how powering the immune system can benefit...
TRANSCRIPT
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How Powering the Immune System Can
Benefit Athletic Performance
March 2013
Company Overview
• Privately held Minnesota biotechnology company founded in 1997.
• Technology platform focused on the innate immune system.
– 40+ U.S. patents and patents pending, plus filings in more than 20 countries.
• Two business units:
– Healthcare Group is focused on protection, providing branded food-grade immune enhancing ingredients to the food, beverage, supplement, animal nutrition and cosmetic markets.
– Pharmaceutical Group is developing injectable immunotherapy drugs with a primary focus in cancer.
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Acute effects of exercise on immunity
• Circulating immune cell numbers and functions are temporarily altered following a prolonged bout of heavy exercise
• Increased numbers of leukocytes (neutrophils & monocytes – but fewer lymphocytes & NK cells)
• Increased plasma concentrations of inflammatory cytokines (TNF, IL-1, IL-6), anti-inflammatory cytokines (IL-1ra, IL-10) and positive acute phase proteins
• Decreased functional responses of neutrophils, NK cells, APCs, T cells, B cells etc.
2.5 to 3 hours of intensive running (n = 62 marathon runners) Nieman (1997) J. Appl. Physiol. 82, 1385-1394
Acute exercise: Circulating leukocytes
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Acute exercise: Phagocytosis and oxidative burst
2.5 hours of intensive running (n = 30 marathon runners) Nieman (1997) J. Appl. Physiol. 82, 1385-1394
Acute exercise: NK cell activity
2.5 hours of intensive running (n = 62 marathon runners & n = 10 resting controls)
Nieman (1997) J. Appl. Physiol. 82, 1385-1394
Impairment may last for days
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2.5 hours of intensive running (n = 62 marathon runners & n = 10 resting controls)
Nieman (1997) J. Appl. Physiol. 82, 1385-1394
Impairment may last for days
# of NK cells drops => decreased activity mirrors the fall in number (activity per NK cell not altered?)
Acute exercise: T cell proliferation
2.5 hours of intensive running (n = 22 marathon runners vs. n = 10 resting controls)
Nieman (1997) J. Appl. Physiol. 82, 1385-1394
May reflect decreased circulating # of T cells
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Acute exercise: Secretory IgA
• Nasal IgA decreased by up to 70% for up to 18 hr after a 31 km run
• Salivary IgA declined following 2 to 3 hr of exhaustive ski competition in elite cross-country skiers
• Salivary IgA declined after 2 hr of hard exercise in cyclists
• Low salivary IgA preceded URTI in elite squash and hockey players
Exercise Stress/Biomarker Study
• Many immune biomarkers show a quick drop that lasts for 2-6 hours following exercise (“open window effect”).
• Study model developed at University of Houston Department of Health and Human Performance.
– 60 recreationally fit subjects/29 male, 31 female (23± 5 yr.)
– Cross over design, double blind, randomized
– Cycling at 100F for approximately one hour (two sessions)
– Blood and saliva samples at day zero (baseline), day 10 (pre-exercise) and post-exercise and 2 hours post-exercise
Br J Nutr. 2012 May 10:1-9.
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Exercise Stress/Biomarker Study
Placebo
Healthy Zone
Challenge zone
Wellmune WGP®
Exercise Stress/Biomarker Study
Biomarker data supports athletic performance benefits
1. Maintains White Blood Cell Levels. Wellmune prevented the drop in protective white blood cells that can occur following intense exercise.
2. Improved Mucosal Immunity. Higher salivary IgA, a protective protein, is associated with improved immune protection of the mucosal. Wellmune helped salivary IgA levels rebound more quickly after exercise.
3. Enhanced Immune Responses to a Simulated Challenge. The Wellmune group had higher levels of key cytokines following Lipopolysaccharide (LPS) stimulation.
Br J Nutr. 2012 May 10:1-9.
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Key Immune Cells: Monocytes
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Baseline Pre Post 2h
Tota
l Mo
noc
yte
s X
103
/ m
l Total Monocyte Concentration
Placebo
Wellmune WGP
*
*Significantly different @ p< 0.05
Wellmune significantly reduced the effect of exercise on circulating monocytes.
Mucosal Immunity
*Significantly different @ p< 0.05
*
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Baseline Pre Post 2h
Saliv
ary
IgA
(p
g/m
l)
Salivary IgA
Placebo
WGP
Wellmune improved salivary IgA recovery at two hours post-exercise.
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LPS-Stimulated Cytokines
8750.00
8800.00
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9000.00
9050.00
Baseline Pre Post 2h
IL-4
(p
g /
ml)
LPS Stimulated Cytokines : IL-4
*
*
*
*Significantly different @ p< 0.05
The change demonstrates Wellmune’s ability to enhance immune responses to a perceived challenge.
Summary of exercise & the immune system
• Neutrophilia and lymphopenia
• Increased (blood) neutrophil and monocyte phagocytosis
• Decreased NK cell activity
• Decreased T cell response
• Decreased secretory IgA
• Maintained humoral responses (B cell driven)
• Increased circulating pro- and anti-inflammatory cytokines
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Why is nutrition important?
Increased demand for energy and for
building blocks (cells, proteins etc.)
“Resting” immune system
“Activated” immune system
Nutrients can also be:
• Precursors of mediators involved in the immune response - Arginine & NO - Arachidonic acid and eicosanoids
• Regulators of mediator production • Regulators of signal transduction & gene
expression in immune cells (& so of cellular responses) - Many micronutrients
• Components of protection system against immune damage to the host - Antioxidants
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Nutritional/non-nutritional approaches
• Carbohydrate
• Glutamine
• Antioxidant vitamins
• Trace elements (zinc)
• Omega-3 fatty acids
• Yeast beta-glucan
• Probiotics & prebiotics
• Others
Glutamine
• Rationale: fuel for immune cells; maintains “optimal” immune function in vitro; beneficial in post-surgery, burns and critical illness; blood concentration declines with exercise
• Limited effect on exercise-induced alterations in immune function when consumed during or after exercise
• One study reported lower URTI in marathon runners who consumed glutamine
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Zinc
• Rationale: Essential for immune function; component of antioxidant defence system (SOD); lost in sweat
• Limited evaluation in the context of exercise
• High doses impair immune function: exercise-induced reduction in T cell function exaggerated by 50 mg Zn + 3 mg Cu/day for 6 days
Probiotics
• Rationale: live bacteria that interact with host gut epithelia and immune system
• In elite distance runners L. fermentum for 28 days decreased risk and severity of respiratory illness and enhanced some immune parameters
• L. acidophilus for one month prevented exercise-induced impairment of T cell function
• L. casei for one month partly prevented exercise-induced decline in NK cell activity
• L. rhamnosus GG for 3 months reduced the duration of GI-symptoms during marathon training and in the 2 weeks following a marathon
• L. casei maintained salivary IgA and lowered incidence of URTI over 4 months in university athletes
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Yeast Beta-glucan as a dietary intervention: Wellmune Science & Technology
Beta 1,3/1,6 Glucan
Beta 1,3/1,6 Glucan
Lipids, Proteins, Nucleic Acids and cellular contents
Mannoprotein
Fibrillar Layer Mannoprotein Mannoprotein Plasma Membrane Cytoplasm. Lipids
Beta 1,3/1,6 Glucan
Wellmune WGP Source
Yeast Cell Yeast Cell Cross Section
Proprietary Strain of Yeast (Saccharomyces Cerevisiae)
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Dr. Ross’s research in the 1980s: How does the body clear a yeast or fungal infection?
Dr. Gordon Ross, Brown Cancer Center Deputy Editor-Journal of Immunology
• Neutrophil responsible for killing yeast and fungal challenges. • Specific receptor (Complement Receptor 3 or CR3) on the surface
of neutrophils that triggered killing. • CR3 requires a specific carbohydrate and complement to initiate
killing.
Technology Background
Immunology Discoveries
Immune Response to Yeast / Fungus
2. Complement (iC3b) binds (fixes) to target
yeast and attracts immune cells
Yeast or Fungus
iC3b
Neutrophil
iC3b
iC3b
1. Natural antibody binds to yeast and activates complement
3. Neutrophil binds to the complement (via CR3) and to the β1,3/1,6 Glucan on the surface of the yeast at the same time which triggers a CR3-mediated killing mechanism.
Complement Receptor 3
β1,3/1,6 Glucan
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Wellmune WGP Priming of Neutrophils
Neutrophil
Wellmune WGP binds to CR3 on neutrophil “priming” the immune cell for activity
Wellmune WGP Priming of Neutrophils
Target: Foreign Challenge
Primed Neutrophil
iC3b iC3b iC3b
4. “Primed” neutrophil binds to complement on target via CR3 which activates CR3-mediated killing mechanism.
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1) Taken orally, Wellmune WGP is taken up into the body via the Peyer’s Patches in the intestines.
2) Immune cells called macrophages containing Wellmune WGP travel to the immune organs throughout the body.
3) Macrophages break down Wellmune WGP into smaller fragments that bind to neutrophils, the most abundant immune cell in the body.
4) Neutrophils more quickly recognize and kill foreign challenges.
How Wellmune WGP Works
Hong et al. (2004) J. Immunol. 173, 797-806
Clinical Research
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Biothera Healthcare Clinical Research
Study Name Presented Published
1) Texas Marathon** 2012 American Soc. of Sports Medicine Accepted J. of Dietary Supplements
2) Exercise Stress*
2011 Int’l Society of Exercise Immunology British Journal of Nutrition, 2012
3) Medical Students*
2010 British Society of Immunology Nutrition, 2012
4) Lifestyle Stress 90-day*
2010 Experimental Biology J. of American College of Nutrition, 2013
5) Lifestyle Stress 28-day*
2007 American College of Nutrition Agro Foods Industry Hi Tech, 2010
6) Allergy* 2011 Experimental Biology Food Science & Nutrition, 2012
7) California Marathon*
2007 American College of Nutrition J. of Sports Science & Medicine, 2009
8) Cold/Flu* 2008 Experimental Biology Journal of Applied Research, 2009
9) Firefighters 2008 American Soc. of Sports Medicine Manuscript in preparation
*Published **Accepted for publication
Wellmune WGP – Human Study Dosage
Study Wellmune Serving (dose)
1) Texas Marathon 250 mg
2) Exercise Stress
250 mg
3) Medical Students
250 mg
4) Lifestyle Stress 90-day
250 mg
5) Lifestyle Stress 28-day
250 mg, 500 mg
6) Allergy 250 mg
7) California Marathon
250 mg, 500 mg
8) Cold/Flu 500 mg
9) Firefighters 250 mg
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Study Protocol § Research conducted by the Health and Human
Performance Lab, University of Houston
§ 182 subjects completed the 2011 Austin TX Marathon
§ Double-blinded, placebo-controlled
§ 250 mg for four weeks post-race
ü Wellmune Soluble and Wellmune Dispersible groups
§ Health questionnaire focusing on (1) upper respiratory tract infection (URTI) symptoms & (2) daily health log of overall physical health
Texas Marathon Stress Study
Baker’s Yeast Beta Glucan Supplementation Reduces the Number of Cold/Flu Symptomatic Days After Completing a Marathon. Presented to the American College of Sports Medicine, San Francisco, CA.
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10.0#
Wellmune'Dispersible' Placebo' Wellmune'Soluble'
Average'Da
ys'with
'Sym
ptom
s'
Average'Symptom'Days'per'Subject'
#1: 2011 Texas Marathon Stress Study
Data presented to the 2012 Am College of Sports Med, San Francisco, CA. Dr. Brian McFarlin, U of North Texas, Department of Exercise Physiology & Nutrition.
*
Overall: >34% Reduction in URTI Symptoms vs Control * p<0.05%
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Firefighters Study Protocol
§ Study design - impact of Wellmune WGP on URTI in fire crews fighting wildfires.
§ 54 subjects.
§ Crossover design, single blind, one crew on Wellmune WGP for 2 weeks, other on placebo; switch groups during rest period (3-5 day rest).
§ Primary endpoint URTI incidence.
§ Secondary endpoint overall health.
§ Study co-funded by US Air Force and conducted by University of Montana.
Stress Study - Firefighters
Presented: American College of Sports Medicine, May 2008. Publication pending.
Study Results
§ Wellmune WGP reduced by 23% the incidence of URTI (p=0.06)
§ Wellmune WGP dramatically improved overall physical health (p=0.006)
§ Subjects reported supplement increased feeling of overall wellness
§ Trend toward increased work output
§ Presented at 2008 American College of Sports Medicine Conference, May 28-31, 2008
Stress Study - Firefighters
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Summary
ü Intensive exercise affects blood immune cells, plasma cytokines, APC, T and NK cell function, secretory IgA.
ü Allows us to study effects of physical stress on immune system and health.
ü Maintaining immune health is an unmet need of many well-designed training programs.
ü Wellmune WGP® is natural and clinically proven to help athletes maintain immunity despite rigorous training.
Discussion