schroecksnadel_DML07

schroecksnadel_DML07
Drug Metabolism Letters, 2007, 1, 166-171
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Antioxidants Suppress Th1-Type Immune Response In Vitro
Katharina Schroecksnadel1,2, Birgit Fischer1, Harald Schennach3, Guenter Weiss2 and
Dietmar Fuchs1,*
1
3
Division of Biological Chemistry, Biocentre, and 2Department of General Internal Medicine, Medical University, and
Central Institute of Immunology and Transfusion Medicine, University Clinics, Innsbruck, Austria
Abstract: Inflammation is a hallmark of various diseases like infections, autoimmune syndromes, cardiovascular and neurodegenerative disorders, and cancer. Thereby, Th1-type cytokine interferon- is a central pro-inflammatory mediator. Antioxidant compounds counteract the activation of T-cells and macrophages. This anti-inflammatory activity could be important for the development of immunotolerance and for treatment of above-mentioned disorders.
Key Words: Antioxidants, inflammation, neopterin, indoleamine (2,3)-dioxygenase, interferon-.
INTRODUCTION
Diseases of the circulatory system account for approximately one third of deaths in the Western world, approximately another 20% of humans dies from cancer. Also
chronic infections still cause serious problems, and with
older age, the great majority of humans is likely to suffer
from neurodegenerative disorders like Alzheimer’s dementia. In the pathogenesis of these clinical conditions, immune
system activation and inflammation are deeply involved.
Pro-inflammatory cytokines like tumor necrosis factor-
(TNF-) and interferon- (IFN-) play a prominent role in
the development of inflammation, whereby the expression of
nuclear factor-B (NF-B) is central within the proinflammatory cascade [1, 2]. In patients, signs of inflammation like accelerated blood sedimentation rate and increased
concentrations of acute phase proteins as C-reactive protein
(CRP) are often present [3]. Likewise, indicators of immune
activation such as neopterin, tryptophan catabolites or soluble cytokine receptors are enhanced in the blood and tissue
of patients [4-7].
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IMMUNE RESPONSE AND INFLAMMATION
Immunosurveillance requires a complex network of cells
and mediators to provide sufficient defence against invading
pathogens and malignant development. Adaptive immune
responses allow establishment of immune memory, which
guarantees accelerated immune response when an attack by
the same invader occurs repeatedly. Adaptive immune responses mainly rely on specific effector cells such as T-cells,
macrophages, and B-cells. Their fine-regulation is controlled
by various mediators, so-called cytokines, released by the
cells upon activation [8, 9]. During adaptive immune response against intracellular pathogens like viruses, type 1 T
helper cells (Th1-type cells) are activated and release specific Th1-type cytokines, such as interleukin-2 and IFN-
(Fig. 1) [8]. IFN- is probably the most important mediator
of anti-microbial and anti-tumoral defence, which includes
high-output of toxic reactive oxygen species (ROS) in
macrophages [10, 11]. They are directed to destroy vital
*Address correspondence to this author at Division of Biological Chemistry,
Biocenter, Innsbruck Medical University, Fritz Pregl Str. 3, A-6020 Innsbruck, Austria; Tel: ++43-512-9003-70350; Fax: ++43-512-9003-73330; Email: dietmar.fuchs@i-med.ac.at
1872-3128/07 $50.00+.00
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Fig. (1). Th1-type cytokine interferon- (IFN-) causes oxidative
stress and inflammation. Th1-type immune response is characterized by production of cytokine interferon- (IFN-), which stimulates several antiproliferative effector functions in monocytederived macrophages (M) like production of reactive oxygen
species (ROS) and expression of enzymes indoleamine (2,3)dioxygenase (IDO) and GTP-cyclohydrolase I (GCH). These enzymes are responsible for the conversion of tryptophan to
kynurenine and the production of neopterin. ROS trigger redoxsensitive signal transduction elements like nuclear factor-B (NFB) which accelerate the production of pro-inflammatory cytokines
such as tumor necrosis factor- (TNF-). Continuous release of
ROS overwhelms antioxidant capacity of cells, and oxidative stress
and inflammation are developing.
cellular structures like lipids and proteins and to inhibit
growth and proliferation of cells and pathogens. ROS also
trigger redox-sensitive intracellular signal-transduction cascades involving, e.g. NF-B [12, 13], which accelerate the
production pro-inflammatory cytokines like TNF- (Fig. 1)
[14]. As a consequence, the production of ROS not only is
part of the killing strategy of effector cells within cellular
immune response, it also amplifies the release of proinflammatory cytokines. During sustained periods of Th1type immune activation, e.g. in chronic infections, the continuous and overwhelming production of ROS leads to the
depletion of antioxidant pools, and oxidative stress is emerging (Fig. 1) [15].
IMMUNE RESPONSE-ASSOCIATED NEOPTERIN
PRODUCTION AND TRYPTOPHAN DEGRADATION
The determination of cytokines in biological fluids of
patients is often limited by their short half-life in the circula©2007 Bentham Science Publishers Ltd.
Antioxidants Suppress Th1-Type Immune Response In Vitro
tion. Cytokines rapidly stick to receptors on target cells or
are neutralized by specific soluble receptors [7]. Activated
Th1-type immune response can be sensitively detected when
secondary messengers of IFN- activity are monitored. For
this purpose, the quantification of neopterin concentrations
[4, 5, 15] and of tryptophan degradation [6, 16] is particularly useful. IFN- stimulates neopterin formation via the
induction of the enzyme guanosine-triphosphate-(GTP)cyclohydrolase I [17], and the same cytokine triggers tryptophan degradation by the enzyme indoleamine (2,3)dioxygenase (IDO) (Fig. 1) [18, 19]. To estimate IDO activity, calculating the ratio of the concentration of the enzyme
product kynurenine (kyn) versus the substrate tryptophan
(trp) (= kyn/trp), is convenient [6].
In the course of diseases with an activated cellular immune response, a concurrent increase of neopterin production and tryptophan degradation is detectable, and kyn/trp
and neopterin concentrations correlate closely [6]. This is
true in a variety of disorders such as infections including
HIV infection, in autoimmune syndromes, in malignant diseases, in coronary heart disease, in neurodegenerative disorders such as Parkinson’s disease and Alzheimer’s dementia,
and also in cytokine-treated patients [4-6, 16, 20]. Striking
associations exist between neopterin production and accelerated tryptophan degradation and the extent, the activity and
the course of the diseases. Moreover, in malignancy and in
HIV infection, higher neopterin concentrations and kyn/trp
predict shorter survival and correlate with the development
of cachexia and anemia. Available data show that by means
of neopterin and kyn/trp measurements a sensitive monitoring of immune activation and inflammatory response is feasible which, especially in chronic situations, also allows conclusions about the oxidative stress status in patients [15].
Drug Metabolism Letters, 2007, Vol. 1, No. 3
production and tryptophan degradation (Fig. 2). Pro-inflammatory cytokines like IL-12 further enhance neopterin concentrations and kyn/trp, whereas Th2-type cytokines IL-4
and IL-10 exert suppressive effects [26]. Similarly, antiinflammatory drugs like aspirin and salicylic acid [27] and
also HMG-CoA reductase inhibitor atorvastatin [21] slowdown mitogen-induced neopterin production and tryptophan
degradation.
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The measurement of neopterin production and tryptophan
degradation is applied to gain direct insight into the interplay
between T-cells and macrophages also in vitro [21-23]. Using peripheral blood mononuclear cells (PBMC), which consist mainly of T-cells and macrophages, the effects of compounds on the interplay of these two cell-types, which are
most important in cellular immune response, is analysed.
Freshly isolated PBMC from healthy donors are stimulated
with mitogens such as phytohaemagglutinin (PHA), concanvanalin A (Con A) or pokeweed mitogen (PWM), and cells
are incubated at 37 °C for 48 hours. Viability of cells is controlled by, e.g., the trypan blue exclusion method and by
FACS-analysis employing propidium iodine staining to test
for apoptosis [21, 22]. To monitor degree of cellular stimulation, neopterin production [24] and tryptophan degradation
[25] are determined in supernatants, e.g., by immunoassays
or HPLC, kyn/trp is calculated.
Cell culture medium for human cells contains approximately 30 mol/L of the essential amino acid tryptophan and
activated IDO is detectable by a decline of the tryptophan
content and a parallel increase of kynurenine concentrations,
consequently, kyn/trp increases. Cell cultures stimulated
with mitogens show a dose-dependent increase of neopterin
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IN VITRO ASSAY TO DETECT ANTI-INFLAMMATORY AND/OR IMMUNOMODULATORY CAPACITY OF COMPOUNDS/DRUGS/EXTRACTS
167
Fig. (2). Neopterin production and degradation of tryptophan
in peripheral blood mononuclear cells (PBMC) are induced by
mitogens. Dose-dependent degradation of tryptophan and production of neopterin is observed in PBMC stimulated with mitogen
phytohemagglutinin (PHA). Degradation of tryptophan is reflected
by decline of tryptophan (upper part, white bars) and an increase of
kynurenine (upper part, black bars). As a consequence, the kynurenine to tryptophan ratio (kyn/trp; black columns, lower part note:
log-scale) increases, in parallel, neopterin is produced (lower part,
white bars).
Several extracts of plants and seeds with supposed antiinflammatory properties suppress neopterin production and
tryptophan degradation [28], among them Peruvian Uncaria
tomentosa [22], a giant vine of the Rubiaceae family,
St.John’s wort (Hypericum perforatum) [29], as well as Cucurbita pepo seeds [30], beetroot [31], and Crinum latifolium
[32], which is popular in Vietnamese and Chinese traditional
medicine, and Tibetan herbal mixture Padma 28 [33] (Table
1). Green and black tea preparations from Camellia sinensis
and other common beverages like red and white wine, or
beer – including their alcohol free analogues like grape juice
and alcohol-free beer - suppress neopterin production and
tryptophan degradation in a dose-dependent way [34, 35].
Finally, pure antioxidant compounds resveratrol [36] and
vitamin C (ascorbic acid) and E (-tocopherol) [37] are also
very effective in suppressing neopterin production and tryptophan degradation (Fig. 3). Likewise, food preservatives
sodium sulfite (E221) and sorbic acid (E200) have a significant suppressive effect on neopterin production, tryptophan
degradation and also on the release of IFN- [38].
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Drug Metabolism Letters, 2007, Vol. 1, No. 3
Table 1.
Schroecksnadel et al.
Pure Antioxidant Compounds and Plant Extracts,
Teas and Beverages with High Antioxidant Content,
Like Th2-type Cytokines and Anti-Inflammatory
Drugs Suppress Mitogen-Stimulated Peripheral
Blood Mononuclear Cells In Vitro
References
Plant extracts
Teas and beverages
Antioxidants
Food preservatives
Uncaria tomentosa
[29]
Hypericum perforatum
[22]
Cucurbita pepo seeds
[30]
Beetroot
[31]
Padma 28
[33]
Crinum latifolium
[32]
Camellia sinensis
[32]
Wine (red, white)
[34]
Grape juice
[34]
Beer
[35]
Ascorbic acid (vitamin C)
[37]
-Tocopherol (vitamin E)
[37]
Sodium sorbate
[38]
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Cytokines
Interleukin-4
Interleukin-10
Drugs
[36]
Aspirin, salicylic acid
Atorvastatin
[38]
[26]
[26]
[27]
[21]
GENERAL DISCUSSION
Antioxidant compounds resveratrol, and vitamin C and E
are found to suppress pro-inflammatory immune activation
pathways. Likewise, extracts of plants with anti-inflamma-
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Resveratrol
Sodium sulfite
tory properties as well as beverages rich in antioxidants exert
a similar effect (Table 1). A marked coincidence exists between the suppression of neopterin production and tryptophan degradation, and in some experiments, in which also
IFN- production was measured, it was observed to be suppressed as well. Thus, results are best summarized with the
conclusion that compounds and extracts suppressed Th-1
type immune response which includes the production of
IFN-. Since plant extracts, teas and beverages gave similar
results as the pure antioxidant compounds, data suggest that
antioxidant contents are also relevant for their suppressive
effect. Compounds like tannins, diester alkaloids, lactones
and resveratrol, antioxidant vitamins, e.g., C and E, phytoestrogens, saponins and flavonoids seem to be especially important for this effect [39]. Data correspond well with the
observation that several herbal compounds and spice-derived
phytochemicals suppress NF-B activation [40, 41]. The
mode of action by which antioxidants suppress stimulated Tcells and IFN- production is most likely due to their capacity to detoxify ROS. Moreover, by suppressing redoxsensitive signal transduction cascades like NF-B and IFN-
production, antioxidants are able to counteract the most important triggers for the production of ROS (Fig. 4), which are
deeply involved in the signaling cascades critical in forwardregulation of pro-inflammatory Th1-type immune response.
Plant extracts and teas have been used for medicinal purposes throughout the ages. They are used for health maintenance and for the treatment or prevention of minor ailments
like common cold or mood disturbances, but sometimes also
for treatment of more serious, particularly chronic diseases
like rheumatoid arthritis, chronic neurologic disorders or
depression. There is indication that part of the functional
activity of plant and herbal medicine is related to their activity to counteract inflammation and thereby to improve or
normalize immune cell functioning. Also beverages with
high antioxidant content as well as pure antioxidants are
widely considered to improve inflammatory conditions, and
their capacity to slow-down Th1-type immune activation
pathways appears important with this respect. Whereas beer
or wine have a significant effect on stimulated PBMC, no
influence of pure ethanol (highest final concentration tested:
0.25% corresponding with the maximum alcohol content of
diluted alcoholic beverages) was seen neither on tryptophan
Fig. (3). Vitamin C and E suppress stimulated peripheral blood mononuclear cells (PBMC). In PBMC neopterin production and degradation of tryptophan is induced by mitogen phytohemagglutinin. Vitamin C and E suppress these effects: neopterin and kynurenine concentrations in stimulated cells were set as 100% (grey bars), upon addition of vitamins (dark bars), the effect of PHA is dose-dependently reverted (*p<0.01; adapted from ref. [37]).
Antioxidants Suppress Th1-Type Immune Response In Vitro
Drug Metabolism Letters, 2007, Vol. 1, No. 3
169
ing. Also Padma 28, a mixture corresponding to a Tibetan
herbal formula, is used against chronic inflammatory diseases, intermittent claudication, atherosclerosis and chronic
active hepatitis B [45], and likewise, consumption of green
and black tea from Camellia sinensis appears to protect, e.g.,
from cardiovascular diseases, bacterial infections and from
several forms of cancer [46].
Fig. (4). Antioxidants may improve mood. Activated Th1-type
immune response is associated with accelerated tryptophan degradation via induction of indoleamine (2,3)-dioxygenase. Tryptophan
levels are diminished and the production of neurotransmitter 5hydroxytryptamine (serotonin) by tryptophan (5)-hydroxylase declines - the susceptibility for depressive mood increases. Antioxidants counteract Th1-type immune response and IDO activation.
Tryptophan and serotonin concentrations normalize and thus mood
status improves.
The observation that plant extracts and antioxidants suppress Th1-type cytokine IFN- and biochemical pathways
induced by IFN-, allows better understanding the background of beneficial effects which are ascribed to the intake
of “healthy food” and beverages and pure antioxidants. Results imply that application of herbal extracts, compounds or
drugs with anti-inflammatory properties in vitro could be of
benefit in slowing-down inflammation also in patients. They
may however also be of some benefit in prophylaxis, although it is well established that inherited genes do influence
disease risks, but behavioral factors like cigarette smoking,
dietary patterns and physical activity can greatly influence
the risk of, e.g., cancer or cardiovascular disorders [47]. Vice
versa, adequate lifestyle and dietary habits may be able to
reduce, e.g., cancer risk by up to 30 – 40 % [48]. To study
the relationship between fruit and vegetable intake and the
incidence of cardiovascular disease and cancer and of deaths
from other causes in vivo is not easy and often gives conflicting results. Recently in two prospective cohorts increased
fruit and vegetable consumption was found to be associated
with only a modest and not statistically significant reduction
in the development of major chronic disease [49]. Recently
also the effect of antioxidant supplements on mortality in
randomized primary and secondary prevention trials was
assessed by a meta-analysis [50]. Whereas the roles of vitamin C and selenium on mortality remained unclear, the
treatment with beta carotene, vitamin A, and vitamin E was
found to probably even increase mortality.
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degradation nor on neopterin production [34, 35]. Thus,
other compounds are likely to be responsible for the antiinflammatory effect of these beverages.
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The spectrum of diseases in which beneficial effects of
antioxidants, of beverages rich in antioxidants and of phythomedicines are believed comprises infections, autoimmune,
malignant, cardiovascular and neurodegenerative disorders,
and appears to perfectly match with the diseases mentioned
earlier, which are accompanied by increased neopterin concentrations and accelerated tryptophan degradation. It is reasonable that at least part of their benefit is due the effect to
slow-down the pro-inflammatory cascades which are stimulated by IFN-. This conclusion holds also true for well characterized and established anti-inflammatory agents like aspirin and salicylic acid [27], and it can also be extrapolated to
statins, of some of which anti-inflammatory and immunosuppressive properties are well established [21, 42]. Notably
due to their chemical nature, also aspirin, salicylic acid and
atorvastatin possess profound antioxidative and radicalscavenging properties.
Cytokine IFN- is very important for functional Th1-type
immune response and to elicit antimicrobial activity during
the acute phase of the cellular immune response. However,
in chronic conditions, the antiproliferative nature of IFN-
becomes more and more relevant also for the host’s immunoresponsiveness. Especially in chronic diseases, cascades of immune activation and of ROS production appear to
precipitate adverse effects and contribute to disease progression [43, 44]. The plant extracts are often applied in traditional folk medicine for complementary treatment of inflammatory conditions like arthritis, cancer, asthma, stomach
ulcers, inflammation of the urinary tract, abscesses, viral
diseases, menstrual disorders and disorders of wound heal-
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Still it is questionable to what extent one can extrapolate
results from in vitro experiments to effects in humans. The
relevance of the in vitro findings could be limited by the fact
that not all of the active compounds can be efficiently absorbed, and a gradient may exist between the concentrations
present in the extracts used and the ones established in the
blood. However, at least in the gastrointestinal tract one can
assume the presence of all compounds at reasonable concentrations which may allow antioxidant reactions [51]. The
antioxidant capacity of ingested compounds could be of
relevance to establish or shift the redox equilibrium in the
gut which then is of benefit for the whole organism.
ANTIOXIDANTS TO IMPROVE MOOD
Tryptophan is precursor of serotonin. Thus, when availability of tryptophan is decreased by IDO during inflammatory conditions, it may negatively affect the biosynthesis of
serotonin (Fig. 4) [52]. Disturbed biochemistry of the neurotransmitter 5-hydroxytryptamine (serotonin) is one important
risk factor for depressive mood which is also a common
symptoms in the later course of chronic disorders like cancer, infections and autoimmune syndromes. Accordingly the
administration of serotonin-reuptake inhibitors is an important treatment choice in such patients. Many patients with
chronic inflammatory diseases not only present with an acti-
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Drug Metabolism Letters, 2007, Vol. 1, No. 3
vated immune system and accelerated tryptophan degradation but also with an increased susceptibility for depressive
mood [52]. Some of the plant extracts tested in our studies
are not only considered useful to combat inflammation, they
are also often used to improve quality of life and signs of
depressive mood, e.g., Hypericum perforatum (St.John’s
wort) is of comparable efficacy as modern drugs to treat
moderate forms of depression [53]. The ability of Hypericum
perforatum to interfere with cytokine cascades and to slowdown IDO activity could represent at least part of its antidepressive activity. Also other plant extracts from, e.g. Uncaria tomentosa, or herbal mixtures like Padma 28, or antiinflammatory drugs like aspirin are described to improve
signs of depressive mood. Since all these compounds and
drugs inhibit cytokine-induced tryptophan degradation, it
appears reasonable that also their beneficial impact on mood
disorders could relate to this specific property. A so-called
“healthy diet” may improve mood when its antioxidant content is able to counteract the degradation of tryptophan. Finally, effects of, e.g., beverages to increase tryptophan availability may also relate to the observed well-being, when
“natural stimulants” like wine or beer are taken in.
POTENTIAL ADVERSE EFFECTS OF ANTIOXIDANTS
Schroecksnadel et al.
Fig. (5). Antioxidants may trigger Th2-type immune response.
There exists a cross-regulatory interplay between Th1-type and Th2type immune response, down-regulating each other when activated.
Reactive oxygen species (ROS) are formed during Th1-type immune response and further amplify Th1-type immunity, they contribute to oxidative stress and inflammation which increase the risk
for coronary artery disease (CAD) and cancer. Whereas antioxidants
not only counteract the deleterious effects of ROS, they also decrease Th1-type immune activation and the production of interferon. Excess antioxidants (“antioxidative stress”) may drive the immune system towards overwhelming Th2-immune response thereby
increasing the risk of allergy and asthma.
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From the accumulated data it appears that remedies and
beverages rich in antioxidants could represent a universal
cure. However, there is at least a theoretical risk for unwanted side effects, when too much of antioxidants are ingested. On the one hand, it may enhance the risk of infection
when first line of immune defence mechanisms, namely production of ROS, is neutralized by antioxidants. On the other
hand, suppression of Th1-type immune response by antioxidants could eventually favour Th2-type immune activation,
due to the cross-regulatory interplay between T-helper cell
subtypes [8, 9] (Fig. 5). Thus antioxidants may increase the
susceptibility for allergic and atopic disease. Referring to our
in vitro data, too much intake of antioxidants could cause a
kind of “antioxidative stress” which would increase the susceptibility for allergic reactions and asthma by downregulating Th1-type immune response and thereby promoting Th2-type cells [54]. The findings agree well with other
experimental data that vitamin C and E suppress inhibit NFB and oxidative pathways in human dendritic cells and that
these vitamins support the generation of regulatory T cells
with a Th2-type phenotype [55]. Rather than being associated with intake of natural products, e.g. fruits and vegetables even when containing ample amounts of antioxidant,
these risks appear to be related more to the increased use of
food additives. The intake of these antioxidants has drastically increased in the past few decades and it could represent
an important aspect within the increasing frequency of allergic diseases in the same time period. In our studies, also food
preservatives like sodium sulfite or food colorants, e.g., derived from beetroot, were found to suppress neopterin production and tryptophan degradation [30, 38]. Thus, such preservatives may have potential to improve the inflammatory
response in a variety of diseases, however, high-dose intake
could also increase the risk for allergies. This could be true
also for high intake of antioxidant vitamins like vitamin C
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and E which were found not only to suppress Th1-type activation of PBMC [37], moreover, they also support the production of Th2-type cytokines like IL-4 and IL-10 [55].
Thus, especially food enriched with antioxidants may increase the susceptibility for allergy and asthma [54]. Notably, some of the antioxidant food preservatives and colorants
are suspected to increase the risk of allergies. These compounds are not necessarily allergens on their own, they may
increase the probability of an allergic response because of
their promotion of Th2-type immune response.
CONCLUSION
Studies demonstrate that plant extracts, teas and pure
antioxidant compounds interfere with immunopathogenetic
pathways which involve the pro-inflammatory cytokine IFN. Antioxidant compounds are able to interrupt pro-inflammatory cytokine cascades in vitro. Thus, antioxidant content
of fruit and vegetable appears to be of importance for their
beneficial and preventive effects. Findings could relate to
their beneficial impact which they are believed to exert on
the course of many inflammatory diseases in patients. The
suppressive influence on cytokine-induced tryptophan degradation could also explain the positive influence of antioxidant compounds on mood. Further definition of compounds,
which are responsible for in vitro effects of plant extracts on
stimulated PBMC and their potential anti-inflammatory activity, may result in the development of new immunomodulators, of new immunotolericing drugs, and in new therapeutic applications of plant extracts. It will be important to set
up further studies to define active dosage and to demonstrate
their activity also in vivo.
Antioxidants Suppress Th1-Type Immune Response In Vitro
Drug Metabolism Letters, 2007, Vol. 1, No. 3
ACKNOWLEDGEMENT
[27]
Supported by the State of the Austrian Tyrol and by the
„Stiftung Propter Homines, Vaduz -Fürstentum Liechtenstein“. The authors thank Miss Astrid Haara for excellent
technical assistance.
[28]
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Revised: March 23, 2007
Accepted: March 24, 2007
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