. Secondary carnitine deficiencies in these individuals may result from nutritional deficiencies, gastrointestinal disturbances, renal losses, or shifts in metabolic pathways. However, tissue depletion precipitated by drug toxicities, particularly zidovudine, is a major etiology and concern. Carnitine deficiency may impact on energy and lipid metabolism, causing mitochondrial and immune dysfunction. There are convincing laboratory data showing the in vitro ameliorative effects of L-carnitine supplementation of zidovudine-induced myopathies and lymphocyte function. Studies measuring the impact of L-carnitine supplementation on clinical characteristics are ongoing.

Oxidative damage and mitochondrial decay in aging.
Shigenaga MK, Hagen TM, Ames BN
Division of Biochemistry and Molecular Biology, University of California, Berkeley 94720
Proc Natl Acad Sci U S A 1994 Nov 8;91(23):10771-8

We argue for the critical role of oxidative damage in causing the mitochondrial dysfunction of aging. Oxidants generated by mitochondria appear to be the major source of the oxidative lesions that accumulate with age. Several mitochondrial functions decline with age. The contributing factors include the intrinsic rate of proton leakage across the inner mitochondrial membrane (a correlate of oxidant formation), decreased membrane fluidity, and decreased levels and function of cardiolipin, which supports the function of many of the proteins of the inner mitochondrial membrane. Acetyl-L-carnitine, a high-energy mitochondrial substrate, appears to reverse many age-associated deficits in cellular function, in part by increasing cellular ATP production. Such evidence supports the suggestion that age-associated accumulation of mitochondrial deficits due to oxidative damage is likely to be a major contributor to cellular, tissue, and organismal aging.

Carnitine depletion in peripheral blood mononuclear cells from patients with AIDS: effect of oral L-carnitine.
De Simone C; Famularo G; Tzantzoglou S; Trinchieri V; Moretti S; Sorice F
AIDS (United States) May 1994, 8 (5) p655-60

OBJECTIVE: Reduced levels of serum carnitines (3-hydroxy-4-N-trimethyl-am monio-butanoate) are found in most patients treated with zidovudine. However, since serum carnitines do not strictly reflect cellular concentrations we examined whether a carnitine depletion could be found in peripheral blood mononuclear cells (PBMC) from AIDS patients with normal serum carnitine levels. In addition, we explored whether it was possible to relate the host's immunoreactivity to the content of carnitine in PBMC and whether carnitine levels can be corrected by oral supplementation of L-carnitine.

DESIGN: Immunopharmacologic study.

METHODS: Twenty male patients with advanced AIDS (Centers for Disease Control and Prevention stage IVCI) and normal serum levels of carnitines were enrolled. Patients were randomly assigned to receive either L-carnitine (6 g/day) or placebo for 2 weeks. At baseline and at the end of the trial, we measured carnitines in both sera and PBMC, serum triglycerides, CD4 cell counts, and the frequency of cells entering the S and G2-M phases of cell cycle following mitogen stimulation.

RESULTS: Concentrations of total carnitine in PBMC from AIDS patients was lower than in healthy controls. A significant trend towards the restoration of appropriate intracellular carnitine levels was found in patients treated with high-dose L-carnitine and was associated with an increased frequency of S and G2-M cells following mitogen stimulation. Furthermore, at the end of the trial we found a strong reduction in serum triglycerides in the L-carnitine group compared with baseline levels.

CONCLUSIONS: Our data indicate that carnitine deficiency occurs in PBMC from patients with advanced AIDS, despite normal serum concentrations. The increase in cellular carnitine content strongly improved lymphocyte proliferative responsiveness to mitogens. Because carnitine status is an important contributing factor to immune function in patients with advanced AIDS, we therefore believe that L-carnitine supplementation could have a role as a complementary therapy for HIV-infected individuals.

Immunological parameters in aging: studies on natural immunomodulatory and immunoprotective substances.
Franceschi C, Cossarizza A, Troiano L, Salati R, Monti D
Institute of General Pathology, University of Modena, Italy.
Int J Clin Pharmacol Res 1990;10(1-2):53-7

Several immune parameters--particularly T-cell dependent immune responses--are altered in aged subjects. To test the hypothesis that they may be the consequence of more general age-related lymphocyte biochemical alterations, and particularly of the energy producing system, the effect of L-carnitine and acetyl-L-carnitine on cell proliferation was studied in peripheral blood lymphocytes from donors of different ages. The results showed that phytohaemagglutinin-induced peripheral blood lymphocyte proliferation was markedly increased in L-carnitine- or acetyl-L-carnitine-preloaded lymphocytes from young and especially from old subjects. Cells from aged subjects considerably improved their defective proliferative capability. Preliminary observations suggest that L-carnitine-preloading also protected peripheral blood lymphocytes from old donors when such cells were exposed to an oxidative stress.

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