fine tuning the immune system with transfer factors
TRANSCRIPT
Fine Tuning the Immune System with
Transfer Factors & Natural Anti-
Inflammatories
Dr. Debby Hamilton, MD, MPH
1
Objectives
1. Understand the basic role of T cells in the immune
system including T helper cells and natural killer cells
2. Learn about different subsets of T helper cells including
Th1, Th2, Th9, Th17, Th22 and Treg cells and their role in
allergic and autoimmune support
3. Learn how transfer factors can affect immune balance
and be used safely for both allergic, infectious and
autoimmune support
4. Integrate anti-inflammatory herbs to help modulate
cytokines influencing immune cell balance
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Immune
Cells
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Cytokines
Chemical messenger from one cell to another
Chemokines: released when an injury to a tissue
triggers inflammation and attracts other immune
cells
Interleukin: chemical passed from one WBC
(Leukocyte) to another WBC
(between leukocytes= interleukin)
4
Lymphocytes:
Natural Killer Cells
NK Cells
No maturation: “Born this way”
Similar to cytotoxic T-cells
Destroy cells identified as non-self (important for
cancer)
Release protein to target cells to begin apoptosis
or cell death (tells the cell to self-destruct)
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Lymphocytes: B-Cells
B-Cells
Mature in Bone Marrow
Form Plasma Cells: make antibodies
to specific antigen (protein marker)
Each B-cell makes 1 antibody for 1
antigen
Need thousands of B cells because
thousands of antigens
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Lymphocytes:
T-cells
T-Cells
Mature in Thymus
CD8+ cells: Cytotoxic T cells: destroy infected cell
CD4+ cells: Helper T cells: communicate with
other cells
Regulatory (Suppressor) T Cells: turns off immune
response
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B-cell and T-cell Immunity
B-cells: Antibody-mediated immunity
B-cell is directed by pathogen to produce antibody
Aimed at protecting the body from bacteria and viruses WITHIN the BLOOD
T-cells: Cell-mediated immunity
T-cells identify pathogens in a cell
Aimed at protecting the body from bacteria, yeast, parasites and cancer cells WITHIN the CELL
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T-cells: CD8+ Cytotoxic T-cells
Targets cells marked with
an antigen
9
T-cells: T-regulatory or T-Suppressor cells
Regulate or suppress the
immune response
When acute infection or
injury is done
Goal: prevent chronic
inflammation
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TH1 and Th2
Th1 immune response: Cell-Mediated
T-helper 1 (Th1)cells release cytokines
Th1 cytokines tell other T cells to make transfer factor which are antibody-like peptides
Th2 immune response: Antibody mediated
T-helper 2 (Th2) cells release cytokines
Th2 cytokines give message for B-cells to make antibodies
Th1 cytokines decrease Th2 cytokines and vice versa
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Goal: Immune Balance
Traditional Paradigm
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Th1 versus Th2
Th1 immune response
needed for:
Viruses
Yeast (Candida)
Cancer
Parasites-some
Intracellular
bacteria
Th2 immune response
needed for:
Bacteria: in the
blood and lymph
Parasites: some
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▪ Allergies
▪ Chronic sinusitis
▪ Atopic eczema
▪ Asthma
▪ Systemic autoimmune
conditions such as lupus
erythematosus
▪ Vaccination-induced
state
▪ Ulcerative colitis
▪ Certain cases of autism
▪ Hyperinsulinism
▪ Malaria
▪ Hepatitis C
▪ Chronic giardiasis
▪ Chronic candidiasis
▪ Cancer
▪ Viral infections
▪ Antibiotics
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Th2 Dominant Conditions
▪ Diabetes type 1
▪ Multiple sclerosis
▪ Rheumatoid arthritis
▪ Uveitis
▪ Crohn’s disease
▪ Hashimoto’s disease
▪ Sjögren’s syndrome
▪ Psoriasis
▪ Sarcoidosis
▪ H. pylori infections
▪ E. histolytica
NOT Absolute because of
Th17 affect on autoimmune
disease
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Th1 Dominant Conditions
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Th17
Role against extracellular pathogens
Recruit neutrophils and macrophages to infected tissue
Helps maintain mucosal barrier (intestine)
Depending on which cytokines activate the T-helper cell
will become
Protective Th17 or
Pro-inflammatory Th17
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Th17
NF-KB when activated leads to release of Il-6, Il-1B, TNF-alpha which then activate Th17
Th17 activated by cytokines:
TGF-B, IL-6, IL-21, IL-23
Th17 produce cytokines:
IL-17, IL-17A, IL-17F, IL-21, IL-22
Increase in pathologic Th17 in RA, MS, Psoriasis, IBD
Role in Autoimmune disease tissue destruction
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Th17- Rheumatoid Arthritis
Increase in Th17 cells in synovium of patients with rheumatoid Arthritis
Increase in IL-17A in synovium
IL-17A regulates bone resorption and therefore influences bone and joint destruction characteristic of Rheumatoid Arthritis
Not primarily a Th1 dominant disease
Kugyelka R. Et al. Enigma of Il-17 and Th17 cells in Rheumatoid Arthritis and in autoimmune animal models of arthritis. Mediators of Inflammation. Volume 2016 (2016), Article ID 6145810.
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Th17-Multiple
Sclerosis
Th17 pathogenic if activated by IL-23
Migrate through BBB
High levels in brain lesions in MS
Lead to neuroinflammation
Jadidi-Niaragh F. Et al. Th17 cell, the new
player of neuroinflammatory process in
multiple sclerosis. Scand J Immunol. 2011
Jul;74(1):1-13.
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Th17-Group A Strep Infections
Th17 dominant response to multiple Group A strep infections
Activated Th17 made in the NALT (nasal associated lymph tissue) migrates into the olfactory bulb
Hurts BBB
Increase in IgG cross reacting antibodies
Neuroinflammation
Dileepan T. et al. Group A streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific Th17 cells. J Clin Invest. 2016 Jan 4;126(1):303-317
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Th9: FunctionsIncreased lymphocytes and mast cells (IL-6) lead
to increased Th17 cells
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Relationship between Th17 and Th9
Regulatory role of Th9 on Th17 for
autoimmune disease
Inflammation moderating affect of
exaggerated Th17 in multiple sclerosis
Promotes mast cell degranulation
Increased Th9 promotes Increase in
Th17
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Th22: Epithelial adapting T helper cell
Induced by TNF-alpha and Il-6
Inhibited by TGF-beta
Similar to Th17 because of their ability to be pro-inflammatory and
protective to tissues.
When protective, Th22 helps protect epithelial cells and supports
wound healing.
When dysregulated, Th22 can exacerbate eczema.
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T helper cell comparison
Cytokine
Inducers ofT cell formation
Cytokines
Produced byT helper cell
Increase Allergic Responses
Increase Autoimmune Responses
Th1 IFN-y IFN-y No Yes
Th2 IL-4 IL-4, IL-5, IL-13 Yes No
Th9 TGF-B, IL-4
IL-9, IL-10 Yes Yes
Th17 IL-23, TGF-B, IL-6
IL-17 Yes Yes
Th22 TNF-alpha,IL-6
IL-22 Yes No
Treg TGF-B, IL-2 TGF-B, IL-10 No No
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Summary
of T helper
cells
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Transfer
Factors
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Transfer Factor: Definition
Small proteins with RNA (nucleotide material)
Made by activated T-helper cells
Transfer Factor by other mammals molecularly similar to our transfer factor:
Our immune system can’t tell the difference
Supplements derived from
Leukocytes(Dialyzable Leukocyte extract: DLE)
Bovine colostrum
Egg yolk
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Transfer FactorEffects of transfer factors on immune response
Binds to specific antigen on an infected cell
Antigen marks the cell for destruction by
cytotoxic T cells
Th1/Th2 balance
Strengthens Th1 immune system
Decreases TH2 if overactivated
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Transfer
Factor:
Improve
Th1 immunity
Helper T cellsIncrease
Natural Killer CellsIncrease
MacrophagesIncrease
Th1 CytokinesIncrease
Th2 CytokinesDecrease
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Transfer Factor Adjunctive Therapy
Antibiotics promote Th2 immune response
Vaccines promote Th2 immune response
Transfer Factors by promoting Th1
response help balance the immune
system
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Transfer Factor
types of transfer factors
Non-specific transfer factor
To keep front line of immune system (NK cell
function) strong
To promote healthy Th1-Th2 balance
Antigen-specific or targeted transfer factor
To promote the body’s healthy response to
specific health issues
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Transfer Factor
Clinical Uses: Herpes Double-blind clinical trial with Transfer Factor versus Acyclovir for acute
herpes zoster infection
28 patients with acute herpes zoster
7 day treatment of either Transfer Factor or Acyclovir with 14 day
clinical follow-up
Transfer Factor better clinical improvement than Acyclovir
P<0.015
Transfer Factor group:
Increase in IFN-gamma (marker of Th1 immunity)
Increase in CD4 + cells(naïve T helper cells)
Estrada-Parra S. et al. Comparative study of transfer factor and acyclovir in the treatment of herpes zoster. Int J
Immunopharmacol. Oct 1998;20(10):521-535
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Transfer Factor
Clinical Uses: Varicella Zoster
Double blind clinical trial in 61 children with acute leukemia and no
immunity to chickenpox given either Transfer Factor specific for
Varicella or placebo: length of study 12 to 30 months
Exposed to chickenpox: 16 in Transfer Factor group
15 in placebo group
Positive clinical and antibody to chickenpox: 1 out of 16 in TF group
13 out of 15 in placebo group
P=1.3 X10-5
Passive transfer of immunity
Steele RW et al. Transfer factor for the prevention of varicella-zoster infection in childhood leukemia. N Engl J
Med. Aug 14 1980;303(7):355-359
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Transfer Factor
Clinical Uses: HIV
HIV virus Triggers Th2 cytokines so Th2 dominant immune system:
Tricking the immune system so making it more difficult to fight the virus
HIV infects T-cells so need a strong Th1 system to fight HIV virus
Ojeda M. et al. Dialyzable Leukocyte Extract Suppresses the Activity of Essential Transcription Factors for HIV-1 Gene Expression in Unstimulated MT-4 Cells. Biochem and Biophys Res Comm. 2000 July. 273(3): 1099-1103.
Granitov VM et al. The use of activated transfer factor in the treatment of HIV patients. Jour of HIV, AIDS and Related Problems. 2002. 6(1):79-80.
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Transfer Factor
Clinical Uses: Lyme (Borrelia)
Lyme disease: Borrelia triggers Th2 cytokines, but has developed
mechanisms for preventing detection by antibodies:
They turn into cysts inside or outside host cells
They multiply in such a way that the new spirochetes have different
antigens in their membranes
They form slime-like coating, making detection very difficult
They can hide inside the cells in a cell wall deficient L-form
To treat Lyme, need strong Th1 response
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Transfer Factor
Clinical Uses: Cancer
Th1 dominant states are characterized by increased amounts of IL-2 and INFγ which limit tumor growth.
Th2 dominant states are characterized by increased amounts of IL-4 and IL-10 which stimulate tumor growth.
As cancer grows, it becomes more hypoxic → further suppression of cellular immunity and upgrade of Th2 response → associated with procarcinogenesis state, which facilitates cancer growth.
Transfer factors limit tumor growth and significantly reduce tumor size and increase CD2+, CD4+,CD8+, killer cell, + increase the percentage of apoptotic tumor cells.
O’Byrne et al. The relationship between angiogenesis and the immune response in carcinogenesis and the progression of malignant disease. European Journal Of Cancer. 36:151-169, 1999 [2]
Lawrence HS: Transfer factor in cellular immunity. The Harvey Lecture Series 68. New York: Academic Press, 1987
38
Transfer Factor
Clinical Uses: Allergies/Asthma
Allergic diseases: Th2 dominant
Asthma
Research showing decrease dose of steroids with TF
Eczema
Food allergies
Food hypersensitivities
Environmental allergies
Espinosa- Padilla SE et al. Effects of transfer factor on treatment with glucocorticoids in a group of pediatric
patients with persistent moderate allergic asthma. Rev Alerg Mex. 2009; 56(3):67-71.
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Transfer Factor
Clinical Uses: Autism
Immune Deficiencies/Imbalance in autism
Decreased NK cell number and function
Increased allergies to food/environment
Low number of helper T-cells (CD4+ cells)
Depressed T-cell responses to activation
Low sIgA (poor mucosal immunity-GI issues)
Autoantibodies: myelin basic protein, neuronal filament
Maternal increase in Th17 cells with increase in IL-17A
Wong H. et al. Maternal IL-17A in autism. Autism. 2017 Apr 25.
Cohly HH. Immunological findings in autism. In. Rev Neurobiol. 2005;71:317-41.
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Transfer Factor
Clinical Uses: Autism 40 infantile autistic patients were studied. They ranged from 6 years
to 15 years of age at entry. 22 were cases of classical infantile autism; whereas 18 lacked one or more clinical defects associated with infantile autism ("pseudo-autism"). Of the 22 with classic autism, 21 responded to transfer factor (TF) treatment by gaining at least 2 points in symptoms severity score average (SSSA); and 10 became normal in that they were main-streamed in school and clinical characteristics were fully normalized. Of the 18 remaining, 4 responded to TF, some to other therapies. After cessation of TF therapy, 5 in the autistic group and 3 of the pseudo-autistic group regressed, but they did not drop as low as baseline levels.
Fudenberg HH. Dialysable lymphocyte extract (DLyE) in infantile onset autism: a pilot study. Biotherapy. 1996;9(1-3):143-7.
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Transfer Factor:
Concerns and Side Effects
Transfer factors contain no milk protein, allergic reactions are rare.
Patients may experience flu-like symptoms and nausea at the start of
the treatment → Classified as Herxheimer reaction
Pregnancy: Transfer Factor not recommended
Naturally a Th2 dominant state
Th1 dominant state could lead to immune rejection of the fetus
Nursing is safe for transfer factor use (transfer factors naturally in
breastmilk)
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Transfer Factor
Clinical Uses: Autoimmune
Combine: Natural anti-inflammatories to help decrease
pathogenic Th17 by decreasing NF-KB and Transfer
Factor to help balance immune system
Identify infections that can trigger autoimmune disease
and treat using specific transfer factor
Ex. Mycoplasma in RA
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Regulation of cytokines and
interleukins
If we decrease IL-23
Will decrease pathologic Th17
Will decrease autoimmune destruction from pathologic TH17
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Curcumin: regulation of T helper cells
Curcumin impairs the differentiation of Th1/Th17 cells in vivo during encephalomyelitis and instead promoted Th2 cells.
Curcumin selectively inhibits IL-12 and IL-23 production by activated dendritic cells
Curcumin silences IL-23/Th17-mediated pathology by enhancing HO-1/STAT3 interaction in dendritic cells.
Bruck J. et al. Nutritional control of IL-23/Th17-mediated autoimmune disease through HO-1/STAT3 activation.Sci Rep. 2017;7:44482.
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N-Acetylcysteine:
Regulation of T helper cells
Role of N-acetylcysteine in decreasing Th17 in RA
Decreased production of proinflammatory cytokines in
RA synovial fibroblasts
Inhibited Th17 cells
Inhibited differentiation of osteoclasts
Kim H-R. N-acetylcysteine controls osteoclastogenesis through regulating Th17
differentiation and RANKL in rheumatoid arthritis. Korean J Intern Med. 2017
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EGCG: Regulation of T helper cells
EGCG impedes Th1, Th9, and Th17 differentiation
EGCG modulates development of CD4(+) T cells ultimately leading to an attenuated autoimmune response.
Prevents IL-6-induced suppression of Treg development.
Wang J. et al. Green tea epigallocatechin-3-gallate modulates differentiation of naïve CD4⁺ T cells into specific lineage effector cells. 2013 Apr;91(4):485-95.
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Resveratrol:Regulation of T helper cells
Small doses of resveratrol (10 µM) reduce cell activation in response to tumor necrosis factor (TNF)-α
Decreased TNF-alpha leads to decrease in Il-12/IL-23 and increase in IL-10
Resveratrol also inhibited T cell proliferation, in response to TNF-α-stimulated Dendritic Cells.
Mechanism: ? Mediated through NF-kB
Silva AM. Et al. Resveratrol as a Natural Anti-Tumor Necrosis Factor-α Molecule: Implications to Dendritic Cells and Their Crosstalk with Mesenchymal Stromal Cells. PLoS One. 2014; 9(3): e91406.
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Dr. Debby Hamilton, MD, MPH
Researched Nutritionals
www.researchednutritionals.com
49
Addendum
References
Researched Nutritionals Products:
Transfer Factors
CytoQuel®
50
References
1. Balajii C. Et al. Long-term persistence of inflammation in children vaccinated with salmonella conjugate vaccine
is associated with augmented Th9-Th17 cytokines. Cytokine 2017. Mar; 91:128-131.
2. Berker M Et. al. Allergies: A T cell perspective in the era beyond the Th1-Th2 paradigm. Clinical Immunology. 2017.
174:73-83.
3. Burkett PR. Et al. Pouring fuel on the fire: Th17 cells, the environment, and autoimmunity. J Clin Invest. 2015 Jun 1;
125(6): 2211–2219.
4. Cohly HH. Immunological findings in autism. Int. Rev Neurobiol. 2005;71:317-41.
5. Dileepan T. et al. Group A streptococcus intranasal infection promotes CNS infiltration by streptococcal-specific
Th17 cells. J Clin Invest. 2016 Jan 4;126(1):303-317.
6. Espinosa- Padilla SE et al. Effects of transfer factor on treatment with glucocorticoids in a group of pediatric
patients with persistent moderate allergic asthma. Rev Alerg Mex. 2009; 56(3):67-71.
7. Estrada-Parra S. et al. Comparative study of transfer factor and acyclovir in the treatment of herpes zoster. Int J
Immunopharmacol. Oct 1998;20(10):521-535.
8. Fudenberg HH. Dialysable lymphocyte extract (DLyE) in infantile onset autism: a pilot study. Biotherapy. 1996;9(1-
3):143-7
9. Granitov VM et al. The use of activated transfer factor in the treatment of HIV patients. Jour of HIV, AIDS and
Related Problems. 2002. 6(1):79-80.
51
References1. Jadidi-Niaragh F. Et al. Th17 cell, the new player of neuroinflammatory process in multiple sclerosis. Scand J
Immunol. 2011 Jul;74(1):1-13.
2. Jager A. et al. Th1, Th17, and Th9 effector cells induce experimental autoimmune encephalomyelitis with
different pathological phenotypes. J Immunol. 2009. Dec 1;183(11):7169-7177.
3. Kim H-R. N-acetylcysteine controls osteoclastogenesis through regulating Th17 differentiation and RANKL in
rheumatoid arthritis. Korean J Intern Med. 2017
4. Kugyelka R. Et al. Enigma of Il-17 and Th17 cells in Rheumatoid Arthritis and in autoimmune animal models of
arthritis. Mediators of Inflammation. Volume 2016 (2016), Article ID 6145810.
5. Kuwaba T. et al. Role of IL-17 and related cytokines in inflammatory autoimmune diseases. Mediators of
Inflammation. 2017.
6. Lawrence HS: Transfer factor in cellular immunity. The Harvey Lecture Series 68. New York: Academic Press, 1987
7. Maeda S. et al. The Various Roles of Th17 cells and Th17-related Cytokines in Pathophysiology of Autoimmune
Arthritis and Allied Conditions. J Clin Cell Immunol. 2013, S10.
8. O’Byrne et al. The relationship between angiogenesis and the immune response in carcinogenesis and the
progression of malignant disease. European Journal Of Cancer. 1999. 36:151-169.
9. Ojeda M. et al. Dialyzable Leukocyte Extract Suppresses the Activity of Essential Transcription Factors for HIV-1
Gene Expression in Unstimulated MT-4 Cells. Biochem and Biophys Res Comm. 2000 July. 273(3): 1099-1103.
52
References
1. Ruocco G. et al. T helper 9 cells induced by plasmacytoid dendritic cells regulate interleukin-17 in multiple
sclerosis. Clin Sci(Lond). 2015 Aug;129(4):291-303
2. Silva AM. Et al. Resveratrol as a Natural Anti-Tumor Necrosis Factor-α Molecule: Implications to Dendritic Cells and
Their Crosstalk with Mesenchymal Stromal Cells. PLoS One. 2014; 9(3): e91406.
3. Steele RW et al. Transfer factor for the prevention of varicella-zoster infection in childhood leukemia. N Engl J
Med. Aug 14 1980;303(7):355-359.
4. Viza D. et al. Transfer Factor: an overlooked potential for the prevention and treatment of infectious diseases.
Folia Biologica. 2013. 59, 53-67.
5. Vojdani A. et al. The role of Th17 in neuroimmune disorders: a target for CAM therapy. Evidence-based
complementary and alternative medicine. Vol 2011, Article ID 548086.
6. Wang J. et al. Green tea epigallocatechin-3-gallate modulates differentiation of naïve CD4⁺ T cells into specific
lineage effector cells. J Mol Med (Berl). 2013 Apr;91(4):485-95.
7. Wong H. et al. Maternal IL-17A in autism. Exp Neurol. 2017 Apr 25.
8. Zajicova A. et al. A Low-Molecular-Weight Dialysable Leukocyte Extract Selectively Enhances Development of
CD4+RORγt+ T Cells and IL-17 Production. Folia Biologica. 2014. 60, 253-260.
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Transfer Factor Multi-Immune™
Non-specific transfer factor Formulated with pure
transfer factor plus other key
researched nutrients to
promote healthy natural kill
cell function
Used by healthy patients to
remain healthy
Used by ill patients (i.e. CFS,
FM, Lyme, etc.) to rebuild
their immune systems
54
Transfer Factor Multi-Immune™NK Cell Research
NK Cell function:
235% 2 caps
620% 2 caps bid
* Research presented at ICIM
55
Transfer Factor Multi-Immune™Research: Institute for Molecular Medicine & Reported in Townsend Letter
NK Cell function:
247% with 2 cap/day
56
57
Transfer Factor L-Plus™
Promote Healthy Response to:
Bartonella
Borrelia burgdorferi
Babesia
Ehrlichia
EBV
HHV6 B
CMV
Chlamydia pneumoniae
58
Transfer Factor PlasMyc™ Promote Healthy Response to:
Borrelia burgdorferi
EBV
HHV6 A&B
CMV
Chlamydia pneumoniae
Human TB
Bovine TB
Herpes 1
Herpes 2
Cryptosporosis
Mycobacterium avium
E. Coli
Parvo virus B19
Varicella Zoster
Candida
MMR (measles, mumps, rubella)
Mycoplasma
Ureaplasma urealyticum
Nanobacterium
Human Papillomaviruses
Staphylococci
Hepatitis A, B, C
Streptococci
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Transfer Factor Enviro™targeted immune support
Promote healthy response to:
Environmental challenges
Penicillinum
Epicoccum
Aspergillus fumigatus (common in chronic sinusitis)
Aspergillus niger
Aspergillus versicolor
Candida albicans
Candida parapsilosis
Cladosporium
Fusarium
Geotrichum
Pithomyces
Ustilago
60
CytoQuel®
healthy cytokine support
Black Tea Extract
Much stronger antioxidant than green tea
Highest EGCG Content - 50%
CurcuWin®
46X absorption of standard curcumin*
35X absorption of BCM-95®*
6X absorption of Meriva®*
Delta Gold® Tocotrienols
Pure delta & gamma
No tocopherols = better absorption
N-Acetyl-cysteine (NAC)
Resveratrol (Natural Trans-Resveratrol)
* Comparative Absorption of Curcumin Formulations. Jager R. Et al Nutr J 2014 Jan 24;13(1):11.
61