stephen holt md-immunotherapies a4m
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IMMUNOTHERAPEUTICSIMMUNOTHERAPEUTICS
1.Disease prevention or treatment
2.Conventional approaches,
immunsuppression, immunemodulators, antivirals
3.Combined immune modulation
with antiviral and antiangiogenictherapies
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The Immune SystemThe Immune System Immune function is a complex harmony of
events involving the interaction of immune
competent cells and their messenger molecules
with most body structures
Research has underscored the importance ofchanges in the direction of quality of immune
responses e.g. autoimmunity
Alternative medicine has obsessed about the
role of NK cell function in disease management,used as a key platform to promote the sale of
dietary supplements and immune-stimulating
nutraceuticals.
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IMMUNE HOUSEKEEPINGIMMUNE HOUSEKEEPING
Maintenance of immune function
supports its housekeeping
programs of Recognition,
Cognition and Action
Antiviral compounds,
antiangiogenic agents and othercomplementary approaches are
immune helpers
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Cells of the Immune System
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CONCEPTS OF IMMUNE DEFICIENCY
Primary: variable deficiencies of T
or B cell function, phagocytosis or
complement pathways, congenital.
Secondary: mainly affecting
phagocytic and lymphocyte functionresulting from HIV, other viruses,
malnutrition, aging, drugs etc.
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IMMUNESENESCENCE
Striking changes in immune status with ageReduced response to vaccination and
increased infections
Involution of the thymus with loss of T cell
education. Decreased NK cell function.Memory T cells (CD45R0+) increase
Limited number of nave T cells
A restricted repertoire with lack of clonalexpansion of T cells, diminishing cell-
mediated immunity
Reductions in humoral immunity
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IMMUNESENESCENCE: HUMORAL IMMUNITY
Antibody specificities change from
foreign to autoantigens
Antibody isotypes change from IgG to
IgM
Antibody affinities change from high to
low
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NATURAL THERAPEUTICS FOR
IMMUNE FUNCTION
The use of drugs or vaccines to stimulate
immunity possess disadvantages and limitations.
Humankind is constantly challenged by
infectious disease and environmental insults to
immunity.
The mainstay of natural approaches for the
modulation of immune function must involve
increasing an individuals immune capabilities and
avoiding damage to immune function.
Rational use of evidence-based nutrients, herbs
or botanicals that modulate immune function.
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KEY PROMOTERS OF IMMUNE
FUNCTION
Nutritional status: antioxidants, vitamins,minerals, fat ratios in the diet, nutraceuticals.
Exercise: A Double-edged Sword
Stress reduction, healing attitudes,
interpersonal relationships etc.
Avoidance of environmental circumstances
that damage immunity, including prevention
of microbial infection.
Correction of common states associated
with impaired immunity e.g. Metabolic
Syndrome X and Type 2 Diabetes.
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Infection-related morbidity is decreased by supplementation
with vitamins and minerals, Chandra, R.K., Lancet, 1992
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NUTRITIONAL AND NUTRACEUTICAL
APPROACHES FOR IMMUNE FUNCTION
Minerals: A Double-edged Sword
Antioxidants
Nutraceuticals, many variable benefits on different
aspects of immune function e.g. mushrooms and
their fermentation products, garlic, echinacea,
ginseng, astragalus, teas, turmeric, ginger.
Popular nutraceuticals: MGN-3, BRM-4,
ImmPower, Peak Immune 4, Epicor, AHCC,
BioDefense, Clinical Immune Modulator etc.(trademarks of different companies who produce
nutraceutical products for immunity) Synergy is
better?
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COMPARISON OF IMMUNE STIMULATING
PROPERTIES OF NATURAL PRODUCTS
Hypotheses to be tested
1. Complex cascades of immunity are best
approached in natural medicine by complex mixed
formulations of natural agents that have an
evidence-base for immune stimulation or
modulation in different areas of immune function
inferred from the complexity of immune cascades.
2. Can the composition of a manufactured
supplement (off the shelf) result in the clinical orlaboratory outcome that may be described in
literature that is applied to the marketing and
promotion of the specific immune supplement?
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THE STUDY
In Vitro and Limited In Vivo Observationson the Ability of Two Off the Shelf Dietary
Supplements to Alter Natural-Killer Cell
Function (NK Cells) and Other Immune
Functions
Independent Laboratory Studies by Gitte S.
Jensen, Aaron N. Hart, sponsored in part byNatural Clinician LLC, New Jersey
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COMPARISON OF IMMUNE STIMULATING
PROPERTIES OF NATURAL PRODUCTS
Method Independent in vitro and limited in vivo
comparisons of immune effects of a complex
botanical formula (Clinical Immune Modulator,
Natural Clinician LLC) vs. a more simplenatural preparation of fermented mushrooms
(MGN-3 or BRM-4, Daiwa, Japan), containing
modified arabinoxylan with shitake mushroom
derivatives.
Products purchased in finished manufactured
form
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THE TWO PRODUCTS TESTED
MGN-3 (BRM-4):A fermentation productresulting from the enzymatic modification of ricebran with an extract from the mycelium ofShiitake mushroom (Lentinus edodes).
Clinical Immune Modulator (Biodefense): Acomplex nutrient and botanical formula, utilizingevidence-based reagents including:Andrographis paniculata, Vitamin C, Green Tea,Turmeric, E. senticosus, Zn, Grape seed extract,Ashwangandha, Oregon Grape, Shiitakemushroom, Echinacea purpurea, Goldenthreadroot, Aloe Vera, Garlic, Astragalus, GinsengPanax, Goldenseal Root, Coriolus mushroom,AHCC, Saccharomyces (beta glucan)
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Results
1. Culturing human lymphocytes in the presence of extracts ofClinical Immune Modulator was found to be a potent
activator of NK cells (induction of CD69 on almost 100% of
peripheral blood NK cells). MGN-3 (BRM-4) produced a
weaker activation of NK cells in vitro.
2. Comparisons of serial dilutions of Clinical Immune
Modulator vs. MGN-3 (BRM-4) showed that the induction ofthe CD69 NK activation required up to 100 fold higher
concentrations of MGN-3 extract to produce the same
effects as the extracts of Clinical Immune Modulator.
3. Clinical Immune Modulator altered responses to T cell
mitogens. BRM-4 did not.4. MGN-3 (BRM-4) appeared to be able to activate a subset of
NK cells but these cells did not express the CD25 marker
and induction of Interferon Gamma was not observed with
MGN-3 (BRM-4)
Comparison of Immune Stimulating Properties of
Natural Products
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Untreated MGN-3 CIM
Activated NK cells Activated NK cellsActivated NK cells
Results of CD69 marker expression in response to extracts of
the two test substances. Clinical Immune Modulator was a
stronger activator of NK cells, based on dry weight estimates,the complex botanical formula was approximately 50 fold
more efficient.
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Results of CD69 marker expression in response to extracts of the
two test substances. Clinical Immune Modulator was a stronger
activator of NK cells, based on dry weight estimates, the complex
botanical formula was approximately 50 fold more efficient.
NK cell activation
0
5
10
15
20
25
0.2 2 20 200
grams/liter
CIM
NK cell activation
MGN-3
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Results show relative changes in the amount of NK cells in the blood
circulation after consumption in a human subject. A reduction in NK
cells in the blood is suggestive of increased immune surveillance(trafficking of NK cells to tissue).
Both test products induced similar levels of NK cell trafficking.
However, the activation status of NK cells was increased by CIM but
not by MGN-3 (BRM-4).
NK cells in circulation
0.6
0.65
0.7
0.75
0.8
0.85
0.9
0.95
1
1.0 5
0 2 4 2 4
Hours after consumption of test product
Activation status of circulating NK cells
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
1.8
2
0 2 4 24
Hours after consumption of test product
In vivo effects of test products
MGN-3
MGN-3
CIM
CIM
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Under the conditions of this study,previously reported substantialactivation of NK cells was not apparentwith MGN-3 (BRM-4) off-the-shelf.
In direct comparison with MGN-3, thecomponents of Clinical ImmuneModulator were highly able to promoteNK activation.
The composition of Clinical Immune
Modulator appears to be moreversatile and powerful at modulatingimmunity in comparison with MGN-3 orBRM-4.
COMPARATIVE STUDY CONCLUSIONS
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ECBALLIUM ELATERIUM: A
NOVEL ANTIVIRAL AGENT
Recognition of pernicious problem withchronic viral hepatitis in Egypt and othermiddle eastern countries (HCV prevalence
up to 20%) Identification of disadvantages and
limitations of all conventional treatmentsfor hepatitis C viral infection
Emerging viral diseases on a global basisof great concern, eg. hepatitis B and C,HIV, combined HIV/HCV, Flu (A, birdH5N1, etc.)
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ECVIR : IN-VITRO
Water soluble evaporate of Ecballiumelaterium fruit
Ecballium elaterium (Cucurbitaceae spp.)Squirting Cucumber, Southern Europe
Putative Actions: antiviral, anti-hepatitis,cirrhosis prevention, anti-cancer, anti-fertility,
phagocyte stimulation, antioxidant Putative bioactive components: cucurbitacins(triterpenes), mono and diterpenes, phenoliccompounds, plant alcohols in evaporate?
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ECVIR : The PlantECVIR : The Plant
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ECVIR Animal Toxicity Studies
Comprehensive animal toxicity testing in
Sprague Dawley rats preformed at the
National Research Centre (Egypt).
No signs of toxicity. Weight gain.
Liver function.
Renal function etc.
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Viral Targets Diseases
IN VITRO and IN VIVO Hepatitis C and B (and others)
Herpes simplex Type II
Influenza A and mixed respiratory
viral pathogens (H3N2)
Herpes zoster
Bovine Viral Diarrhea (in vitro)
Capri-poxvirus (lumpy skin disease)
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ECVIR : Clinical Studies
Principal Investigators: Said Shalaby MD andEssam Hob Allah PhD, National Research Centre,Egypt
Hepatitis C studies
Hepatitis B studies
Influenza (common cold)
Chronic recurrent sinusitis
Diabetes mellitus Type II
Herpes zoster (topical) Herpes simplex (topical)
Impending renal failure (glomerulonephritis)
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ECVIR : Hepatitis C Virus
ECVIR (Ecballium Elixir)administered in open-label
observations in 482 individuals
diagnosed with HCV by clinicalmethods confirmed by polymerase
chain reaction (PCR) testing.
Sequential observations in 183 patients
with 9-12m Rx.
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ECVIR : HCV Studies :
Patient Characteristics
Liver Clinic attendees, Cairo Egypt;primary or secondary referral
Symptoms, signs of liver diseaseconfirmed to be due to HCV infection byPCR
Inclusion of all patients with chronic
active hepatitis of a mild, moderate orsevere nature
Excluding other etiologies e.g. alcohol
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Disease Severity Assessments of HCV
Infection(interim analysis, n=183)
Clinical Symptoms/Signs
Liver Enzymes
Serum Albumin Prothrombin Time
Altered viral load on PCR
Observations on sequential liver biopsy (n=9,
undertaken baseline and after 9-12m) Documentation of change in clinical status or
decompensations or complications attributedto HCV or administered ECVIR
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Symptoms and Signs (n=183)
Baseline
Weakness : 50%
RHP : 45%
Weight change :
20%
Oedema: 14% Fetor Hepat.: 13%
Somnolence : 11%
Ending (9-12m)
Weakness: 4%
RHP : 0%
Weight change: 5%
Oedema: 2% Fetor Hepat.: 0%
Somnolence: 2%
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Symptoms and Signs (cont..)
Baseline
Jaundice: 8.5%
Pruritis : 8.5%
Pigmentation : 6%
Ending (9-12m)
Jaundice: 0%
Pruritis : 0%
Pigmentation : 4%
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SGPT (ALT) expressed as ratio of total
measurement divided by upper normal limit
(three fold difference)
SGPT baseline
Mean 3.5,
range 1.6-5.6
SGPT (9-12m)
Mean 1.1
range 1.0-1.7
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SGOT (AST) expressed as ratio of total
measurement divided by upper normal limit
(Three fold difference)
SGOT baseline
Mean 3.8
range 2.2-5.1
SGOT (9-12m)
Mean 1.3
range 1-2.2
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Synthetic Liver Functions : HCV
Baseline
PT concentration:
mean 68%, range 36-100%
Albumin mean 2.7,
range 2.2-4.6
Bilirubin mean total
3.5 : mean
conjugated 1.5
9-12m
PT concentration:
mean 86%, range 54-100%
Albumin mean 3.9,
range 3.4-4.8
Bilirubin mean total
1.3 : mean
conjugated 0.6
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PCR Testing
Baseline
n=183
100% positive
9 -12m
n=110
64% positive
70 out 110 individuals remained HCV
positive, but mean viral loaddecreased by 40% (approx) . Viral
kill?
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Liver Biopsy Example : Patient 1
Before ECVIR Treatment
Fig.1: Hepatitis Cbefore treatment
with ECVIR Elixir;
showing dense
portal infiltrationwith inflammatory
cells, moderate
activity, HAI 11/18,
no fibrosis, stage0/6 (mag. X100)
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Fig.2 : Hepatitis C
after 9-12m of
treatment with
ECVIR Elixir;
showing minimal
inflammatory cells
in portal tract, mildactivity, HAI 5/18,
no fibrosis, stage
0/6 (mag. x100)
Liver Biopsy Example
After ECVIR Treatment
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Silver Colloids
Subject to marketing mumbo-jumbo
Silver is a toxic heavy metal withexcellent qualities when used in
suspensions of parts per million
The measure of the ideal silver colloid
is microbial kill
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Silver Colloid Jargon
Pseudoscience: particle size, shape,
ionic change and pretty pictures are
irrelevant
The measure to identify is microbial
kill
The proof is in-vitro comparative anti-
microbial testing
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Advances in Silver Colloid
Technology
Good manufacturing practice
The addition of synergistic
components that enhance oraugment the actions of silver colloids
Patent pending synergy with xylitol,
polysorbate (20x) and essential oils(200x) (Technology of Natural
Clinician LLC)
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Conclusion
Immune modulation with nutraceuticals isbest achieved with complex, synergisticformulae that work on many components ofcomplex immune cascades of events
Some botanicals have both immune
modulating and antiviral properties, e.g.Ecballium elaterium, Andrographispaniculata
Therapeutic helpers include antimicrobialactions of silver colloid which can be given
in augmented formulations Borrowed science presents great problems
in the ethical marketing of somenutraceuticals