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Larch Arabinogalactan is a Novel Immune Modulator
PETER D'ADAMO, ND
Originally published in: J. Naturopath. Med 1996 (4);32-39
Copyright 2000-2009 All Rights
Reserved. Unauthorized reproduction prohibited by law.
This paper discusses some of the applications and characteristics of
naturally occurring arabinogalactans, with a special emphasis on
those arabinogalactans derived from Western Larch. The unusual
immunological properties of larch arabinogalactan (wood gum, wood
sugar, larch gum, "Stractan", "ARA-6") suggest
it may be used in numerous, exciting future applications. Evidence
of this can be seen in the medicinal chemical, pharmaceutical, and
bio-technical fields where current research and development has
resulted in the creation of arabinogalactan-based products with
unique characteristics. Larch arabinogalactan possesses minimal
toxicity and is approved for food use. (55 references, 1
illustration)
PHYSICAL CHARACTERISTICS
Arabinogalactans are class of long, densely branched high-molecular
polysaccharides MW: 10,000-120,000 (1). In nature, arabinogalactans
are found in several microbial systems, especially acid-fast
Mycobacteria (2) where it is complexed between peptidoglycans and
mycolic acids as a component of the cell wall and influences
monocyte-macrophage immunoreactivity of Tubercular antigen (3). Many
edible and inedible plants are rich sources of arabinogalactans,
mostly in glycoprotein form, bound to a protein spine of either
threonine, proline or serine ("arabinogalactan protein").
These include leek seeds (4), carrots (5), radish (6), black gram
beans (7), pear (8), maize (9), wheat (10,11), red wine (12,13),
Italian ryegrass (14), tomatoes (15), ragweed (16), sorghum and
bamboo grass (17), coconut meat and milk (18). Several of the major
naturopathic immune "enhancer" herbs contain signifcant
amounts of arabinogalactans, such as Echinacea purpurea, Baptisia
tinctoria, Thuja occidentalis (19), Angelica acutiloba (20) and
Curcuma longa (21).
The major commercial source of arabinogalactan is the Larch tree.
Two sources are Western Larch (Larix occidentalis) and Mongolian
Larch (Larix dahurica) (22). Most commercial arabinogalactan is
produced from Western Larch, a renewable resource, through a
counter-current extraction process. The resultant liquor is refined
into a light cream-colored powder having an indefinite shelf life.
High-grade larch arabinogalactan is composed of greater than 98%
arabinogalactan. Arabinogalactan gum is 100% water soluble and
produces low viscosity solutions. As produced, larch arabinogalactan
is a dry, free-flowing powder, with a very slight pine-like odor and
sweetish taste. As compared with other natural polysaccharides, the
unique properties of larch arabinogalactan are: ease of solution,
complete solubility; good body properties without viscosity buildup;
excellent dispersant and surfactant properties; and stability over a
wide range of concentrations, pH and temperature.
CHEMICAL NATURE
Larch arabinogalactan is composed of galactose and arabinose units
in a 6:1 ratio, with a trace of uronic acid. The molecular weights
of the major fractions of arabinogalactan in larch are 16,000 and
100,000. Gel chromatography indicates arabinogalactan is a single
species of 19 kDa, while light scattering gave a molecular weight of
40 kDa. Glycosyl linkage analysis of arabinogalactan is consistent
with a highly branched structure comprising a backbone of 1,3-linked
galactopyranose connected by 1,3-glycosidic linkages, comprised of
3,4,6-,3,6-, and 3,4- as well as 3-linked residues (23). [See figure
1]
EFFECT ON IMMUNOLOGIC SYSTEMS
Natural Killer cell (NK) and Macrophage activation The receptor
specificity of arabinogalactan is not well characterized. Cultures
of human peripheral blood mononuclear cells as well as cultures of
preseparated peripheral non-adherent cells and monocytes showed
enhancement of natural killer cytotoxicity against K562 tumor cells
when pretreated with larch arabinogalactan for 48-72 h. Moreover,
preseparated peripheral non-adherent cells and monocytes of
individual donors could exhibit various responses to arabinogalactan
when cultures derived from bleedings after intervals of several
months were assayed. Arabinogalactan-mediated enhancement of NK
cytotoxicity was not initiated directly but was found to be governed
by the cytokine network. Generally, larch arabinogalactan
pretreatment induced an increased release of interferon gamma (IFN
gamma), tumor necrosis factor alpha, interleukin-1 beta (IL-1 beta)
and IL-6 but only IFN gamma was involved in enhancement of NK
cytotoxicity (1).
A similar response has been noted for arabinogalactans isolated from
Echinacea purpurea (47) This polysaccharide induced macrophages to
produce tumor necrosis factor (TNF-alpha), interleukin-1 (IL-1), and
interferon-beta.
Acidic arabinogalactan, a highly purified polysaccharide from plant
cell cultures of Echinacea purpurea, with a molecular weight of
75,000, was effective in activating macrophages to cytotoxicity
against tumor cells and microorganisms (Leishmania enriettii). This
arabinogalactan did not activate B cells and did not induce T cells
to produce interleukin-2, interferon-beta 2, or interferon-gamma,
but it did induce a slight increase in T-cell proliferation. When
injected ip, arabinogalactan stimulated macrophages. Other known
immunomodulatory plants with effects known to be derived from their
polysaccharide fraction include Baptisia tinctoria, Angelica
acutiloba, and Thuja occidentalis. Researchers have concluded that
the antigenic regions of immunoreactive arabinogalactans from all
the sources, (Echinacea, Baptisia, Thuja and Larix) show structural
differences (19). Initial information obtained from comparative
studies indicates that larch arabinogalactan presumably interacts
with a receptor that showed specificity for a
NK-cytotoxicity-enhancing oligo-saccharide from Viscum album, since
the action of both components was not synergistic but rather
competitive (1).
Reticuloendothelial activation
Low to middle MW (5,000_50,000) arabinogalactan polysaccharrides
were found to have strong immunostimulating properties with
simultaneous anti-inflamatory properties, and were especially
suitable as radiation protecting agents in doses as low as 20-50mg
orally (47). The anti-inflamatory effects were also shown to be
effective in the treatment of numerous allergies (46).
Ukonan C, a phagocytosis-activating arabinogalactan isolated from
the rhizome of Curcuma longa L., was found to have
reticuloendothelial system-potentiating action. Oxidation caused a
decrease in or disappearance of the immunological activities (21).
Sanchinan-A, a reticuloendothelial system-activating arabinogalactan
has also been isolated from sanchi-ginseng (roots of Panax
notoginseng) (22).
Saposhnikovan A, an acidic arabinogalactan polysaccharide isolated
from the roots and rhizomes of Saposhnikovia divaricata, showed
remarkable reticuloendothelial system-potentiating activity in a
carbon clearance test (24).
Effects on complement
An anti-complementary polysaccharide, AR-arabinogalactan, was
isolated from the roots of Angelica acutiloba Kitagawa (Japanese
name = Yamato-Tohki), After incubation of serum with
AR-arabinogalactan in the absence of Ca2+ ions, a cleavage of C3 in
the serum was detected by immunoelectrophoresis as well as from the
consumption of complement when rabbit erythrocytes were used in the
assay system. A marked consumption of C4 was also observed to have
occurred when serum was incubated with AR-arabinogalactan in the
presence of Ca2+ ions. Collectively considered these results
indicate that the mode of complement activation by
AR-arabinogalactan is via both the alternative and the classical
pathway (25,26).
AR-arabinogalactan is comprised of comprised one neutral and two
acidic arabinogalactan units and one neutral arabinan unit). Neutral
arabinogalactan showed the most potent anti-complementary activity,
while both acidic arabinogalactans had simliar moderate activities,
but arabinan had weak activity. Acidic arabinogalactan anti-complemenary
activity is expressed mainly through the classical pathway, whereas
neutral arabinogalactan had markedly increased activity through the
alterative pathway (27).
Ukonan C, the reticuloendothelal actvating arabinogalactan from the
rhizome of Curcuma longa L., was also found to have
anti-complementary activities (21).
Antiviral effects
Arabinogalactans enhance the effectiveness of viral nucleotide
analogs. Daily injections of a conjugate consisting of adenine
arabinoside 5'-monophosphate (araAMP, vidarabine monophosphate) and
arabinogalactan (7.9 residues araAMP per molecule arabinogalactan),
at a dose of 3 mg of araAMP/kg, into woodchuck carriers of woodchuck
hepatitis virus (WHV) decreased serum levels of WHV DNA. A dose of 3
mg/kg of unconjugated araAMP was ineffective, while a higher dose of
araAMP (15 mg/kg, 14 days) produced a slight drop in WHV DNA. After
cessation of dosing with the conjugate, serum viral DNA levels
remained depressed for 42 days. In contrast, after cessation of
dosing with araAMP alone, WHV DNA rapidly returned to original
levels (28).
EFFECTS IN METASTATIC DISEASE
Blocking of organ-specific
experimental metastasis
Metastatic disease most commonly spreads to the liver, in preference
to other organ sites. This has been theorized to be the result of a
reaction between the galactose-based glycocongates on the metastatic
cells and a hepatic-specific lectin (e.g., the D-galactose-specific
hepatic binding protein) found in liver parenchyma. Several studies
have compellingly shown that arabinogalactan inhibits this reaction,
thus acting as a "reverse lectin."
In one study, the effects of arabinogalactan was investigated in a
syngeneic tumor-host system using a new tumor which primarily
colonizes the liver upon intravenous injection. The study included
systemic treatment with D-galactose and arabinogalactan as well as
cell pretreatment with arabinogalactan and two other glycoconjugates.
Treatment with arabinogalactan reduced the amount of liver
metastases and prolonged the survival times of the animals in both
studies. Host treatment was more effective than tumor cell
pretreatment. This was shown to be an effect of arabinogalactan
blockade of potential liver receptorsby covering of
galactose-specific binding sites (29). Ths was also verified in a
repeat study (30).
In a third study, the rapid clearance and uptake by the liver of
tritiated alpha 1-acid (asialo)glycoprotein from the circulation of
Balb/c mice was markedly delayed after preinjection of D-galactose
or arabinogalactan. The preinjection (1 h) and regular application
(for 3 days after tumor cell inoculation in Balb/c mice) of the
receptor blocking agents D-galactose and arabinogalactan prevented
the settling of sarcoma L-1 tumor in the liver completely. Other
galactans, dextrans, and phosphate-buffered saline showed no effect.
Therefore, when lectins were blocked with competitive-specific
glycoconjugates, colonization was prevented (31).
Arabinogalactan completely prevented the settling of metastatic
cells of sarcoma L-1 tumor in the liver of Balb/c mice and greatly
reduced the colonization process of highly metastatic Esb lymphoma
cells of the liver of DBA/2 mice. Therefore, when hepatic lectins
were blocked with competitive glycoconjugates, tumor cell
colonization of the liver could be prevented in two different model
systems (32).
USES IN LABORATORY PRACTICE
Contamination of platelets
Contamination with plasma proteins could not be detected with use of
unlabeled platelets that had been incubated with radiolabeled plasma
proteins followed by washing with larch arabinogalactan ("Stractan").
The arabinogalactan washed platelets were assessed for function by
using aggregometry. The response of arabinogalactan washed platelets
to collagen and thrombin was identical to that of unwashed
platelets. The morphology of the arabinogalactan-washed platelets
indicated that degranulation had not occurred. With use of
antibodies directed against the alpha granule membrane protein
GMP-140 or fibrinogen, no evidence of secretion or plasma protein
contamination was observed. The results indicate that this procedure
is a convenient method for the separation of platelets from
platelet-rich plasma, free of plasma proteins, which are suitable
for bioassays, functional studies, and morphologic investigations
(33).
As a carrier molecule for drug or
diagnostic agents
Arabinogalactan has properties that make it suitable as a carrier
for delivering diagnostic or therapeutic agents to hepatocytes via
the asialoglycoprotein receptor (23). Arabinogalactan produced no
adverse reactions in single intravenous dose (mouse, 5000 mg/kg) and
repeat dose toxicity studies (rats, 500 mg/kg/day, 90 days) (23).
The 9 kDa and 37 kDa fractions from larch arabinogalactan are
apparently the best candidates for use in hepatocyte directed drug
delivery (34). Larch arabinogalactan improves liver contrast
enhancement, and has a significant effect on hepatic lesion
detection as assessed by CNR (35).
EFFECTS ON VASCULAR PERMIABILITY
Several studies have shown larch arabingalactan to enhance vascular
permiability (36). Intravenous injection of arabinogalactan together
with pontamine sky-blue dye into mice increased vascular
permeability and led to marked blueing of the ears. Arabinogalactan
caused a rapidly progressing ear blueing (maximal coloration 20-30
min after injection). This response was suppressed by pretreating
the animals with the histamine H1-antihistamines levocabastine and
loratadine (37).
OCCURENCE IN MICROBIAL SYSTEMS
As a component of Mycobacteria
As previously mentioned, arabinogalactan is a structural component
of the cell wall of most acid-fast bacteria, including M.
Tuberculosis (3), M. Leprae (38) and M. smegmatis (39). The
antitubercular drug ethambutol's mechanism of action is thought to
be through the inhibition of arabinogalactan synthesis (40). During
tuberculosis, exposure of monocytes to circulating factors,
including arabinogalactan, may induce the suppressor activity
observed in some anergic patients. In addition, TB plasma and
arabinogalactan directly inhibited the phytohemagglutinin-stimulated
responses of T lymphocytes. In a quantitative assay of monocyte
attachment to plastic, both TB plasma and AG significantly increased
monocyte adherence from basal levels, suggesting that
arabinogalactans circulating alone or bound in immune complexes may
account for the observed effects of TB plasma.
Similar in vivo exposure may contribute to the cell-mediated
suppression of lymphocyte responses in tuberculosis (41), although
it is highly unlikely that that larch arabinogalactan could produce
the same effects, as particular arabinogalactan receptors are highly
individualized (1,19), and much of the anergy-inducing activity of
TB arabinogalactan is probably produced by its matrixing with
peptidoglycan (41).
Until appropriate studies are performed, I would not recommend using
arabinogalactans in an active tuberculosis patient. Nonetheless, it
is intriguing to note the often observed lack of malignant disease
in tubercular populations (52).
Fecal breakdown
Larch arabinogalactan is also an excellent source of dietary fiber
(48), and has been shown to increase the production of short-chain
fatty acids (SCFA), principally butyrate. Butyrate has a
particularly important role in the colon. It is the preferred
substrate for energy generation by colonic epithelial cells (49) and
it has also been shown that butyrate protects these cells against
agents that lead to cellular differentiation (50).
In one study in vitro faecal incubation system was used to study the
metabolism of complex carbohydrates by intestinal bacteria.
Homogenates of human faeces were incubated anaerobically with added
lactulose, pectin, arabinogalactan, and cellulose, both before and
after subjects had been pre-fed each carbohydrate. Fermentation of
added substrate was assessed by the production of short-chain fatty
acids and suppression of net ammonia generation over 48 h of
incubation.
Arabinogalactan increased the yield of SCFA and acetate in all
samples at all times and butyrate concentrations exceeded propionate
in all samples. Faecal homogenates incubated with cellulose showed
no greater SCFA production than controls. Pectin and arabinogalactan
also decreased ammonia generation, but the reductions were not
significant unless subjects were pre-fed these materials; cellulose
had no effect on ammonia generation (42,43). Larch arabinogalactans
are easily digested by human colonic Bacteroides growing in
continuous culture, yielding butyrate (44).
E.coli adherance
Arabinogalactans are useful for therapeutic treatment of infections
caused by pathogenic microorganisms, particularly intestinal
bacteria, such as Gram-negative types. Treatment with
arabinogalactan is particularly applicable to bacterias of the
Enterobacteriaceae type such as Escherichia coli bacteria,
particularly those strains manifesting K88+ fimbrae.
Arabinogalactans were shown to have dramatic effects on bacterial
adherence (45).
Blood group activity
Some arabinogalactans appear to have blood group H activity,
although this may be species specific (51).
SAFETY AND TOXICITY
Preliminary acute toxicity tests performed on albino rats have
indicated that larch arabinogalactan is significantly less toxic
than methyl cellulose (48). Other studies have shown that laboratory
diets comprising of up to 50% larch arabinogalactan had no apparent
ill-effects on animal subjects after 6 months (47).
Larch arabinogalactan is FDA approved for use in food applications
as per 121.1174 and 121.1219 (Code of Federal Regulations, Title 21,
1974)and may be safely used as anemulsifier, stabilizer, binder, or
bodying agent in essential oils, nonnutritive sweeteners, flavor
bases,non-standard dressings, and pudding mixes. The use of Larch
arabinogalactan has also been formally approved by the Canadian
Governor-in-Council (Canada Gazette, Part II, Vol. 105, January 27,
1971).
DISCUSSION
It is possible that the multiplicity of biologic actions in those
medicinal plants known to contain polysaccharides result from a
series of "ranges" in which certain size polysaccharides
produce either immune augmentation or inhibition?
In general, it may be said that "low" molecular weight
polysaccharides (5,000-15,000) tend to produce more of an anti-inflamatory,
anti-complementary, anti-allergy effect (25,46); whereas
"high" molecular weight polysaccharides (75,000-125,000)
produce more reticuloendothelial stimulation (21,24) and monocyte-enhanced
natural killer cytotoxicity (1). The "mid" weight
polysaccharides (15,000-50,000) seem to act in an altogether
different way, enhancing carbon and other types of toxin clearance
by macrophages (24). The molecular weights of the major fractions of
larch arabinogalactan are 16,000 (low/mid) and 100,000 (high) which
perhaps explain its peculiarly diverse actions.
Use in conjunction with other
agents
In general, oxidative agents inhibit the activity of most
polysaccharides (21) whilst reduction can notably enhance them (53),
typically by "reducing" side chains into more antigenic
forms. Thus, concurrent administration of arabinogalactans with
anti-oxidants such as ascorbate may enhance their efficacy. The use
of halide donors, such as potassium iodide, in conjunction with
arabinogalactan and ascorbate can produce quite prodigious increases
in cellular myeloperoxidase activity, as measured by a candicidal
index (54). Myeloperoxidase levels are typically depressed in
chronic candidasis and increased in breast cancer (55).
The reticuloendothelial-activating effects of arabinogalactan would
certainly dovetail well in such a therapeutic scenario. Larch
arabinogalactan has been studied for use in experimental models of
metastatic disease spread to the liver, including its use in
conjunction with modified citrus pectin. Both polysaccharides work
in essentially the same way, that is, by inhibiting the attachment
of metastatic cells to liver parenchyma by competive binding to a
liver lectin, the hepatic galactose receptor.
Use in pediatric otitis media
Prophylactic use of larch arabinogalactan can decrease the frequency
and severity of pediatic otitis media (54), especially in
circumstances where the predominant organisms are gram negative rods
(46). This may be the result of phagocytosis enhancement,
improvement in opsonization, competitive binding of bacteral
fimbrae, or all three.
Use in HIV
Although shown to produce only slight increases in CD4 cells,
treatment of HIV disease with larch arabinogalactan can result in
significant improvement in succeptibility of HIV related
opportunistic infections (54). This may result from activation or
enhancement of macrophage/monocyte/NK cell activity, typically the
role of CD4 cells.
Use as a delivery adjunct
Because of its effects on vascularity and rate of hepatic uptake,
concurrent administration of larch arabinogalactan with other
therapeutic agents can be considered rational. This may apply to
anti-hepatitis agents in addition to hepatoprotective drugs. The
immunoaugmentive effects, anti-radiation effects and drug
facilitative effects of larch arabinogalactan indicate promise as a
concurrent therapy in patients undergoing conventional cancer
treatment.
Use as a fiber supplement
Because of its ability to increase colonic butyrate and decrease
colonic amonia concentrations, arabinogalactan may be a preferable
form of fiber therapy, as the major commercial source, methyl
cellulose does not do this to any significant degree (in addition to
having a lower LD50!)
Copyright 1996 Peter D'Adamo. All
rights reserved. Unauthorized reproduction without the express
consent of the author is prohibited.
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