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Modulation of cytokine production by
dehydroepiandrosterone (DHEA) plus melatonin (MLT)
supplementation of old mice.
Inserra P, Zhang Z, Ardestani SK, Araghi-Niknam M, Liang
B, Jiang S, Shaw D, Molitor M, Elliott K, Watson RR.
Arizona Prevention Center, University of Arizona, Tucson
87524, USA.
Proc Soc Exp Biol Med 1998 May;218(1):76-82
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-gamma 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.
Preventive nutrition:
disease-specific dietary interventions for older
adults.
Johnson K; Kligman EW Dept. of Family and Community
Medicine, University of Arizona College of Medicine,
Tucson.
Geriatrics Nov 1992, 47 (11) p39-40, 45-9
Disease prevention through dietary management is a
cost-effective approach to promoting healthy aging. Fats,
cholesterol, soluble fiber, and the trace elements copper
and chromium affect the morbidity and mortality of CHD.
Decreasing sodium and increasing potassium intake improves
control of hypertension. Calcium and magnesium may also
have a role in controlling hypertension. The antioxidant
vitamins A and beta-carotene, vitamin C, vitamin E, and the
trace mineral selenium may protect against types of cancer.
A decrease in simple carbohydrates and an increase in
soluble dietary fiber may normalize moderately elevated
blood glucose levels. Deficiencies of zinc or iron diminish
immune function . Adequate levels of calcium and vitamin D
can help prevent senile osteoporosis in both older men and
women. (27 Refs.)
Inhibition of
intracellular cathepsin activities and suppression of
immune responses mediated by helper T lymphocyte type-2 by
peroral or intraperitoneal administration of vitamin
B6.
Katunuma N, Matsui A, Endo K, Hanba J, Sato A, Nakano M,
Yuto Y, Tada Y, Asao T, Himeno K, Maekawa Y, Inubushi T.
Tokushima Bunri University, Institute for Health Sciences,
Japan.
Biochem Biophys Res Commun 2000 May 27;272(1):151-5
We reported that pyridoxal phosphate (PAP), a coenzyme
form of vitamin B6, strongly inhibits activities of
cathepsin B and weakly inhibits those of cathepsins S, K,
and C in vitro. Either intraperitoneal injection or peroral
administration of medication doses of vitamin B6 in the
diet caused dose-dependent inhibition of hepatic cathepsins
B, L, S, and C, and the inhibition was exhibited much more
significantly in the case of a high protein diet than in a
low protein diet. Administration of vitamin B6 induced the
suppression of immune responses against ovalbumin (OVA)
mediated by helper T lymphocyte type-2, based on the
suppression of antigen processing by cathepsin B
inhibition, as in the case of CA-074 administration, a
cathepsin B specific inhibitor. Ovalbumin-dependent
production of immunoglobulins IgE, IgG1 and interleukin
IL-4 was suppressed by administration of medication doses
of pyridoxal (PA) or pyridoxine (PI), while the production
of IgG2alpha and interferon (INF)-gamma mediated by helper
T lymphocyte type 1 was not changed. Administration of
medication doses of vitamin B6 caused the inhibition of
intracellular cathepsin B activity due to suppression of
the functions of helper T lymphocyte type-2.
Activation of immune
function by dehydroepiandrosterone (DHEA) in age-advanced
men.
Khorram O, Vu L, Yen SS. Department of Reproductive
Medicine, University of California, San Diego School of
Medicine, USA.
J Gerontol A Biol Sci Med Sci 1997 Jan;52(1):M1-7
BACKGROUND: Substantial data from animal studies have
demonstrated a stimulatory effect of dehydroepiandrosterone
(DHEA) on immune function. However, little is known about
the effects of DHEA on the human immune system. Since aging
is associated with a decline in immune function and in DHEA
production, we proposed that oral administration of DHEA to
elderly men would result in activation of their immune
system.
METHODS: Nine healthy age-advanced men (mean age of 63
years) with low DHEA-sulfate levels participated in this
study. They were treated nightly with an oral placebo for 2
weeks followed by DHEA (50 mg) for 20 weeks. Fasting
(0800h-0900h) blood samples were obtained at 4- to 8-week
intervals for immune function studies and hormone
determinations. Freshly isolated peripheral lymphocytes
were used for flow cytometric identification of lymphocyte
subsets, cells expressing the IL-2 receptor (IL-2R),
mitogen stimulation studies, and for determining natural
killer (NK) cell number and cytotoxicity. Levels of
interleukin-2 (IL-2) and IL-6 secreted from cultured
lymphocytes were determined under basal and mitogen
stimulated conditions. Sera were analyzed for soluble IL-2
Receptor (sIL-2R) levels, insulin-like growth factor-I
(IGF-I) and IGF binding protein-I (IGFBP-I)
concentrations.
RESULTS: Baseline levels of serum DHEA sulfate (DHEAS),
a stable marker of circulating DHEA levels, were 2 standard
deviations below young adult values and increased 3-4 fold
within 2 weeks. These levels were sustained throughout the
duration of DHEA administration. When compared with
placebo, DHEA administration resulted in a 20% increase (p
< .01) in serum IGF-I, a decreasing trend in
IGFBP-I, and a 32% increase in the ratio of IGF-I/IGFBP-I
(p < .01). Activation of immune function occurred
within 2-20 weeks of DHEA treatment. The number of
monocytes increased significantly (p < .01) after 2
(45%) and 20 (35%) weeks of treatment. The population of B
cells fluctuated with increases (p < .05) at 2 (35%)
and 10 (29%) weeks of treatment. B cell mitogenic response
increased 62% (p < .05) by 12 weeks unaccompanied by
changes in serum IgG, IgA, and IgM levels. Total T cells
and T cell subsets were unaltered. However, a 40% increase
(p < .05) in T cell mitogenic response, 39% increase
in cells expressing the IL-2R (CD25+) (p < .05), and
20% increase in serum sIL-2R levels (p < .01) were
found at 12-20 weeks of DHEA treatment, suggesting a
functional activation of T lymphocytes occurred. In vitro
mitogen stimulated release of IL-2 and IL-6 was enhanced
50% (p < .05) and 30% (p < .01) respectively
by 20 weeks of treatment without basal secretion being
affected. NK cell number showed a 22-37% increase (p
< .01) by 18-20 weeks of treatment with a
concomitant 45% increase (p < .01) in cytotoxicity.
There were no adverse effects noted with DHEA
administration.
CONCLUSION: Administration of oral DHEA at a daily dose
of 50 mg to age-advanced men with low serum DHEAS levels
significantly activated immune function. The mechanism(s)
to account for the immunoenhancing properties of DHEA are
unclear. Consideration is given to the potential role of an
increase in bioavailable IGF-I, which by virtue of its
mitogenic effects on immune cell function, may mediate the
DHEA effects. While extended studies are required, our
findings suggest potential therapeutic benefits of DHEA in
immunodeficient states.
Essential fatty acids,
immune function, and exercise.
Konig D; Berg A; Weinstock C; Keul J; Northoff H
Department of Rehabilitation, Prevention and Sports
Medicine, Freiburg University Hospital, Germany.
Exerc Immunol Rev 1997, 3 p1-31
The immunologic response to exercise comprises numerous
alterations within the immune system, but how these
processes are regulated is still largely unknown.
Exercise-related immunological changes include signs of
inflammation, such as release of inflammatory mediators,
activation of various white blood cell lines and
complement, and induction of acute phase proteins.
Nevertheless, signs of immunosuppression, such as decreased
T and B cell function or impaired cytotoxic or phagocytic
activity, can also be observed. Some data suggest that
essential fatty acids help regulate inflammatory processes,
modulating both cytokine release and the acute phase
response. Positive effects of changing dietary essential
fatty acids have been demonstrated in chronic inflammatory
diseases. In contrast, little is known about the
contribution of fatty acids to the exercise-induced
immunologic reaction. Essential fatty acids may determine
alterations within the immune system following exercise.
Therefore, future studies are necessary to evaluate the
influence of the fatty acid composition on the inflammatory
or immunosuppressive component following heavy exertion.
(236 Refs.)
Melatonin.
Kostogloy-Athanassiou, I.
Arch. Hellenic Med. 1998; 15(3): 281-306.
No abstract available.
[Administration of RU
41740, a preventive anti-infective immunomodulator in an
acute respiratory episode. Synthesis of 3 clinical
trials] [Article in French]
Lacaille F. Hopital Necker-Enfants malades, Paris.
Presse Med. 1988 Jul 27;17(28):1453-7.
In both adults and children RU 41740 exerts an
immunomodulating effect and prevents recurrent respiratory
infections. Patients with such infections frequently
consult for acute episodes, and it was deemed necessary to
evaluate the safety of the drug given concomitantly with
antibiotic in acute infections. Three double-blind, drug
versus placebo studies were conducted in fragile
institutionalized or hospitalized patients. Antibiotics
were administered simultaneously with RU 41740 in one group
and with a placebo in another group. The studies performed
by Albarede and Ollivier showed that in acute respiratory
infections RU 41740 was well tolerated and resulted in a
more rapid improvement of severity score. Grassi and al.
studied chronic bronchitis patients admitted for acute on
chronic episode. RU 41740 produced a more rapid improvement
in the most severely ill patients, and it was well
tolerated. It is concluded that RU 41740 can be initiated
safely in acute episodes occurring in subjects with
recurrent respiratory infections, and that it results in a
faster improvement of clinical symptoms.
Nutrition and immunity in
the elderly: modification of immune responses with
nutritional treatments.
Lesourd BM. Laboratoire d'Immunologie du vieillissement,
Faculte de Medecine Pitie-Salpetriere, Paris, France.
Am J Clin Nutr 1997 Aug;66(2):478S-484S
Nutrition has a strong influence on the immune system of
the elderly. Aging induces dysregulation of the immune
system, mainly as a result of changes in cell-mediated
immunity. Aging is associated with changes to the
equilibrium of peripheral T and B lymphocyte subsets, such
as decreases in the ratios of mature to immature, naive to
memory, T helper 1 subset (TH1) to TH2, and CD5- to CD5+
cells. As a consequence, cell-mediated immune responses are
weaker and neither cell-mediated nor humoral responses are
as well adapted to the antigen stimulus. Undernutrition,
common in aged populations, also induces lower immune
responses, particularly in cell-mediated immunity.
Protein-energy malnutrition is associated with decreased
lymphocyte proliferation, reduced cytokine release, and
lower antibody response to vaccines. Micronutrient
deficits, namely of zinc, selenium, and vitamin B-6, all of
which are prevalent in aged populations, have the same
influence on immune responses. Because aging and
malnutrition exert cumulative influences on immune
responses, many elderly people have poor cell-mediated
immune responses and are therefore at a high risk of
infection. Nutritional therapy may improve immune responses
of elderly patients with protein-energy malnutrition.
Supplementation with high pharmacologic doses of a single
nutrient (zinc or vitamin E) may be useful for improving
immune responses of self-sufficient elderly people living
at home. Therefore, nutritional deficiency must be treated
in the elderly to reduce infectious risk and possibly slow
the aging process.
Trace elements that act
as antioxidants in parenteral micronutrition
Leung F.Y. Dr. F.Y. Leung, University Campus, London
Health Sciences Centre, Department of Clinical
Biochemistry, 339 Windermere Road, London, Ont. N6A 5A5
Canada Journal of Nutritional Biochemistry, 1998, 9/6
(304-307)
The trace elements - copper, manganese, selenium, and
zinc - act as cofactors of antioxidant enzymes to protect
the body from oxygen free radicals (OFR) that are produced
during oxidative stress. It is necessary to maintain a
balance between the harmful pro-oxidant components produced
and the antioxidant compounds that counter these effects. A
delicate balance also exists for the redox trace elements
such as copper, which can initiate free radical reactions
but is also a cofactor of Cu/Zn-superoxide dismutase, a
free radical scavenging enzyme. Metal chelators such as
ceruloplasmin play an important function to contain the
reactive Cu ion. Similarly, transferrin and transferrin
receptor maintain homeostatic control of iron, allowing
little or no free iron to participate in formation of the
reactive hydroxyl radical. Selenium is found to be most
severely deficient in traumatized patients who need
adequate supplementation during parenteral micronutrition
to assist the free radical scavenging activity of
glutathione peroxidase and the immune system .
The efficacy of
echinacea compound herbal tea preparation on the severity
and duration of upper respiratory and flu symptoms: a
randomized, double-blind placebo-controlled
study.
Lindenmuth GF, Lindenmuth EB. Rest Haven-York, York
College of Pennsylvania, USA.
J Altern Complement Med. 2000 Aug;6(4):327-34.
OBJECTIVES: The aim of this study was to determine the
efficacy of an Echinacea compound herbal tea preparation
(Echinacea Plus) given at early onset of cold or flu
symptoms in a random assignment double-blind
placebo-controlled study. DESIGN AND SUBJECTS: A total of
95 subjects with early symptoms of cold or flu (runny nose,
scratchy throat, fever) were randomly assigned to receive
Echinacea Plus tea five to six cups per day titrating to 1
over 5 days or placebo in a double-blind situation. Each
participant completed a questionnaire 14 days after
beginning the program. The efficacy, number of days the
symptoms lasted, and number of days for change were
measured with a self scoring questionnaire. RESULTS: The
study period was 90 days (January 1, 1999 to March 30,
1999). There was a significant difference between the
experimental group (Echinacea Plus) and control group
(placebo) for all 3 questions measured: p < 0.001.
There were no negative effects reported by any of the
subjects in either group. CONCLUSIONS: Treatment with
Echinacea Plus tea at early onset of cold or flu symptoms
was effective for relieving these symptoms in a shorter
period of time than a placebo.
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.
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.
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.
Partial and complete
regression of breast cancer in patients in relation to
dosage of coenzyme Q10.
Lockwood K, Moesgaard S, Folkers K. Pharma Nord, Vejle,
Denmark.
Biochem Biophys Res Commun. 1994 Mar
30;199(3):1504-8.
Relationships of nutrition and vitamins to the genesis
and prevention of cancer are increasingly evident. In a
clinical protocol, 32 patients having -"high-risk"- breast
cancer were treated with antioxidants, fatty acids, and 90
mg. of CoQ10. Six of the 32 patients showed partial tumor
regression. In one of these 6 cases, the dosage of CoQ10
was increased to 390 mg. In one month, the tumor was no
longer palpable and in another month, mammography confirmed
the absence of tumor. Encouraged, another case having a
verified breast tumor, after non-radical surgery and with
verified residual tumor in the tumor bed was then treated
with 300 mg. CoQ10. After 3 months, the patient was in
excellent clinical condition and there was no residual
tumor tissue. The bioenergetic activity of CoQ10, expressed
as hematological or immunological activity, may be the
dominant but not the sole molecular mechanism causing the
regression of breast cancer.
Apparent partial
remission of breast cancer in 'high risk' patients
supplemented with nutritional antioxidants, essential fatty
acids and coenzyme Q10.
Lockwood K, Moesgaard S, Hanioka T, Folkers K. Private
Outpatient Clinic, Copenhagen, Denmark.
Mol Aspects Med. 1994;15 Suppl:s231-40.
Thirty-two typical patients with breast cancer, aged
32-81 years and classified 'high risk' because of tumor
spread to the lymph nodes in the axilla, were studied for
18 months following an Adjuvant Nutritional Intervention in
Cancer protocol (ANICA protocol). The nutritional protocol
was added to the surgical and therapeutic treatment of
breast cancer, as required by regulations in Denmark. The
added treatment was a combination of nutritional
antioxidants (Vitamin C: 2850 mg, Vitamin E: 2500 iu,
beta-carotene 32.5 iu, selenium 387 micrograms plus
secondary vitamins and minerals), essential fatty acids
(1.2 g gamma linolenic acid and 3.5 g n-3 fatty acids) and
Coenzyme Q10 (90 mg per day). The ANICA protocol is based
on the concept of testing the synergistic effect of those
categories of nutritional supplements, including vitamin
Q10, previously having shown deficiency and/or therapeutic
value as single elements in diverse forms of cancer, as
cancer may be synergistically related to diverse
biochemical dysfunctions and vitamin deficiencies.
Biochemical markers, clinical condition, tumor spread,
quality of life parameters and survival were followed
during the trial. Compliance was excellent. The main
observations were: (1) none of the patients died during the
study period. (the expected number was four.) (2) none of
the patients showed signs of further distant metastases.
(3) quality of life was improved (no weight loss, reduced
use of pain killers). (4) six patients showed apparent
partial remission.
Progress on therapy of
breast cancer with vitamin Q10 and the regression of
metastases.
Lockwood K, Moesgaard S, Yamamoto T, Folkers K. Pharma
Nord, Vejle, Denmark.
Biochem Biophys Res Commun. 1995 Jul 6;212(1):172-7.
Over 35 years, data and knowledge have internationally
evolved from biochemical, biomedical and clinical research
on vitamin Q10 (coenzyme Q10; CoQ10) and cancer, which led
in 1993 to overt complete regression of the tumors in two
cases of breast cancer. Continuing this research, three
additional breast cancer patients also underwent a
conventional protocol of therapy which included a daily
oral dosage of 390 mg of vitamin Q10 (Bio-Quinone of Pharma
Nord) during the complete trials over 3-5 years. The
numerous metastases in the liver of a 44-year-old patient
"disappeared," and no signs of metastases were found
elsewhere. A 49-year-old patient, on a dosage of 390 mg of
vitamin Q10, revealed no signs of tumor in the pleural
cavity after six months, and her condition was excellent. A
75-year-old patient with carcinoma in one breast, after
lumpectomy and 390 mg of CoQ10, showed no cancer in the
tumor bed or metastases. Control blood levels of CoQ10 of
0.83-0.97 and of 0.62 micrograms/ml increased to 3.34-3.64
and to 3.77 micrograms/ml, respectively, on therapy with
CoQ10 for patients A-MRH and EEL.
Regulation of the
immune response by dehydroepiandrosterone and its
metabolites
Loria R.M.; Padgett D.A.; Huynh P.N. Department of
Microbiology, Virginia Commonwealth University, Medical
College of Virginia, Richmond, VA 23298-09678 USA
Journal of Endocrinology (United Kingdom), 1996,
150/Suppl. (S209-S220)
Dehydroepiandrosterone (5-androsten-3beta-ol-17-one,
DHEA) has been shown to protect mice from a variety of
lethal infections. This includes, but is not limited to,
infection with viruses (herpes virus type 2, coxsackie
virus B4 (CB4)), bacteria (Enterococcus faecalis,
Pseudomonas aeruginosa), and a parasite (Cryptosporidium
parvum). We have previously reported that androstenediol
(5-androstene-3beta,17beta-diol, AED), derived from DHEA,
is at least 100 x more effective in up-regulating systemic
resistance against CB4 infection than its precursor.
Furthermore, androstenetriol
(5-androstene-3beta,7beta,17beta-triol, AET) which is
formed by 7beta hydroxylation of AED, was more effective
against CB4 infection than its precursor, AED. Neither
steroid, however, has shown any significant direct
antiviral effects. The in vitro influences of DHEA, AED and
AET on a mitogen-induced mixed splenocyte proliferation
assay were determined. The results showed that DHEA
suppressed the proliferation of concanavalin A (ConA)- or
lipopoly-saccharide-activated cultures in a dose-dependent
manner. AED had little influence on the activation
response. However, AET potentiated the response to both
mitogens significantly above the control level. The
regulation of interleukin (IL)-2 and IL-3 secretion from
ConA-activated lymphocytes was analogous to these
observations. These functions were depressed by DHEA,
unaffected by AED, and potently increased by AET. Moreover,
the classic immunosuppressive effects of hydrocortisone on
ConA-induced lymphocyte proliferation, as well as IL-2 and
IL-3 production, were unaffected by co-culture with DHEA
and only minimally counteracted by AED. In contrast, AET
significantly counteracted the effect of hydrocortisone
when co-cultured together. These data show that while DHEA,
AED and AET each function in a similar manner in vivo, in
vitro their effects are dramatically different from one
another with only AET potentiating the cellular response by
increasing lymphocyte activation and counteracting the
immunosuppressive activity of hydrocortisone.
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.
Dairy proteins protect
against dimethylhydrazine-induced intestinal cancers in
rats.
McIntosh GH, Regester GO, Le Leu RK, Royle PJ, Smithers
GW. CSIRO Division of Human Nutrition, Adelaide, South
Australia.
J Nutr. 1995 Apr;125(4):809-16.
The impact of different dietary protein sources (whey,
casein, soybean, red meat) on the incidence, burden and
mass index of intestinal tumors induced by
dimethylhydrazine in male Sprague-Dawley rats was assessed.
A purified diet (based on AIN-76A) with a fat concentration
of 20 g/100 g and other proteins substituted for casein (20
g/100 g) was used. Whey and casein diets were more
protective against the development of intestinal tumors
than were the red meat or soybean diets, as evidenced by a
reduced incidence of rats affected (P = 0.15), fewer tumors
per treatment group (burden, P < 0.005), and a
reduced pooled area of tumors (tumor mass index) that
formed (P = 0.39). Intracellular concentration of
glutathione, an antioxidant and anticarcinogenic
tripeptide, measured in liver, was greatest in whey
protein- and casein-fed rats and lowest in soybean-fed
animals (P < 0.001). For other tissues (spleen,
colon, tumor) the differences were not significant,
although the whey-fed animals had the highest
concentrations of glutathione (P = 0.8). Whey is a source
of precursors (cysteine-rich proteins) for glutathione
synthesis and may be important in providing protection to
the host by stimulating glutathione synthesis. A positive
correlation was observed between mean fecal fat
concentrations for rats in each treatment group and large
intestinal tumor burden (r2 = 0.898, P = 0.05). Fecal fat
could be involved in aiding initiation and/or promotion of
carcinogenesis. Whatever the mechanism(s), dairy proteins,
and whey proteins in particular, offer considerable
protection to the host against dimethylhydrazine-induced
tumors relative to the other protein sources examined.
Echinacea for
preventing and treating the common cold.
Melchart D, Linde K, Fischer P, Kaesmayr J. Munchener
Modell - Centre for Complementary Medicine Research,
Technical University/Ludwig-Maximilians-University,
Kaiserstr. 9, Munich, Germany, 80801.
Muenchener.Modell@lrz.uni-muenchen.de
Cochrane Database Syst Rev. 2000;(2):CD000530.
BACKGROUND: Extracts of the plant Echinacea (family
Compositae) are widely used in some European countries and
the USA for upper respiratory tract infections. OBJECTIVES:
The objective of this review was to assess the effects of
preparations containing extracts of Echinacea in the
prevention and treatment of the common cold. SEARCH
STRATEGY: We searched the Cochrane Acute Respiratory
Infections Group and Complementary Medicine Field's trials
registers, MEDLINE, EMBASE, Phytodok and reference lists of
articles. We also contacted researchers and manufacturers.
Date of last search: Spring 1998. SELECTION CRITERIA:
Randomised and quasi-randomised trials comparing
preparations containing an extract of Echinacea compared
with a placebo, no treatment, or another treatment for
common colds. DATA COLLECTION AND ANALYSIS: At least two
independent reviewers assessed trial quality and extracted
data. MAIN RESULTS: Sixteen trials (eight prevention
trials, and eight trials on treatment of upper respiratory
tract infections) with a total of 3396 participants were
included. Variation in preparations investigated and
methodological quality of trials precluded quantitative
meta-analysis. Overall, the results suggested that some
Echinacea preparations may be better than placebo.
REVIEWER'S CONCLUSIONS: The majority of the available
studies report positive results. However there is not
enough evidence to recommend a specific Echinacea product,
or Echinacea preparations for the treatment or prevention
of common colds.
Vitamin E
supplementation and in vivo immune response in healthy
elderly subjects: A randomized controlled
trial
Meydani S.N.; Meydani M.; Blumberg J.B.; Leka L.S.;
Siber G.; Loszewski R.; Thompson C.; Pedrosa M.C.; Diamond
R.D.; Stollar B.D. Dr. S.N. Meydani, Nutritional Immunology
Laboratory, JM USDA HNRCA, Tufts University, 711 Washington
St, Boston, MA 02111 USA
Journal of the American Medical Association (USA), 1997,
277/17 (1380-1386)
Objective. - To determine whether long-term
supplementation with vitamin E enhances in vivo, clinically
relevant measures of cell-mediated immunity in healthy
elderly subjects.
Design. - Randomized, double-blind, placebo- controlled
intervention study.
Setting and Participants. - A total of 88 free-living,
healthy subjects at least 65 years of age. Intervention. -
Subjects were randomly assigned to a placebo group or to
groups consuming 60, 200, or 800 mg/d of vitamin E for 235
days.
Main Outcome Measures. - Delayed- type hypersensitivity
skin response (DTH); antibody response to hepatitis B,
tetanus and diphtheria, and pneumococcal vaccines; and
autoantibodies to DNA and thyroglobulin were assessed
before and after supplementation.
Results. - Supplementation with vitamin E for 4 months
improved certain clinically relevant indexes of
cell-mediated immunity in healthy elderly. Subjects
consuming 200 mg/d of vitamin E had a 65% increase in DTH
and a 6-fold increase in antibody titer to hepatitis B
compared with placebo (17% and 3- fold, respectively),
60-mg/d (41% and 3-told, respectively), and 800-mg/d (49%
and 2.5-fold, respectively) groups. The 200-mg/d group also
had a significant increase in antibody titer to tetanus
vaccine. Subjects in the upper tertile of serum
alpha-tocopherol (vitamin E) concentration (>48.4
micromol/L (2.08 mg/dL)) after supplementation had higher
antibody response to hepatitis B and DTH. Vitamin E
supplementation had no effect on antibody titer to
diphtheria and did not affect immunoglobulin levels or
levels of T and B cells. No significant effect of vitamin E
supplementation on autoantibody levels was observed.
Conclusions. - Our results indicate that a level of
vitamin E greater than currently recommended enhances
certain clinically relevant in vivo indexes of
T-cell-mediated function in healthy elderly persons. No
adverse effects were observed with vitamin E
supplementation.
Oral supplementation
with whey proteins increases plasma glutathione levels of
HIV-infected patients.
Micke P, Beeh KM, Schlaak JF, Buhl R. Pulmonary
Division, III. Medical Department, Mainz University
Hospital, D-455101 Mainz, Germany.
p.micke@3-med.klinik.uni-mainz.de
Eur J Clin Invest. 2001 Feb;31(2):171-8.
HIV infection is characterized by an enhanced oxidant
burden and a systemic deficiency of the tripeptide
glutathione (GSH), a major antioxidant. The semi-essential
amino acid cysteine is the main source of the free
sulfhydryl group of GSH and limits its synthesis.
Therefore, different strategies to supplement cysteine
supply have been suggested to increase glutathione levels
in HIV-infected individuals. The aim of this study was to
evaluate the effect of oral supplementation with two
different cysteine-rich whey protein formulas on plasma GSH
levels and parameters of oxidative stress and immune status
in HIV-infected patients. In a prospective double blind
clinical trial, 30 patients (25 male, 5 female; mean age
(+/- SD) 42 +/- 9.8 years) with stable HIV infection (221
+/- 102 CD4 + lymphocytes L-1) were randomized to a
supplemental diet with a daily dose of 45 g whey proteins
of either Protectamin (Fresenius Kabi, Bad Hamburg,
Germany) or Immunocal (Immunotec, Vandreuil, Canada) for
two weeks. Plasma concentrations of total, reduced and
oxidized GSH, superoxide anion (O2-) release by blood
mononuclear cells, plasma levels of TNF-alpha and
interleukins 2 and 12 were quantified with standard methods
at baseline and after therapy. Pre-therapy, plasma GSH
levels (Protectamin: 1.92 +/- 0.6 microM; Immunocal: 1.98
+/- 0.9 microM) were less than normal (2.64 +/- 0.7 microM,
P = 0.03). Following two weeks of oral supplementation with
whey proteins, plasma GSH levels increased in the
Protectamin group by 44 +/- 56% (2.79 +/- 1.2 microM, P =
0.004) while the difference in the Immunocal group did not
reach significance (+ 24.5 +/- 59%, 2.51 +/- 1.48 microM, P
= 0.43). Spontaneous O2- release by blood mononuclear cells
was stable (20.1 +/- 14.2 vs. 22.6 +/- 16.1 nmol h-1 10-6
cells, P = 0.52) whereas PMA-induced O2- release decreased
in the Protectamin group (53.7 +/- 19 vs. 39.8 +/- 18 nmol
h-1 10-6 cells, P = 0.04). Plasma concentrations of
TNF-alpha and interleukins 2 and 12 (P > 0.08, all
comparisons) as well as routine clinical parameters
remained unchanged. Therapy was well tolerated. In
glutathione-deficient patients with advanced HIV-infection,
short-term oral supplementation with whey proteins
increases plasma glutathione levels. A long-term clinical
trial is clearly warranted to see if this "biochemical
efficacy" of whey proteins translates into a more
favourable course of the disease.
Immunostimulation of
neutrophil phagocytic function by RU41740 (Biostim) in
elderly subjects.
Minonzio F, Ongari AM, Palmieri R, Bochicchio D, Guidi
G, Capsoni F. Istituto di Clinica Medica I, Universita di
Milano.
Allergol Immunopathol (Madr). 1991
Mar-Apr;19(2):58-62.
On this randomized, double-blind trial we investigated
the effect of RU41740, a glycoprotein extracted from
Klebsiella pneumoniae, on human neutrophil function after
oral administration to elderly subjects with a previously
demonstrated phagocytic defect. Six subjects were given
RU41740 orally at a daily dose of 2 mg for one week the
first month and of 1 mg for one week the second month,
while six subjects received placebo. Already after the
first week of treatment with RU41740 (T1) and more
evidently 3 weeks after the last administration of the
first course of therapy (T2), a significant improvement of
the neutrophil phagocytic capacity was observed; at the
time T2, as well as at the end of the second course of
therapy (T3), the phagocytic capacity was completely
restored with no differences between control and aged
subjects. Similar results were obtained in the
chemiluminescence assays. As expected, placebo had no
significant effect on neutrophil functions. No significant
differences were observed between the two group of elderly
subjects for total or differential leukocyte number. These
results suggest that RU41740 exerts, almost in part, its
clinical effect, i.e. the prevention of recurrent
infections, by stimulating blood neutrophil phagocytic
function.
Interaction of
ascorbate and alpha-tocopherol.
Niki E.
Ann N Y Acad Sci. 1987;498:186-99.
Vitamins C and E function as water-soluble and
lipid-soluble chain-breaking antioxidants, respectively,
and protect lipids, proteins, and membranes from oxidative
damage. Vitamin C scavenges oxygen radicals in the aqueous
phase, whereas vitamin E scavenges oxygen radicals within
the membranes. Vitamin C regenerates vitamin E by reducing
vitamin E radicals formed when vitamin E scavenges the
oxygen radicals. This interaction between vitamin C and
vitamin E radicals can take place not only in homogeneous
solutions but also in liposomal membrane systems where
vitamins C and E reside separately outside and within the
membranes respectively, and vitamin C can act as a
synergist.
Contrasting effects of
lactoferrin on human lymphocyte and monocyte natural killer
activity and antibody-dependent cell-mediated
cytotoxicity.
Nishiya K, Horwitz DA.
J Immunol. 1982 Dec;129(6):2519-23.
Iron and the iron-binding protein lactoferrin (LF) have
significant effects on natural killer (NK) and
antibody-dependent cellular cytotoxicity (ADCC). Human
adherent and nonadherent blood mononuclear cells were
incubated with K562 cells and antibody-sensitized Chang
cells in short-term chromium-release assays. Ferric citrate
(10(-3) M) inhibited both adherent and nonadherent NK cell
activity, but had no effect upon ADCC. LF markedly affected
adherent monocyte cytotoxicity, but had no effect on
nonadherent lymphocytes. LF enhanced NK in a dose-dependent
manner, but similar concentrations paradoxically inhibited
ADCC. LF acted directly upon the adherent effector cell
because pretreatment of cells for 30 min was sufficient for
enhancement. Fe-saturated LF as well as the unsaturated
protein enhanced adherent cell NK. Transferrin in all
concentrations tested did not alter NK activity. These
studies show inhibitory effects of iron on immune function
in addition to those previously described and reveal a new
regulatory role for LF. The selective effect of LF on
adherent cells provides further evidence that monocytes, at
least in the adherent state, can have potent NK activity.
The opposite effects of LF on NK and ADCC are unexplained
and may serve as a probe to define the mechanisms
involved.
Self-regulation of
salivary immunoglobulin A by children.
Olness K, Culbert T, Uden D. Minneapolis Children's
Medical Center.
Pediatrics. 1989 Jan;83(1):66-71.
In a prospective randomized controlled study, the
possibility that children could regulate their own salivary
immunoglobulins was investigated using cyberphysiologic
techniques. Fifty-seven children were randomly assigned to
one of three groups. Group A subjects learned self-hypnosis
with permission to increase immune substances in saliva as
they chose; group B subjects learned self-hypnosis with
specific suggestions for control of saliva immunoglobulins;
group C subjects were given no instructions but received
equal attention time. At the first visit, saliva samples
(baseline) were collected, and each child looked at a
videotape concerning the immune system and was tested with
the Stanford Children's Hypnotic Susceptibility Scale. At
the second visit, an initial saliva sample was collected
prior to 30 minutes of self-hypnosis practice or
conversation. At the conclusion of the experiment, a third
saliva sample was obtained. Salivary IgA and IgG levels for
all groups were stable from the first to the second
sampling. Children in group B demonstrated a significant
increase in IgA (P less than .01) during the experimental
period. There were no significant changes in IgG. Stanford
Children's Hypnotic Susceptibility Scale scores were stable
across groups and did not relate to immunoglobulin
changes.
Lipopolysaccharide-induced enhancement of
natural killer cell cytotoxicity: Comparison of rats fed
menhaden, safflower and essential fatty acid deficient
diets
Penturf M.E.; McGlone J.J.; Griswold J.A. USA
Journal of Nutritional Immunology (USA), 1997, 5/2
(47-56)
The n-6 and n-3 families of fatty acids serve as
precursors in the formation of mediators observed in
inflammation. Eicosanoids from the cyclooxygenase and
lipoxygenase pathways have been shown to influence natural
killer (NK ) cell activity . In this study, rats were fed
diets either deficient in essential fatty acids (EFAD), or
diets that contained marine oil (15% menhaden, MEN) or
safflower oil (15% safflower, SAF). Rats were then
subjected to either in vivo lipopolysaccaride (LPS) or a
sham procedure. LPS treated animals had higher (p <
0.05) NK activity than those of the sham group. EFAD-fed
animals had higher (p < 0.05) NK activity than
animals fed diets containing lipids. Dietary treatment and
LPS interactions were not significant, indicating that
major shifts in cell lipid concentrations did not alter
endotoxin-induced enhancement of NK activity. Rats fed EFAD
diets had enhanced NK activity in both sham and LPS-treated
animals.
Use of echinacea in
medicine.
Percival SS. Food Science and Human Nutrition
Department, The University of Florida, Gainesville, FL
32611, USA. ssp@gnv.ifas.ufl.edu
Biochem Pharmacol. 2000 Jul 15;60(2):155-8.
Echinacea, also known as the purple coneflower, is an
herbal medicine that has been used for centuries,
customarily as a treatment for the common cold, coughs,
bronchitis, upper respiratory infections, and some
inflammatory conditions. Research on echinacea, including
clinical trials, is limited and largely in German. More
information is needed before a definitive statement about
the efficacy of echinacea can be made. Future work needs to
clearly identify the species of echinacea and distinguish
between the efficacy of the different plant parts (roots
versus upper plant parts). Although many of the active
compounds of echinacea have been identified, the mechanism
of action is not known, nor is the bioavailability,
relative potency, or synergistic effects of the active
compounds known. Interpretation of existing literature
suggests that echinacea should be used as a treatment for
illness, not as a means for prevention of illness. The
consensus of the studies reviewed in this article is that
echinacea is indeed effective in reducing the duration and
severity of symptoms, but that this effect is noted only
with certain preparations of echinacea. Studies show that
the plant and its active components affect the phagocytic
immune system, but not the specifically acquired immune
system.
Systemic augmentation
of the immune response in mice by feeding fermented milks
with Lactobacillus casei and Lactobacillus
acidophilus.
Perdigon G, de Macias ME, Alvarez S, Oliver G, de Ruiz
Holgado AP. Centro de Referencia para Lactobacilos
(CERELA), Chacabuco, Tucuman, Argentina.
Immunology 1988 Jan;63(1):17-23
This study investigates the effect of feeding fermented
milks with Lactobacillus casei, Lactobacillus acidophilus
and a mixture of both micro-organisms on the specific and
non-specific host defence mechanisms in Swiss mice. Animals
fed with fermented milk for 8 days (100 micrograms/day)
showed an increase in both phagocytic and lymphocytic
activity. This activation of the immune system began on the
3rd day, reached a maximum on the 5th, and decreased
slightly on the 8th day of feeding. In the 8-day treated
mice, boosted with a single dose (100 micrograms) on the
11th day, the immune response increased further. The
feeding with fermented milk produced neither hepatomegaly
nor splenomegaly. These results suggest that L. casei and
L. acidophilus, associated with intestinal mucosae, can
influence the level of activation of the immune system. The
possible clinical application of fermented milks as
immunopotentiators is also discussed.
Molecules of Emotion:
Why You Feel the Way You Feel 1999.
Pert, C.B.
New York: Simon & Schuster.
Effects of zinc
deficiency on Th1 and Th2 cytokine shifts.
Prasad AS. Wayne State University, University Health
Center, Detroit, MI 48201, USA. prasada@karmanos.org
J Infect Dis. 2000 Sep;182 Suppl 1:S62-8.
Nutritional deficiency of zinc is widespread throughout
developing countries, and zinc-deficient persons have
increased susceptibility to a variety of pathogens. Zinc
deficiency in an experimental human model caused an
imbalance between Th1 and Th2 functions. Production of
interferon-gamma and interleukin (IL)-2 (products of Th1)
were decreased, whereas production of IL-4, IL-6, and IL-10
(products of Th2) were not affected during zinc deficiency.
Zinc deficiency decreased natural killer cell lytic
activity and percentage of precursors of cytolytic T cells.
In HuT-78, a Th0 cell line, zinc deficiency decreased gene
expression of thymidine kinase, delayed cell cycle, and
decreased cell growth. Gene expression of IL-2 and IL-2
receptors (both alpha and beta) and binding of NF-kappaB to
DNA were decreased by zinc deficiency in HuT-78. Decreased
production of IL-2 in zinc deficiency may be due to
decreased activation of NF-kappaB and subsequent decreased
gene expression of IL-2 and IL-2 receptors.
Zinc deficiency:
changes in cytokine production and T-cell subpopulations in
patients with head and neck cancer and in noncancer
subjects.
Prasad AS; Beck FW; Grabowski SM; Kaplan J; Mathog RH
Department of Internal Medicine, Wayne State University
School of Medicine, Detroit, MI
Proc Assoc Am Physicians Jan 1997, 109 (1) p68-77
Cell-mediated immune dysfunctions and susceptibility to
infections have been observed in zinc -deficient human
subjects. In this study, we investigated the production of
cytokines and characterized the T-cell subpopulations in
three groups of mildly zinc -deficient subjects. These
included head and neck cancer patients, healthy volunteers
who were found to have a dietary deficiency of zinc, and
healthy volunteers in whom we induced zinc deficiency
experimentally by dietary means. We used cellular zinc
criteria for the diagnosis of zinc deficiency. We assayed
enzyme-linked immunosorbent assay the production of
cytokines from phytohemagglutinin-stimulated peripheral
blood mononuclear cells and assessed by flow cytometry the
differences in T-cell subpopulations. Our studies showed
that the cytokines produced by TH1 cells were particularly
sensitive to zinc status, inasmuch as the production of
interleukin-2 (IL-2) and interferon-gamma were decreased
even though the deficiency of zinc was mild in our
subjects. TH2 cytokines (IL-4, IL-5, and IL-6) were not
affected by zinc deficiency. Natural killer cell lytic
activity also was decreased in zinc -deficient subjects.
Recruitment of naive T cells (CD4+CD45 RA+) and CD8+ CD73+
CD11b-, precursors of cytolytic T cells, were decreased in
mildly zinc -deficient subjects. An imbalance between the
functions of TH1 and TH2 cells and changes in T-cell
subpopulations are most probably responsible for
cell-mediated immune dysfunctions in zinc deficiency.
Vitamin B6 and immune
competence.
Rall LC, Meydani SN. Nutritional Immunology Laboratory,
USDA Human Nutrition Research Center on Aging, Tufts
University, Boston, MA 02111.
Nutr Rev 1993 Aug;51(8):217-25
Animal and human studies suggest that vitamin B6
deficiency affects both humoral and cell-mediated immune
responses. Lymphocyte differentiation and maturation are
altered by deficiency, delayed-type hypersensitivity
responses are reduced, and antibody production may be
indirectly impaired. Although repletion of the vitamin
restores these functions, megadoses do not produce benefits
beyond those observed with moderate supplementation.
Additional human studies indicate that vitamin B6 status
may influence tumor growth and disease processes.
Deficiency of the vitamin has been associated with
immunological changes observed in the elderly, persons
infected with human immunodeficiency virus (HIV), and those
with uremia or rheumatoid arthritis. Future research
efforts should focus on establishing the mechanism
underlying the effects of vitamin B6 on immunity and should
attempt to establish safe intake levels that optimize
immune response.
Effect of micronutrient
status on natural killer cell immune function in healthy
free-living subjects aged >/=90 y.
Ravaglia G, Forti P, Maioli F, Bastagli L, Facchini A,
Mariani E, Savarino L, Sassi S, Cucinotta D, Lenaz G.
Department of Internal Medicine, Cardioangiology, and
Hepatology, the Department of Angiology and Blood
Coagulation, and the Division of Geriatric Medicine,
University Hospital Sant'Orsola-Malpighi, Bologna, Italy.
ravaglia@almadns.unibo.it
Am J Clin Nutr. 2000 Feb;71(2):590-8.
BACKGROUND: Natural killer (NK) cells play a role in
natural immunity against tumor and infected cells. Advanced
aging is associated with functional impairment of NK cells
and increased susceptibility to nutritional
deficiencies.
OBJECTIVE: Our objective was to test whether
micronutrient status affects NK cell activity in an older
population. DESIGN: The relations between NK cell variables
(percentage of leukocytes and cytotoxicity) and blood
concentrations of selected micronutrients were studied in
62 healthy, free-living northern Italian subjects (25 men,
37 women) aged 90-106 y. Anthropometric measurements were
also made.
RESULTS: All subjects were well nourished according to
age-specific anthropometric norms but many of them had
micronutrient deficiencies. The prevalence of micronutrient
deficiency was highest for selenium (in approximately 50%
of both sexes), zinc (in 52% of men and 41% of women), and
vitamin B-6 (in 40% of men and 59% of women), followed by
vitamin A (in 16% of men and 27% of women) and vitamin E,
vitamin B-12, and folate (each in <10% of both
sexes). Ubiquinone-10 status was inadequate in 40% of women
and 24% of men (P = 0.02). The percentage of NK cells was
associated with serum zinc (men: r = 0.573, P = 0. 007;
women: r = 0.373, P = 0.031) and selenium (women: r =
0.409, P = 0.018) concentrations. In women only, NK cell
cytotoxicity at different effector-target cell ratios was
positively associated with plasma vitamin E and
ubiquinone-10 concentrations (P < 0.05). No
significant associations with NK cell variables were found
for the other measured nutrients.
CONCLUSIONS: The results of this study strengthen the
hypothesis that individual micronutrients may affect the
number and function of NK cells in old age. The study also
confirms the high prevalence of micronutrient deficiencies
in healthy and apparently well-nourished persons aged
>/=90 y.
Natural killer cell
activity in elderly men is enhanced by beta-carotene
supplementation
Santos M.S.; Meydani S.N.; Leka L.; Wu D.; Fotouhi N.;
Meydani M.; Hennekens C.H.; Gaziano J.M. Nutritional
Immunology Laboratory, Jean Mayer USDA HNRCA, Tufts
University, 711 Washington Street, Boston, MA 02111 USA
American Journal of Clinical Nutrition (USA), 1996, 64/5
(772-777)
Natural killer (NK) cell activity has been postulated to
be an immunologic link between beta-carotene and cancer
prevention. In a cross- sectional, placebo-controlled,
double-blind study we examined the effect of 10-12 y of
beta-carotene supplementation (50 mg on alternate days) on
NK cell activity in 59 (38 middle-aged men, 51-64 y; 21
elderly men, 65-86 y) Boston area participants in the
Physicians' Health Study. No significant difference was
seen in NK cell activity due to beta-carotene
supplementation in the middle-aged group. The elderly men
had significantly lower NK cell activity than the
middle-aged men; however, there was no age-associated
difference in NK cell activity in men supplemented with
beta-carotene. beta-carotene- supplemented elderly men had
significantly greater NK cell activity than elderly men
receiving placebo. The reason for this is unknown; however,
it was not due to an increase in the percentage of NK
cells, nor to an increase in interleukin 2 (IL-2) receptor
expression, nor to IL-2 production. beta- carotene may be
acting directly on one or more of the lytic stages of NK
cell cytotoxicity, or on NK cell activity-enhancing
cytokines other than IL-2, such as IL-12. Our results show
that long-term beta-carotene supplementation enhances NK
cell activity in elderly men, which may be beneficial for
viral and tumoral surveillance.
Mechanism for the
antitumor and anticachectic effects of n-3 fatty
acids.
Sauer LA, Dauchy RT, Blask DE. Bassett Research
Institute, Cooperstown, New York 13326, USA.
lensauer@juno.com
Cancer Res. 2000 Sep 15;60(18):5289-95.
Dietary intake of the n-6 fatty acid (FA) linoleic acid
(LA) has a strong growth-promoting effect on many rodent
tumors and human tumor xenografts grown in immunodeficient
rodents. n-3 FAs such as alpha-linolenic and
eicosapentaenoic acids (EPAs), which differ from LA and
arachidonic acid, respectively, by only a single double
bond in the n-3 position, are recognized cancer
chemopreventive and anticachectic agents. Understanding how
this seemingly small structural difference leads to such
remarkable functional differences has been a challenge. In
a previous study, we showed that LA uptake, [3H]thymidine
incorporation into DNA, and total DNA content were
decreased in tissue-isolated hepatoma 7288CTC perfused in
situ with arterial blood containing alpha-linolenic acid,
EPA, or docosahexaenoic acids. The Ki for the inhibition of
LA uptake and [3H]thymidine incorporation by
alpha-linolenic acid was 0.18 and 0.25 mM, respectively.
Here we show that the addition of alpha-linolenic acid or
EPA to arterial blood inhibits tumor FA uptake, including
LA, and the subsequent conversion of LA to the mitogen
13-hydroxyoctadecadienoic acid (13-HODE) in vivo and during
perfusion in situ. [3H]Thymidine incorporation during
perfusion in situ was also inhibited. Addition of 13-HODE
to the arterial blood reversed the inhibition of
[3H]thymidine incorporation but had no effect on FA uptake.
These two n-3 FAs also inhibited FA transport in inguinal
fat pads in vivo and during perfusion in situ in fed (FA
uptake) and fasted (FA release) rats. The effects of EPA
and talinolenic acid on transport of saturated,
monounsaturated, and n-6 polyunsaturated FAs in hepatoma
7288CTC and inguinal fat pads during perfusion in situ were
reversed by the addition of forskolin (1 microM), pertussis
toxin (0.5 microg/ml), or 8-bromo-cyclic AMP (10 microM) to
the arterial blood. We conclude that the antitumor and
anticachectic effects of n-3 FAs on hepatoma 7288CTC and
inguinal fat pads in vivo result from an inhibition of FA
transport. These inhibitions are mediated by a putative n-3
FA receptor via a Gi protein-coupled signal transduction
pathway that decreases intracellular cyclic AMP. A specific
decrease in LA uptake and its conversion to the mitogen
13-HODE causes the tumor growth inhibition.
Zinc deficiency impairs
immune responses against parasitic nematode infections at
intestinal and systemic sites.
Scott ME, Koski KG. Institute of Parasitology, School of
Dietetics and Human Nutrition, McGill University, Macdonald
Campus, Ste-Anne de Bellevue, Quebec H9X 3V9, Canada.
J Nutr. 2000 May;130(5S Suppl):1412S-20S.
Research on the complex interactions among host
nutritional status, parasitic infection and immune
responsiveness has focused on the detrimental consequences
of parasitic infections on host nutritional status and on
mechanisms by which malnutrition impairs immunocompetence.
Curiously, relatively few studies have examined the effects
of malnutrition on the immune response in the
parasite-infected host, and even fewer have considered the
events occurring at the intestinal level, where absorption
of nutrients occurs, intestinal parasites reside, and the
gastrointestinal-associated lymphoid tissues play a role in
directing both the local and the more systemic immune
responses. Our work using a zinc-deficient
nematode-infected mouse model reveals that parasites are
better able to survive in the zinc-deficient hosts than in
well-nourished hosts; that the production of interleukin-4
in the spleen of zinc-deficient mice is depressed, leading
to depressed levels of IgE, IgG(1) and eosinophils; and
that the function of T cells and antigen-presenting cells
is impaired by zinc deficiency as well as by energy
restriction. Given the paramount role of the
gastrointestinal-associated lymphoid tissues in inducing
and regulating immune responses to intestinal parasites and
in orchestrating responses in the spleen and peripheral
circulation, we conclude that zinc deficiency (in
association with energy restriction) exerts profound
effects on the gut mucosal immune system, leading to
changes in systemically disseminated immune responses and,
importantly, to prolonged parasite survival.
Synergism of nutrition,
infection, and immunity: an overview.
Scrimshaw NS, SanGiovanni JP. Food and Nutrition
Programme for Human and Social Development, United Nations
University (Program Office), Boston, MA 02114-0500, USA.
Scrimshaw@inf.unu.edu
Am J Clin Nutr 1997 Aug;66(2):464S-477S
Infections, no matter how mild, have adverse effects on
nutritional status. The significance of these effects
depends on the previous nutritional status of the
individual, the nature and duration of the infection, and
the diet during the recovery period. Conversely, almost any
nutrient deficiency, if sufficiently severe, will impair
resistance to infection. Iron deficiency and protein-energy
malnutrition, both highly prevalent, have the greatest
public health importance in this regard. Remarkable
advances in immunology of recent decades have increased
insights into the mechanisms responsible for the effects of
infection. These include impaired antibody formation; loss
of delayed cutaneous hypersensitivity; reduced
immunoglobulin concentrations; decreased thymic and splenic
lymphocytes; reduced complement formation, secretory
immunoglobulin A, and interferon; and lower T cells and T
cells subsets (helper, suppressor-cytotoxic, and natural
killer cells) and interleukin 2 receptors. The effects
observed with single or multiple nutrient deficiencies are
due to some combination of these responses. In general,
cell-mediated and nonspecific immunity are more sensitive
than humoral immunity.
Zinc and immune
function: the biological basis of altered resistance to
infection.
Shankar AH; Prasad AS Department of International
Health, The Johns Hopkins University School of Public
Health, Baltimore, MD 21205, USA. ashankar@jhsph.edu
Am J Clin Nutr Aug 1998, 68 (2 Suppl) p447S-463S
Zinc is known to play a central role in the immune
system, and zinc-deficient persons experience increased
susceptibility to a variety of pathogens. The immunologic
mechanisms whereby zinc modulates increased susceptibility
to infection have been studied for several decades. It is
clear that zinc affects multiple aspects of the immune
system, from the barrier of the skin to gene regulation
within lymphocytes. Zinc is crucial for normal development
and function of cells mediating nonspecific immunity such
as neutrophils and natural killer cells. Zinc deficiency
also affects development of acquired immunity by preventing
both the outgrowth and certain functions of T lymphocytes
such as activation, Th1 cytokine production, and B
lymphocyte help. Likewise, B lymphocyte development and
antibody production, particularly immunoglobulin G, is
compromised. The macrophage, a pivotal cell in many
immunologic functions, is adversely affected by zinc
deficiency, which can dysregulate intracellular killing,
cytokine production, and phagocytosis. The effects of zinc
on these key immunologic mediators is rooted in the myriad
roles for zinc in basic cellular functions such as DNA
replication, RNA transcription, cell division, and cell
activation. Apoptosis is potentiated by zinc deficiency.
Zinc also functions as an antioxidant and can stabilize
membranes. This review explores these aspects of zinc
biology of the immune system and attempts to provide a
biological basis for the altered host resistance to
infections observed during zinc deficiency and
supplementation. (271Refs.)
Aging, exercise,
training, and the immune system.
Shinkai S; Konishi M; Shephard RJ Department of Public
Health, Ehime University School of Medicine, Japan.
Exerc Immunol Rev 1997, 3 p68-95
Human immune function undergoes adverse changes with
aging, including development of a relative immune
deficiency and an immune dysregulated state. The T cells
show the largest age-related differences in distribution
and function. The antibody production capacity of B cells
also shows an age-related decline. Acute bouts of exercise
modulate many immune parameters as seen in peripheral
blood. With regard to NK cell activity, a single bout of
moderate exercise seems to be well tolerated by the
elderly, and the resting NK cell activity of elderly
subjects seems to increase with training. Cross-sectional
comparisons of immune status imply that habitual physical
activity may enhance NK cell activity and check certain
aspects of the age-related decline in T cell function.
Future studies are required to clarify whether such
long-term exercise and resulting improvements of immune
function give rise to any beneficial effects on infections,
malignancies, and autoimmune disorders. (162 Refs.)
Dehydroepiandrosterone
sulfate decreases the interleukin-2-mediated overactivity
of the natural killer cell compartment in senile dementia
of the Alzheimer type
Solerte S.B.; Fioravanti M.; Schifino N.; Cuzzoni G.;
Fontana I.; Vignati G.; Govoni S.; Ferrari E. Dr. S.B.
Solerte, Department of Internal Medicine, University of
Pavia, Ospedale S. Margherita, Piazza Borromeo 2, I-27100
Pavia Italy
Dementia and Geriatric Cognitive Disorders
(Switzerland), 1999, 10/1 (21-27)
Since dehydroepiandrosterone sulfate (DHEAS) has been
involved in the regulation of cellular immunity, the aim of
the presence study was to evaluate whether the
age-dependent reduction of DHEAS was associated with
changes of natural killer (NK) immune function in healthy
elderly subjects and in patients with senile dementia of
the Alzheimer type (SDAT). Circulating DHEAS was determined
throughout 24 h (circadian profile). NK cytotoxic activity
was measured as spontaneous and induced cytotoxicity during
exposure with DHEAS (10-7 M), interleukin-2 (IL-2; 100 IU)
and IL-2 (100 IU) coincubated with DHEAS (10-7 M). DHEAS
was significantly reduced in healthy subjects (mesor M plus
or minus SD = 2.3 plus or minus 0.5 micromol/l) and SDAT
(1.6 plus or minus 0.4 micromol/l) patients compared to
healthy young subjects (6.7 plus or minus 0.9 micromol/l; p
< 0.001); significant differences were also found
when healthy elderly subjects and SDAT patients were
compared (p < 0.01). A significant inverse
correlation between age and DHEAS levels was demonstrated
in SDAT and healthy elderly subjects (p < 0.05). The
decrease in 24-hour DHEAS secretion was associated with a
higher NK cytotoxic response to DHEAS in the healthy
elderly subject group than in healthy subjects of young age
(p < 0.01). Increased NK cell activity during IL-2
incubation was found in patients with SDAT in comparison
with the healthy elderly subject (p < 0.001). On the
contrary, NK cell cytotoxic response of SDAT patients was
less pronounced during DHEAS exposure and when DHEAS was
coincubated with IL-2 (p < 0.001). These data
suggest an immunomodulatory role of DHEAS on NK functional
activity in physiological aging and SDAT. The antagonizing
effect of DHEAS on NK overactivity during exposure with
cytokines might counteract some neuroimmune components
related to the pathogenesis and progression of the
disease.
Effect of psychosocial
treatment on survival of patients with metastatic breast
cancer.
Spiegel D, Bloom JR, Kraemer HC, Gottheil E. Department
of Psychiatry and Behavioral Sciences, Stanford University
School of Medicine, California.
Lancet. 1989 Oct 14;2(8668):888-91.
The effect of psychosocial intervention on time of
survival of 86 patients with metastatic breast cancer was
studied prospectively. The 1 year intervention consisted of
weekly supportive group therapy with self-hypnosis for
pain. Both the treatment (n = 50) and control groups (n =
36) had routine oncological care. At 10 year follow-up,
only 3 of the patients were alive, and death records were
obtained for the other 83. Survival from time of
randomisation and onset of intervention was a mean 36.6 (SD
37.6) months in the intervention group compared with 18.9
(10.8) months in the control group, a significant
difference. Survival plots indicated that divergence in
survival began at 20 months after entry, or 8 months after
intervention ended.
Antioxidant defense:
vitamins E and C and carotenoids.
Stahl W, Sies H. Institut fur Physiologische Chemie I,
Heinrich-Heine-Universitat Dusseldorf, Germany.
Diabetes. 1997 Sep;46 Suppl 2:S14-8.
Reactive oxygen species are thought to be implicated in
the pathogenesis of various human diseases. They are
generated endogenously under physiological and pathological
conditions but also upon exposure to exogenous challenge.
The organism maintains defense systems against reactive
oxygen species, including enzymes and low-molecular-weight
antioxidants. Important antioxidants such as vitamins E and
C and carotenoids are provided from the diet. Vitamin E, as
the major chain-breaking antioxidant, inhibits lipid
peroxidation, thus preventing membrane damage and
modification of low-density lipoproteins. It is regenerated
by the water-soluble vitamin C. Carotenoids efficiently
scavenge singlet molecular oxygen and peroxyl radicals.
There is increasing evidence from epidemiological studies,
animal experiments, and in vitro investigations that an
increased intake of antioxidants is associated with a
diminished risk for several diseases.
Treatment of systemic
lupus erythematosus with dehydroepiandrosterone: 50
patients treated up to 12 months.
van Vollenhoven RF; Morabito LM; Engleman EG; McGuire JL
Division of Immunology and Rheumatology, Stanford
University Medical Center, CA 94305-5111, USA.
J Rheumatol, 1998 Feb, 25:2, 285-9
OBJECTIVE: To determine whether longterm therapy (up to
1 year) with the weakly androgenic adrenal steroid
dehydroepiandrosterone (DHEA) is feasible and beneficial in
patients with mild to moderate systemic lupus erythematosus
(SLE).
METHODS: In a prospective, open label, uncontrolled
longitudinal study 50 female patients (37 premenopausal, 13
postmenopausal) with mild to moderate SLE were treated with
oral DHEA 50-200 mg/day.
RESULTS: DHEA therapy was associated with increases in
the serum levels of DHEA, DHEA sulfate, and testosterone
and, for those patients who continued DHEA, with decreasing
disease activity measured by SLE Disease Activity Index
score (p < 0.01), patient global assessment (p
< 0.01), and physician global assessment (p <
0.05), compared to baseline. Concurrent prednisone doses
were reduced (p < 0.05). These improvements were
sustained over the entire treatment period. Thirty-four
patients (68%) completed 6 months of treatment and 21
patients (42%) completed 12 months. Mild acneiform
dermatitis was the most common adverse event (54%). Pre and
postmenopausal women experienced similar efficacy and
adverse effects from DHEA.
CONCLUSION: DHEA was well tolerated and appeared
clinically beneficial, with the benefits sustained for at
least one year in those patients who maintained
therapy.
Influence of level of
dietary lipids and exercise on immune status in
athletes.
Venkatraman, J.T., Rowland, J.A., Denardin, E., Horvath,
P.J., Pendergast, D.R.
FASEB J. 1996; 10(3): A556.
No abstract available.
[Double-blind study of
an immunomodulator of bacterial origin (Biostim) in the
prevention of infectious episodes in chronic
bronchitis] [Article in French]
Viallat JR, Costantini D, Boutin C, Farisse P.
Poumon Coeur. 1983 Jan-Feb;39(1):53-7.
A double-blind trial was conducted to evaluate the
capacity of an immunomodulator of bacterial origin
(Biostim) to diminish the frequency of infectious episodes
in chronic bronchitis. The study duration was 9 months,
Biostim being administered orally initially, with follow-up
examinations after 2 and 4 months. Of the 73 subjects
selected, 38 received Biostim and 35 a placebo (no
significant differences between the two groups). By the 9th
month, the duration in days of infectious episodes and of
antibiotic therapy was 13 +/- 1.3 and 11.5 +/- 1.4 days
respectively for the group receiving Biostim, and 33 +/-
5.8 and 41 +/- 9.5 respectively for the placebo group (p
less than 0.05). No signs of intolerance and particularly
no immunotoxicity were observed: absence of elevation of
IgE or anti-Biostim antibody titres. Pre-winter
administration of Biostim to subjects at high risk would
appear to significantly diminish the frequency of
infectious episodes and thus the consumption of
antibiotics.
Vitamin A
supplementation: implications for morbidity and mortality
in children.
Villamor E, Fawzi WW. Departments of Nutrition and
Epidemiology, Harvard School of Public Health, Boston,
Massachusetts 02115, USA.
J Infect Dis. 2000 Sep;182 Suppl 1:S122-33.
Vitamin A deficiency impairs epithelial integrity and
systemic immunity and increases the incidence and severity
of infections during childhood. However, findings from
vitamin A supplementation trials are not consistent.
Supplementation has resulted in significant reductions in
mortality in several (but not all) large community-based
trials among apparently healthy children. In hospital-based
studies, vitamin A supplements have been consistently found
to reduce the severity of measles infection, but no effect
on nonmeasles respiratory infections has been observed. In
some cases, the supplements were associated with an
apparently increased risk of lower respiratory infection.
Vitamin A supplements also reduced the severity of diarrhea
in most (but not all) trials. Potential explanations for
the differences in efficacy across trials are reviewed.
While vitamin A supplementation is effective in reducing
total mortality and complications from measles infections,
it is likely to be more effective in populations suffering
from nutritional deficiencies.
The therapeutic effect
of bovine lactoferrin in the host infected with
Helicobacter pylori.
Wada T, Aiba Y, Shimizu K, Takagi A, Miwa T, Koga Y.
Dept. of Infectious Diseases, Tokai University School of
Medicine, Kanagawa, Japan.
Scand J Gastroenterol 1999 Mar;34(3):238-43
BACKGROUND: It remains unclarified whether bovine
lactoferrin (bLF) can exert a therapeutic effect on the
host infected with Helicobacter pylori.
METHODS: Germfree BALB/c mice were orally inoculated
with H. pylori to induce infection. Three weeks after
infection the mice were given bLF orally once daily for 2
or 4 weeks and were then killed to examine the bacterial
number in the stomach and the serum antibody titer to H.
pylori. To count the number of epithelium-bound H. pylori,
the resected stomach was agitated in phosphate-buffered
saline to remove non-bound H. pylori before bacterial
enumeration.
RESULTS: The administration of 10 mg bLF for 3 to 4
weeks decreased the number of H. pylori in the stomach to
one-tenth and also exerted a significant inhibitory effect
on the attachment of H. pylori to the stomach. As a result,
the serum antibody titer to H. pylori, whose level is
presumed to represent the size of the immune response by
the host, thereby reflecting the degree of bacterial
attack, decreased to an undetectable level.
CONCLUSIONS: These findings suggest that bLF exerts an
inhibitory effect on colonizing H. pylori by detaching the
bacterium from the gastric epithelium and by exerting a
direct anti-bacterial effect.
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