Stephen Holt MD-Immunotherapies A4M

8/8/2019 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

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Stephen Holt MD-Immunotherapies A4M