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Linking vitamin A and childhood immunizations
Semba R.D.
Wilmer Building, Johns Hopkins Hospital, 600 North Wolfe
Street, Baltimore, MD 21287 USA
Journal of Nutritional Immunology (USA), 1996, 4/1-2
(87-109)
Although studies conducted over the last twenty-five years
have demonstrated that vitamin A and related retinoids are
immune enhancers, the use of vitamin A and related retinoids
to enhance responses to immunization has been limited.
Numerous animal studies have now demonstrated that vitamin A
and related retinoids, when given at or prior to immunization,
will enhance antibody responses and cell-mediated immune
responses to protein antigens. Recent studies with humans show
that vitamin A supplementation enhances the IgG response to
tetanus toxoid, and that related retinoids can be used to
enhance antibody responses to protein antigens. Vitamin A
enhances immune responses to poor immunogens, and this may be
relevant to vaccines which are characterized by low
seroconversion rates. Although most known adjuvants have too
many side effects for human use, vitamin A and related
retinoids appear to enhance antibody and cell-mediated
immunity without severe side effects. Vitamin A, through its
metabolites, acts to modify biological responses through
specific nuclear receptors which activate gene transcription.
Thus, the mechanism for immune enhancement by vitamin A
appears to be different from that of known adjuvants. Vitamin
A and related retinoids have potential as a safe and effective
means of enhancing immune responses to vaccination
antigens.
Interleukin-2 and human immunodeficiency virus
infection: Pathogenic mechanisms and potential for immunologic
enhancement
Kinter A.; Fauci A.S.
LIR, NIAID, NIH, Building 10, 10 Center Drive, MSG-1576,
Bethesda, MD 20892-1576 USA
Immunologic Research (Switzerland), 1996, 15/1
(1-15)
A hallmark of human immunodeficiency virus (HIV) infection
is the progressive loss of CD4+ T lymphocytes; however,
qualitative defects in immune responses occur prior to the
precipitous drop CD4+ T cell numbers. One of the first
immunologic defects to be described in HIV-infected
individuals is a deficiency in interleukin (IL)-2 production.
The addition of IL-2 in vitro to cultures of mononuclear cells
from HIV-infected individuals partially or completely restored
certain defective cellular immune responses. However,
production of or addition of IL-2 has also been associated
with increased viral replication in infected T cells. These
observations underscore the pernicious correlation between
immune activation and HIV replication. However, recent in
vitro and in vivo studies have provided promising preliminary
results suggesting that, at least at certain stages of
disease, the benefits of IL-2-mediated immune enhancement may
outweigh or override the inductive effects of this cytokine on
HIV production.
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.
Cellular activation induced by BCG is a
PTK-dependent event
Mendez-Samperio P.; Hernandez-Garay M.; Vazquez A.N.
Departamento de Inmunologia, ENCB, IPN, Carpio y Plan de
Ayala, Mexico, D.F. 11340 Mexico
Cellular Immunology (USA), 1996, 171/1 (147-152)
Mycobacterial antigens including BCG stimulate human
peripheral blood mononuclear cells resulting in cellular
proliferation and the release of inflammatory cytokines such
as TNF-alpha. However, the signal transduction mechanisms
responsible for the BCG-induced cell activation are not
completely understood. In this study, we investigated the role
of PTK as a signal transduction pathway in BCG-induced cell
activation, with the use of two PTK inhibitors (genistein
and tyrphostin). Our results indicated that genistein
significantly inhibited BCG-induced cell growth determined by
thymidine uptake in a dose-dependent manner. BCG-induced
TNF-alpha secretion was completely suppressed by genistein in
a dose-dependent manner, producing 92% inhibition at a
concentration of 50 microM. In addition, strong inhibition
(81%) of BCG-induced TNF-alpha secretion was observed with
tyrphostin (30 microM), another specific protein tyrosine
kinase with a different mechanism of action. These inhibitory
effects were not attributed to an alteration in cell viability
as judged by trypan blue staining, and were not due to LPS
contamination. On the other hand, monoclonal antibodies
directed against HLA-DR and DQ inhibited the BCG-induced
secretion of TNF-alpha. Taken together, these findings suggest
that PTK may play an essential role in BCG-induced cellular
activation.
Stress-induced suppression of the cellular immune
reactions: On the neuroendocrine control of the immune
system
Hassig A.; Wen-Xi L.; Stampfli K.
Studiengruppe Ernahrung/Immunitat, Elisabethenstrasse 51,
CH-3014 Bern Switzerland
Medical Hypotheses (United Kingdom), 1996, 46/6
(551-555)
Immune competence is considered as a state of equilibrium
between humoral and cellular immunity. This notion fits well
with the functionally antagonistic cytokine profiles in cell
groups of CD4+-helper cells as described by Mosmann and
Coffman. The Th-1 cells release mainly IL-2, IL-12 and
IFNgamma and thereby stimulate the cellular immune reactions.
Conversely, the Th-2 cells produce predominantly IL-4, IL-6
and IL-10, thus enhancing humoral immune reactions. Recently,
it has been shown that the lymphokine profiles in Th-2 are
linked to changes of the humoral balance between cortisol and
dehydroepiandrosterone. These studies show that there exist
states of equilibrium between T- and B-cell-mediated immune
reactions, which may selectively be altered to the
disadvantage of the T-cellular immunity by a stress-induced
enhancement of cortisol release. In an attempt to restitute
stress-induced immunosuppression, a dampening of the cortisol
release hormone in the hypothalamus should, therefore, be of
primary importance.
Localization and synthesis of acetylcholine in
human leukemic T cell lines
Fujii T.; Tsuchiya T.; Yamada S.; Fujimoto K.; Suzuki T.;
Kasahara T.; Kawashima K.
Department of Pharmacology, Kyoritsu College of Pharmacy,
1-5-30 Shibakoen, Minato-ku, Tokyo 105 Japan
Journal of Neuroscience Research (USA), 1996, 44/1
(66-72)
In order to clarify the origin of acetylcholine (ACh) in
human blood, we measured the content and synthesis activity of
ACh in several human leukemic cell lines. The intracellular
ACh content determined by a specific and sensitive
radioimmunoassay in the human leukemic T cell lines, HSB-2,
MOLT- 3, and CEM, was 79.6, 36.2, and 9.5 pmol/106 cells,
respectively. These values were 9-70-fold higher than those of
other cell lines, including a helper T cell line, Jurkat.
Stimulation of HSB-2 and MOLT-3 by phytohemagglutinin (PHA)
increased both the intracellular content and release of ACh
into the culture medium, but did not influence the
intracellular content and release of ACh in CEM. ACh synthesis
activity was found in all the T cell lines tested.
Bromoacetylcholine (100 microM), a choline acetyltransferase
(CHAT) inhibitor, and bromoacetyl-L-carnitine (100 microM), a
carnitine acetyltransferase (CarAT) inhibitor, decreased
ACh-synthesizing activity in MOLT-3, and HSB-2 and CEM, by
about 50% and 30%, respectively, indicating that both CHAT,
and to a lesser extent CarAT, are involved in ACh synthesis in
T cells. These results suggest that T lymphocytes have the
potential to synthesize and release ACh, which may play a role
in regulating T cell-dependent immune responses.
Adrenal and gonadal steroid hormone deficiency in
the etiopathogenesis of rheumatoid arthritis
Wilder R.L.
NIAMS, NIH, National Institutes of Health, Bethesda, MD 20892
USA
Journal of Rheumatology (Canada), 1996, 23/Suppl. 44
(10-12)
Rheumatoid arthritis (RA) is a multifactonal disease in
which both environmental and genetic factors play a role. Data
also suggest that neuroendocrine factors are involved. I
briefly summarize observations that support this hypothesis.
RA is characterized by striking age-sex disparities. The
incidence of disease in women increases steadily from the age
of menarche to its maximal incidence around menopause. The
disease is uncommon in men under age 45, but its incidence
increases rapidly in older men and approaches the incidence in
women. These observations strongly suggest that androgens play
a major suppressive role, and, in fact, testosterone levels
are depressed in most men with RA. Mechanistically, many data
indicate that testosterone suppresses both cellular and
humoral immune responses. Dehydroepiandrosterone (DHEA), an
adrenal product, is the major androgen in women. Its
production is strikingly dependent upon age. Peak production
is in the 2nd and 3rd decades, but levels decline
precipitously thereafter. DHEA levels are low in both men and
women with RA, and recent data show that levels of this
hormone may be depressed before the onset of disease. The role
of DHEA in immune diseases, however, is controversial. The
menopausal peak of RA onset suggests estrogen and/or
progesterone deficiency play-a role in the disease, and many
data Indicate that estrogens suppress cellular immunity but
stimulate humoral immunity, i.e., deficiency promotes cellular
(Th1-type) immunity. Recent data also indicate that
progesterone stimulates a switch for Th1 to Th2-type immune
responses, RA often develops or flares in the postpartum
period, particularly if the mother breastfeeds. This is again
consistent with gonadal steroid deficiency playing a role in
the onset of disease. Breastfeeding is associated with blunted
hypothalamic-pitu itary-adrenal function and elevated
prolactin synthesis. Gonadal and adrenal steroid hormone
deficiency, plus elevated prolactin, probably greatly
facilitates the expression of Th1-type immunity, which is
widely believed to be critical in the pathogenesis of RA. By
contrast, RA typically remits during pregnancy, in parallel
with the increasing levels of corticosteroids, estrogens, and
progesterone. Pregnancy is characterized by a shift in immune
function from Th1-type to Th2-type. Oral contraceptives, which
generate a condition of pseudopregnancy, also decrease the
risk of RA. These data argue that adrenal and gonadal steroid
hormones suppress the development. of RA. Several studies
indicate that corticosteroid production is inappropriately low
in patients with RA, and are reminiscent of observations in
Lewis rat models of chronic erosive arthritis. In summary, a
growing body of data indicate that RA develops as a
consequence of a deficiency in both adrenal and gonadal
steroid hormone production. This hypothesis clearly has
potential clinical implications.
Can the length of hospital stay be influenced by
enteral immunonutrition?
Bastian L.; Weimann A.; Weissflog D.; Frei A.; Regel G.
Dr. L. Bastian, Unfallchirurgische Klinik, Medizinische
Hochschule, D-30623 Hannover Germany
Anasthesiologie und Intensivmedizin (Germany), 1997, 38/3
(137-147)
The balance of current clinical data suggests that early
enteral nutrition may influence infectious complications in
the critically ill patients. Certain nutrients may affect
organ function, independent of their general nutritional
effects. Four of these nutrients are arginine, nucleotides,
omega-3-fatty acids and glutamine. The target cells for the
action of these nutrients appear to be T-lymphocytes and
macrophages. An enteral nutrition enriched with such
nutrients is called 'immunonutrition'. Recent evidence has
suggested that an immunonutrition can have a beneficial effect
on the prevention of infectious complications and SIRS,
reduction of ventilator days, ICU- and hospital stay. This
seems to be translated into a reduction in hospital charges.
Beside a therapeutic approach with specific inhibitors and
receptor antagonists the so called 'immunonutrition' seems to
have a place in the therapy of the critically ill patient.
Immunohistochemical localization of cysteine-rich
intestinal protein in rat small intestine
Fernandes P.R.; Samuelson D.A.; Clark W.R.; Cousins
R.J.
R.J. Cousins, Food Science/Human Nutrition Dept., Center for
Nutritional Sciences, Univ. of Florida, PO Box 110370,
Gainesville, FL 32611 USA
American Journal of Physiology - Gastrointestinal and Liver
Physiology ( USA), 1997, 272/4 35-4 (G751-G759)
Cysteine-rich intestinal protein (CRIP) is a LIM
(cysteine-rich motif of leu-11, isl-1, and mec-3 genes) domain
protein with a double zinc finger motif. The protein is
abundantly expressed in the intestine, peritoneal macrophages,
and peripheral blood mononuclear cells. The function of CRIP
is not known. The purpose of this study was to determine the
cellular distribution of CRIP in rat intestine, as an initial
step toward eventual determination of a function.
Immunohistochemical and immunogold labeling electron
microscopy using a purified polyclonal rabbit antibody to a
synthetic peptide representing a zinc finger domain of rat
CRIP were carried out on sections of rat duodenum. Western
blotting was used to detect signal specificity of the
antibodies. These immunohistochemical and electron microscopy
studies showed particularly high abundance of CRIP in the
cytoplasmic granules of Paneth cells of the intestine. Some
evidence of CRIP expression was also found in cells of the
villus tip, but abundance was less than that found in the
Paneth cells. The localization of CRIP in Paneth cells and its
presence in mononuclear cells suggests that CRIP may be
involved in host defense mechanisms and/or tissue
differentiation/remodeling processes common to these cell
types.
Effect of early vitamin A supplementation on
cell-mediated immunity in infants younger than 6 mo
Rahman M.M.; Mahalanabis D.; Alvarez J.O.; Wahed M.A.; Islam
M.A.; Habte D.
J.O. Alvarez, Department of International Health, University
of Alabama at Birmingham, 106 Tidwell Hall, Birmingham, AL
35294-0008 USA
American Journal of Clinical Nutrition (USA), 1997, 65/1
(144-148)
One hundred twenty infants were randomly as signed to
receive either 15 mg vitamin A or placebo with each of three
DPT/OPV (diphtheria, pertussis, tetanus/oral polio vaccine)
immunizations at monthly intervals. Sixty-two received vitamin
A and 58 received placebo. One month after the third
supplementation dose, the response to the delayed cutaneous
hypersensitivity test (multitest cell-mediated immunity (CMI)
skin evaluation) for tetanus, diphtheria, and tuberculin
(purified protein derivative, PPD) was the same in the vitamin
A and placebo infants. The number of anergic infants was 17
(27%) and 19 (33%) in the vitamin A and placebo groups,
respectively. The number of positive tests among
well-nourished infants was significantly higher than that in
malnourished infants irrespective of supplementation (P <
0.001). Among the infants with adequate serum retinol
concentrations (> 0.7 micromol/L) after supplementation,
the vitamin A-supplemented infants had a significantly higher
proportion of positive CMI tests than the placebo infants
(chi-square test: 8.99, P = 0.008). Among the infants with low
serum retinol concentrations (< 0.7 micromol/L) after
supplementation, vitamin A supplementation had no effect on
CMI response. These results indicate that CMI in young infants
was positively affected by vitamin A supplementation only in
those infants whose vitamin A status was adequate (ie, serum
retinol > 0.7 micromol/L) at the time of the CMI test. CMI
was consistently better in well-nourished infants irrespective
of supplementation.
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.
Molecular mechanisms of vitamin A action and their
relationship to immunity
Chytil F.
Department of Biochemistry, Vanderbilt University, School of
Medicine, Nashville, TN 37232-0146 USA
Journal of Nutritional Immunology (USA), 1996, 4/1-2
(35-45)
This paper addresses the molecular mechanisms by which
vitamin A (retinol) could influence the immune system, and the
relationships of these mechanisms to the better known
mechanisms in which retinol affects other non-immune
biological phenomena, such as epithelial cell differentiation,
embryogenesis, and organ development. In many tissues, the
sequential molecular actions of the retinoids have been well
defined. However, major questions remain about the action of
retinoids on lymphocytes. Much evidence indicates an important
role for vitamin A molecules (called retinoids) in the
function of both the cellular and the humoral arms of the
immune system. Attention should also be paid to the nuclear
retinoic acid receptors (RAR) in various cells. These protein
receptors are similar to those which bind steroids, thyroid
hormones, and vitamin D. The nuclear retinoic acid receptors,
and another analogous receptor family initially called 'orphan
receptor' now designated 'nuclear RXR receptors,' together
with other described cellular binding proteins, appear to be
involved in regulating, as well as transmitting, the effects
of the retinoids on the molecular machinery of various body
cells, including the lymphocytes.
Historical overview of nutrition and immunity, with
emphasis on vitamin A
Beisel W.R.
Dept Molecular Microbiol Immunology, School of Hygiene and
Public Health, The Johns Hopkins University, Baltimore, MD
USA
Journal of Nutritional Immunology (USA), 1996, 4/1-2
(1-16)
In retrospect, the foundations for Nutritional Immunology
emerged in the early 1800s with the finding that severe
malnutrition would lead to thymic atrophy, and for most of
that century, all evidence for a relationship between
malnutrition and the immune system was based on anatomical
findings. With the discovery of vitamins, it became evident
that single essential nutrients each played an important role
in host resistance. During the 1920s and 1930s, vitamin A
became known as the 'anti-infective' vitamin, and the first
attempts were made to use vitamin A therapeutically during
infectious illnesses. With the gradual emergence of knowledge
about the details of immune system functions, malnutrition was
found to depress humoral immunity (by reducing the production
of antibodies to vaccines), cell mediated;immunity (by
inducing anergy to skin tests), and allergic symptoms. But the
first systematic studies of immunonutritional
interrelationships in laboratory animals were initiated in
1947 by Abraham E. Axelrod and his students. Human studies
followed soon thereafter, and by the late 1970s the field of
nutritional immunology was well established. The importance of
vitamin A in reducing the morbidity and mortality caused by
measles and other infectious illnesses has now re-emerged. The
potential importance of correcting vitamin A deficiency, as a
practical and inexpensive public health strategy to reduce
childhood mortality in the Third World, is being tested in
many locations, with The Johns Hopkins School of Hygiene and
Public Health playing an important role.
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.
Zinc deficiency: Changes in cytokine production and
T-cell subpopulations in patients with head and neck cancer
and in noncancer subjects
Prasad A.S.; Beck F.W.J.; Grabowski S.M.; Kaplan J.; Mathog
R.H.
USA
Proceedings of the Association of American Physicians (USA),
1997, 109/1 (68-77) 50X
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.
Immunotherapy of leprosy
Katoch K.
India
Indian Journal of Leprosy (India), 1996, 68/4
(349-361)
Immunotherapy aims to modify the defective cell-mediated
immune response in a section of leprosy cases. This
presentation reviews the various immunomodulators
developed/investigated for this purpose. Among the various
mycobacterial agents, BCG, BCG + M. leprae, Mycobacterium w,
ICRC bacillus and M. vaccae have been tried in leprosy
patients and varying degrees of beneficial effects on
bacterial killing and clearance have been observed. Studies
carried out at CJIL, Agra and elsewhere suggest an important
role for these mycobacteria as immunotherapeutic agents. Other
mycobacteria - M. habana, M. phlei, M. gordonae - have also
been reported to be promising experimentally. In addition,
various drugs such as levamisole, zinc and RACA 854
have been observed to have immunomodulatory role in leprosy
cases. Other promising immunomodulators include transfer
factor, interferon gamma, interleukin 2 and acetoacetylated M.
leprae. The progress achieved shows that immunotherapy may be
considered as adjunct to chemotherapy to enhance bacterial
killing as well as bacterial clearance and thus may be
recommended to shorten the treatment period, especially in
bacilliferous leprosy cases.
Immune and nutritional recovery of severely
malnourished children
Chevalier P.; Sevilla R.; Zalles L.; Sejas E.; Belmonte G.;
Parent G.; Jambon B.
ORSTOM, Laboratoire de Nutrition Tropicale, BP 5045, 34032
Montpellier Cedex 2 France
Cahiers Sante (France), 1996, 6/4 (201-208)
In developing countries, more than 123 million children die
each year from the combined effects of malnutrition and
infection. Malnourished children have impaired cellular
immunity and are particularly sensitive to opportunistic
infections. However, immune recovery has rarely been
investigated during nutritional rehabilitation. Indeed,
mortality remains high during renutrition, and relapses are
frequent. We established a center in Cochabamba, Bolivia,
specifically to save these children by treating both clinical
and nutritional problems and restoring immune function. The
CRIN (center for immuno-nutritional recovery) admits children
with severe malnutrition from the Cochabamba suburban area.
They are from low income families, in crowded living
conditions with poor sanitation and are weaned early.
Nutritional diagnosis was based on weight-for-height, arm to
head circumference ratio and clinical examination for edema,
loss of subcutaneous tissue and diminished muscle mass. The
children were examined daily and first treated for respiratory
and intestinal infections. Sociological and psychological
aspects were also included in our holistic approach to
treating severe malnutrition. Children received a four-stage
diet lasting 2 months. During the initial phase (1 week) they
were given an oil-sugar-mild based diet, with half lactose
concentration, seven times a day. This supplied 1.5 to 2.5 g
of protein and 120 to 150 kcal/kg of body weight, according to
the PEM pattern. Protein and energy intake was then slowly
increased during the transition phase (1 week). During the
next, 'calorific-protein bombing' phase (6 weeks) 5 g of
protein and 200 kcal/kg of body weight were given daily, such
that there was sufficient energy for protein accumulation.
During the last, discharge phase (1 week), the protein and
energy contents were slowly decreased. Weight, height, arm and
head circumferences, and triceps skin-fold thickness were
measured weekly by standardized methods. Thymus size was
assessed weekly by mediastinal ultrasound scanning with a
portable scanner (ALOKA SSD-210 DXII, Tokyo) using a 5 MHz
linear pediatric probe. Lymphocyte subpopulations in
peripheral blood were investigated monthly using monoclonal
antibodies. Compared to controls, the malnourished group had
severe involution of the thymus, a significantly higher
proportion of circulating immature T lymphocytes and a lower
proportion of mature T lymphocytes. The two month longitudinal
study showed that normal anthropometric values (90% NCHS
weight for height) were recovered after one month of
rehabilitation. However, immune recovery (thymic area of 350
mm2) required two months. This may explain the frequent
relapses among malnourished children discharged after one
month on the basis of 'apparent nutritional health'. Such
children may remain immunodepressed, and should therefore be
considered as high risk children. To test an immunostimulatory
treatment, we designed a historical cohort study of
malnourished children who received 2 mg of zinc per day. The
children were matched for age, sex, anthropometric criteria
and nutritional status with malnourished control children
(treated previously without zinc). Anthropometric recovery was
obtained in both groups in one month. Children receiving zinc
attained immunological recovery within one month, whereas
children not receiving zinc took two months. Thus zinc
hastened immunological recovery concomitant with nutritional
recovery such that the duration of hospitalization could be
halved: after one month of this immuno-nutritional treatment,
malnourished children appear to be sufficiently healthy to
face their pathogenic home environment.
Aspects of airway defence mechanisms
Korpas J.; Honda Y.
Department Pathophysiology, Jessenius Medical Faculty,
Comenius University, Slabinska 26, 037 53 Martin Slovak
Republic
Pathophysiology (Netherlands), 1996, 3/2 (81-86)
This review deals with recent findings in the airways and
lung defence. It is well known that the respiratory tract
forms the largest part of the human body surface which is
directly exposed to the influence of inspired air. This can
differ with regard to temperature, humidity, capacity of
harmful gases, vapors, pollutants, and living and non-living
particles. Therefore the airways and lungs have very effective
defence processes consisting of reflex and non-reflex
mechanisms. The reflex reactions include coughing, sneezing,
aspiration and apnoeic reflexes, laryngo- and bronchospasms
and mucociliary transport which has been considered to be a
non-reflex reaction. The electrostatic filter of the tonsilar
ring, immunological and antimicrobial defence,
oxidant-antioxidant and protease-antiprotease systems and the
architecture of the airways belong to the non-reflex group.
Considerable progress has been made in understanding molecular
mechanisms over the last decade. From this viewpoint the
defence complex of activated pulmonary epithelial and
inflammatory cells together with their mediators is very
important. This complex has not previously been identified in
the airways defence system. Both reflex and non-reflex
mechanisms are independent units, but they normally interact.
It is paradoxical that an original physiological defence
activity can change its character into a pathological one if
it is inadequate, survives the cause of its activation or
triggers some secondary pathological process. In spite of
intensive study of the respiratory tract defence systems in
the last few years there are many links in structure and
function which need further elucidation. Thus these large
complexes of defence mechanisms require further study.
Cellular and humoral immunity in rats after
gestational zinc or magnesium deficiency
Vormann J.; Michalski L.; Gunther T.
Freie Universitat, Inst. fur Molekularbiologie/Biochem.,
Arnimallee 22, D-14195 Berlin Germany
Journal of Nutritional Biochemistry (USA), 1996, 7/6
(327-332)
The effects of gestational Mg or Zn deficiency on the
humoral or cellular immunity of newborn rats were
investigated. Mg deficiency was induced by feeding a diet
containing 180 ppm Mg from day 0 to day 21 of gestation and Zn
deficiency was induced by feeding a diet containing 1.5 ppm Zn
from day 0 to day 19. Controls were fed a diet with 1,000 ppm
Mg and 100 ppm Zn from day 0 to day 21. Thereafter, all
maternal rats and newborns were fed diets with normal amounts
of Mg or Zn. Three and six weeks after birth, T-cell
subpopulations in blood and thymus and B-cells in blood of the
newborns were detected by flow cytometry. Plasma contents of
IgG, IgM, and IgA were determined by radial immunodiffusion.
Mg deficiency reduced litter size and pup weight. Three weeks
after birth, the total number of leukocytes and lymphocytes in
blood was significantly decreased, due to a reduction of
T-helper and cytotoxic T-cells. Activated T-cells and B-cells
were unchanged. Six weeks after birth, T-cell subpopulations
approached controls values, whereas IgG content in plasma was
slightly reduced. Gestational Zn deficiency reduced litter
size and induced malformations. Three and six weeks after
birth, body weight, number of leukocytes, lymphocyte, and
T-cell subpopulations were not significantly changed. Plasma
IgM was decreased 3 weeks after birth in correlation to the
number of B-cells, which represented only 4% of total
lymphocytes. These effects were repaired by the sixth week.
Plasma IgG was reduced at 6 weeks. No effects on T-cell
subpopulations in isolated thymocytes were detected after
gestational Mg or Zn deficiency.
Immunomodulation by Pycnogenol (R) in
retrovirus-infected or ethanol-fed mice
Cheshier J.E.; Ardestani-Kaboudanian S.; Liang B.;
Araghiniknam M.; Chung S.; Lane L.; Castro A.; Watson
R.R.
Dept. of Family/Community Medicine, University of Arizona,
Tucson, AZ 85724 USA
Life Sciences (USA), 1996, 58/5 (PL-87-PL-96)
Pycnogenol (R) is a commercial mixture of bioflavonoids
that exhibits antioxidative activity. The effects of dietary
pycnogenol on immune dysfunction in normal mice as well as
those fed ethanol or infected with the LP-BM5 murine
retrovirus were determined. The ethanol consumption and
retrovirus infection cause abnormalities in the function
and/or structure of a broad array of cells involved in humoral
and cellular immunity. Pycnogenol enhanced in vitro IL-2
production by mitogen-stimulated splenocytes if its production
was suppressed in ethanol-fed or retrovirus-infected mice.
Mitogenesis of splenocytes did not show a significant change
in mice treated with pycnogenol. It reduced the elevated
levels of interleukin-6 produced in vitro by cells from
retrovirus infected mice and IL-10 secreted by spleen cells
from mice consuming ethanol. Natural killer cell cytotoxicity
was increased with pycnogenol treatment.
Iron in liver diseases other than
hemochromatosis
Bonkovsky H.L.; Banner B.F.; Lambrecht R.W.; Rubin R.B.
Div. of Digestive Disease/Nutrition, Univ. of Massachusetts
Med. Center, 55 Lake Avenue, North, Worcester, MA 01655
USA
Seminars in Liver Disease (USA), 1996, 16/1
(65-82)
There is growing evidence that normal or only mildly
increased amounts of iron in the liver can be damaging,
particularly when they are combined with other hepatotoxic
factors such as alcohol, porphyrogenic drugs, or chronic viral
hepatitis. Iron enhances the pathogenicity of microorganisms,
adversely affects the function of macrophages and lymphocytes,
and enhances fibrogenic pathways, all of which may increase
hepatic injury due to iron itself or to iron and other
factors. Iron may also be a co-carcinogen or promoter of
hepatocellular carcinoma, even in patients without HC or
cirrhosis. Based on this and other evidence, we hope that the
era of indiscriminate iron supplementation will come to an
end. Bloodletting, a therapy much in vogue 2 centuries ago, is
deservedly enjoying a renaissance, based on our current
understanding of the toxic effects of iron and the benefits of
its depletion.
Viamin E supplementation induces an early recovery
of cellular immunity decreased following X-ray
irradiation
Moriguchi S.; Oonishi K.; Kishino Y.; Umegaki K.
Department of Nutrition, School of Medicine, University of
Tokushima, Tokushima 770 Japan
Nutrition Research (USA), 1996, 16/4 (645-656)
We have previously reported that vitamin E has an ability
to enhance T cell differentiation in rat thymus. The aim of
this study is to investigate whether T cell differentiation
enhanced by vitamin E supplementation is effective in
decreasing cellular immunity after X-ray irradiation in rats.
Male Fisher rats, 4-weeks old, were fed control (50 mg vitamin
E/kg diet) or high vitamin E diet (585 mg vitamin E/kg diet)
for 4 weeks and then irradiated X-ray. On 2, 5 and 9 days
after X-ray irradiation, rats were killed under anesthesia and
their cellular immune functions were assayed. Vitamin E
supplementation did not result in decreased thymic weights or
change in the numbers of thymocytes and peripheral blood
lymphocytes (PBL) following X-ray irradiation. In addition,
proliferation of PBL with T cell mitogens, phytohemagglutinin
(PHA) and concanavalin A (ConA), also decreased in both
control and high vitamin E groups following X-ray irradiation.
On the contrary, proliferation of bone marrow cells (BMC) was
maintained much the same as pretreatment of X-ray irradiation
in high vitamin E group even after X-ray irradiation compared
to a significant decrease in the control group. The
proliferation of thymocytes with PHA or ConA also showed an
early recovery in high vitamin E, which was associated with
not the production of interleukin 2 (IL2), T cell growth
factors, but early recovery in the proportion of CD4+CD8+ T
cells in thymocyte. These results suggest that vitamin E
supplementation accelerates the recovery of the X-ray
irradiation- induced decrease in cellular immunity. The signs
of accelerated recovery were enhanced T cell differentiation
in thymus and the maintenance of bone marrow cell (BMC)
proliferation during X-ray irradiation.
Effects of short-term zinc supplementation on
cellular immunity, respiratory symptoms, and growth of
malnourished Equadorian children
Sempertegui F.; Estrella B.; Correa E.; Aguirre L.; Saa B.;
Torres M.; Navarrete F.; Alarcon C.; Carrion J.; Rodriguez A.;
Griffiths J.K.
Inmunologia y Bioquimica, Facultad de Medicina, Universidad
Central del Ecuador, PO Box 60, Sucursal 16 CEQ, Quite
Ecuador
European Journal of Clinical Nutrition (United Kingdom),
1996, 50/1 (42-46)
Objective: To assess the effect of zinc supplementation on
respiratory tract disease, immunity and growth in malnourished
children. Design: A randomized double-blind placebo-controlled
trial.
Setting: A day-care center in Quite, Ecuador.
Subjects: Fifty children (12-59 months old) recruited by
height-for-age and weight-for-age deficit.
Interventions: Twenty-five children (supplemented, S group)
received 10 mg/day of zinc as zinc sulfate, and 25
(nonsupplemented, NS group) received a placebo during 60 days.
All were also observed during a 60-day postsupplementation
period. Two children of the S group dropped out. Daily the
clinical presence of cough, respiratory tract secretions, and
fever, was recorded. On days 0, 60 and 120, the cutaneous
delayed-type hypersensitivity (DTH) to multiple antigens, and
anthropometric parameters were assessed. On days 0 and 60
serum zinc levels were also measured.
Results: On day 60, DTH was significantly larger (20.8 plus
or minus 7.1 vs 16.1 plus or minus 9.7 mm), and serum zinc
levels were significantly higher (118.6 plus or minus 47.1 vs
83.1 plus or minus 24.5 microg/dl) in the S group than in the
NS group (P < 0.05 for each). The incidence of fever
(relative risk (RR): 0.30, c.i. = 0.08-0.95, P = 0.02), cough
(RR): 0.52, c.i. = 0.32-0.84, P = 0.004) and upper respiratory
tract secretions (RR):0.72, c.i. = 0.59-0.88, P = 0.001) was
lower in the S group than in the NS group at day 60. At the
end of the postsupplementation observation period (day 120),
the incidence of fever and upper respiratory tract secretions
was the same in both the S and NS groups. The incidence of
cough was higher at day 120 in the S group than in the NS
group (RR): 2.28, c.i. = 1.37-3.83, P = 0.001).
Conclusions: This study supports a role for zinc in
immunity, and immunity to respiratory infections, while
pointing out the need for larger studies.
Selenium: a quest for better understanding.
Badmaev V; Majeed M; Passwater RA
Sabinsa Corporation, Piscataway, NJ, USA.
Altern Ther Health Med (United States) Jul 1996, 2 (4)
p59-62, 65-7
Selenium is an essential trace element in nutrition for the
prevention of disease in humans. Epidemiological studies
indicate an association between low nutritional selenium
status and increased risks of cardiomyopathy, cardiovascular
disease, and carcinogenesis in various sites of the body. The
role of selenium supplementation in the prevention and
treatment of AIDS-related pathology has been considered.
Selenoproteins discovered in mammalian cells may account for
the essentiality of selenium in the body's antioxidant
defense; thyroid hormone function; immune system function,
particularly the cellular immunity; formation of sperm; and
functioning of the prostate gland. The seleno-organic
compounds, primarily L-(+)-selenomethionine, generally are
recognized as safe and effective forms of selenium
supplementation. The nutritionally recommended dose of
elemental selenium is estimated at 50 to 200 mg per day. There
is, however, increased discussion of a pharmacological dose of
selenium, significantly higher than the nutritional dose of
the microelement, to treat active conditions. One way of
increasing the tissue levels of selenium is to combine its
ingestible form with a nutrient bioavailability enhancing
compound. (87 Refs.)
In vitro effects of echinacea and ginseng on
natural killer and antibody-dependent cell cytotoxicity in
healthy subjects and chronic fatigue syndrome or acquired
immunodeficiency syndrome patients.
See DM; Broumand N; Sahl L; Tilles JG
Department of Medicine, U.C. Irvine Medical Center, Orange
92668, USA.
Immunopharmacology (Netherlands) Jan 1997, 35 (3)
p229-35
Extracts of Echinacea purpurea and Panax ginseng were
evaluated for their capacity to stimulate cellular immune
function by peripheral blood mononuclear cells (PBMC) from
normal individuals and patients with either the chronic
fatigue syndrome or the acquired immunodeficiency syndrome.
PBMC isolated on a Ficoll-hypaque density gradient were tested
in the presence or absence of varying concentrations of each
extract for natural killer (NK) cell activity versus K562
cells and antibody-dependent cellular cytotoxicity (ADCC)
against human herpesvirus 6 infected H9 cells. Both echinacea
and ginseng, at concentrations > or = 0.1 or 10
micrograms/kg, respectively, significantly enhanced
NK-function of all groups. Similarly, the addition of either
herb significantly increased ADCC of PBMC from all subject
groups. Thus, extracts of Echinacea purpurea and Panax ginseng
enhance cellular immune function of PBMC both from normal
individuals and patients with depressed cellular immunity.
Allium sativum (garlic) treatment for murine
transitional cell carcinoma.
Riggs DR; DeHaven JI; Lamm DL
Department of Urology, West Virginia University School of
Medicine, Morgantown 26506, USA.
Cancer (United States) May 15 1997, 79 (10)
p1987-94
BACKGROUND: Currently, immunotherapy with Bacillus
Calmette-Guerin (BCG) is the most effective treatment for
superficial bladder carcinoma, but treatment-related toxicity
may limit its use in some patients. Alternative treatments are
needed for patients who fail to respond to BCG immunotherapy.
Allium sativum (AS), or garlic, is known to have a broad range
of biologic activities, including immune stimulation and
reported antitumor activity. For these reasons, the authors
conducted a series of experiments designed to explore the
possible therapeutic effects of AS in the MBT2 murine bladder
carcinoma model.
METHODS: C3H/HeN mice were randomized prior to initiation
of each experimental protocol. Mice received 1 x 10(3) MBT2
cells in 0.1 mL RPMI-1640, administered subcutaneously into
the right thigh, on Day 0 of the experiment. AS was injected
at the site of tumor transplantation on Day 1 and at 2- to
7-day intervals up to Day 28. To evaluate the effects of oral
AS in this model, treatment was initiated 30 days prior to
tumor inoculation and continued for 30 days after tumor
inoculation. Animals in all experiments were followed for
tumor incidence, tumor growth, and survival.
RESULTS: In the initial experiments, subcutaneous AS
significantly reduced tumor volume compared with the saline
control (P < 0.05). Unfortunately, treatment-related death
was also observed, requiring reduction in the total dose of
AS. Animals that received 5 weekly immunizations of AS (5 mg,
5 mg, 1 mg, 1 mg, and 1 mg; cumulative dose = 13 mg) had
significantly reduced tumor incidence, tumor growth, and
increased survival when compared with animals that received
the saline control. No treatment-related deaths were observed
with this treatment schedule. To determine whether systemic AS
administration might be effective, orally administered AS was
tested at doses of 5 mg, 50 mg, and 500 mg per 100 mL of
drinking water. Mice that received 50 mg oral AS had
significant reductions in tumor volume (P < 0.05) when
compared with animals that received the saline control, and
mice that received 500 mg oral AS had significant reductions
in both tumor volume and mortality (P < 0.05).
CONCLUSIONS: The significant antitumor efficacy of
subcutaneous and oral AS warrants further investigation and
suggests that AS may provide a new and effective form of
therapy for transitional cell carcinoma of the bladder.
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