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Specific Formulation of Camellia sinensis Prevents Cold and Flu Symptoms and Enhances T Cell Function: A Randomized, Double-Blind, Placebo-Controlled Study

Food Science and Human Nutrition Department, University of Florida (C.A.R., M.P.N., S.S.P.), Gainesville, Florida
Divison of Rheumatology, Allergy & Immunology, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School (J.F.B.)
Nutritional Science Research Institute (J.F.B.), Boston, Massachusetts

Address reprint requests to: Susan S. Percival, PhD, Food Science and Human Nutrition Department, University of Florida, Gainesville, Florida 32611. E-mail: Percival{at}ufl.edu

	ABSTRACT

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Objective: Determine if a specific formulation of Camellia sinensis (CSF) can prevent illness and symptoms due to cold and flu, and enhance T cell function

Methods: Design: Randomized, double-blind, placebo-controlled study. Subjects: Healthy adults 18–70 years old. Intervention: Proprietary formulation of Camellia sinensis (green tea) capsules, or a placebo, twice a day, for 3 months. Measures of Outcome: As assessed by daily symptom logs, percentage of subjects experiencing cold and flu symptoms, number of days subjects experienced symptoms, and percentage of subjects seeking medical treatment. Mean in vivo and ex vivo proliferative and interferon gamma responses of subjects’ peripheral blood mononuclear cells to T cell antigen stimulation.

Results: Among subjects taking CSF there were 32.1% fewer subjects with symptoms (P = 0.035), 22.9% fewer overall illnesses of at least 2 days duration (P = 0.092), and 35.6% fewer symptom days (P < 0.002), compared to subjects taking placebo. T cells from subjects taking CSF proliferated 28% more (P = 0.017) and secreted 26% more IFN- (P = 0.046) in response to T cell antigens, as compared to T cells from subjects taking placebo. CSF was well-tolerated.

Conclusions: This proprietary formulation of CSF is a safe and effective dietary supplement for preventing cold and flu symptoms, and for enhancing T cell function.

Abbreviations: CSF, Camellia sinensis formulation • EGCG, epigallocatechin gallate • PBMC, peripheral blood mononuclear cells • IFN-, interferon gamma

	INTRODUCTION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
For centuries, tea beverage has been linked to good health. Most studies have been observational, showing benefit in cardiovascular, anti-aging, neurodegenerative, anti-cancer, and bone areas [1, 2]. There are numerous other studies consistent with no health benefits [3, 4]. These studies, both positive and negative, are fraught with confounding variables that are inherent in observational studies employing free-living human beings as subjects. Such studies are further complicated by the nature of tea beverage. There are hundreds of varieties of the tea species, Camellia sinensis, and numerous ways to process tea that can lead to different components in a cup of tea [5, 6]. Storing and brewing methods lead to further variability that is difficult to standardize. Another obvious source of conflict is that there is no general agreement on what quantity constitutes a cup of tea. Thus, it is not surprising that the results of many published trials conflict with one another.

Whereas most clinical tea research has focused on cardiac and cancer outcomes, there are no available clinical human data on prevention of cold and flu symptoms. These symptoms are the most common afflictions in humans, resulting in misery, loss of productivity, and absence from work and school [6]. Further, recent studies that call in to question the efficacy of zinc-based nasal sprays and lozenges [7], and Echinacea [8] make new research into cold and flu more important. There is emerging evidence that components found in tea beverage may have anti-infective and anti-inflammatory effects.

L-theanine, an amino acid found uniquely in tea, is catabolized to ethylamine, a molecule that specifically activates human T lymphocytes to proliferate and make interferon gamma, a powerful antimicrobial cytokine [9, 10]. Subjects who drank six cups of tea per day had up to a 15-fold increase in interferon gamma production in as little as one week, when their peripheral blood mononuclear cells (PBMC) were exposed to bacteria [10]. Coffee drinking had no such effect.

There is ample evidence supporting the role of T cells as a first line defense against infection. In mice, studies using specific T cell mAbs and T cell knockout mice provide compelling evidence for protective roles against bacterial, parasitic, and viral infection [11–15]. In humans, T cells expand up to 50-fold in the peripheral blood 6- to 10 days after infection with many bacterial, viral, and parasitic microbes [16–20]. These T cell expansions can be reproduced in vitro by exposure of PBMC to purified nonpeptide microbial products (alkylamines and organophosphates), pharmacologic agents that mimic bacterial antigens, such as nitrogen-containing bisphosphonates, as well as heat killed bacteria and parasites, bacterial or parasitic extracts, and virus-infected cells [21–24]. Using a severe combined immunodeficiency mouse reconstituted with human PBMC (hu-SCID) model, Wang et al. showed that the presence of human T cells is necessary for survival during infection by E. coli or M. morganii, and that protection is associated with secretion of large quantities of gamma interferon (IFN-) by these T cells [25]. The antibacterial effect of human T cells in vivo is evident as early as 17h post-infection, indicating that T cell expansion is not required for an antibacterial response and suggesting that T cell-mediated cytokine secretion is a crucial component of protection. PBMC primed with alkylamine or nitrogen-containing bisphosphonate antigens such as risedronate and pamidronate, specific for V2V2 T cells, produced higher amounts of IFN- and provided more protection against infection than unprimed PBMC [25].

Epigallocatechin gallate (EGCG), a powerful catechin antioxidant found in green and white teas, can directly kill bacteria and viruses, including the influenza virus [26–29]. EGCG is also highly anti-inflammatory. This activity is potentially important in cold and flu infections, since soluble mediators of inflammation cause symptoms. EGCG inhibits the production of pro-inflammatory mediators such as chemokines [30, 31], prostaglandins [31], and tumor necrosis factor (TNF) [32]. EGCG also inhibits adhesion molecule expression [33], MAP kinases [34], and neutrophil migration [35].

Based on these promising data, we hypothesized that ingestion of tea extracts containing standardized amounts of the tea components L-theanine and EGCG would enhance systemic immunity, and prevent cold and flu symptoms in healthy individuals. We conducted a randomized, double-blind, placebo-controlled interventional study using a specific proprietary formulation of these key tea components (Camellia sinensis formulation; CSF) with a primary endpoint of reduction in the number of subjects who developed illness due to cold and flu. We describe here results showing that this CSF reduces by about one third the number of subjects who develop illness due to cold and flu, while enhancing T cell proliferation and IFN- secretion in response to antigen.

	MATERIALS AND METHODS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Subjects
Healthy men (n = 52) and women (n = 72) between 21 and 70 (mean = 29) years of age were recruited to participate in a 12-wk randomized, double-blind placebo controlled parallel study. Subjects were recruited from the University of Florida campus, and the Gainesville, Florida community, during January of 2006. The University of Florida Institutional Review Board approved the study protocol, and informed written consent was obtained from each subject. Screening for the study occurred by telephone and/or personal interviews. Exclusion criteria consisted of the following: had not had a cold in the past two years; vegetarian diet; steroids; chemotherapy or other immune suppressing therapy within the last year; chronic antibiotics or other infectious disease preventative; chronic illness; recent surgery or illness; pregnant and/or lactating females. Also excluded were those who daily consumed: greater than one cup (250mL) of tea; an average of seven or more servings of fruits and vegetables; herbal supplements, vitamins other than a multivitamin or vitamin D, or osteoporosis medicine or medications containing bisphosphonates, that are activators of T cells [36]. The study was conducted from late January through early May of 2006. Participants were in contact with the enrolling research assistant by e-mail and telephone throughout the study, and returned to fill out an exit questionnaire upon study completion. Overall study compliance was monitored through the exit questionnaire and by enumeration of remaining capsules in returned bottles at the end of then study [37].

Study Protocol
The study was conducted from late January through early May of 2006, to coincide with normal cold and flu season. The CDC weekly report of influenza activity in Florida was as follows: January-March regional to widespread, March-April widespread to local activity, April-May local activity to sporadic.

Subjects were randomly assigned to supplement and placebo groups. Both subjects and investigators were blinded as to the treatments. Nutraceutical Holdings, LLC (Orlando, FL) provided ImmuneGuard®, a proprietary Camellia sinensis formulation (CSF) and placebo capsules. This decaffeinated formulation contains a proprietary mixture of L-theanine (Suntheanine®, standardized at 99%; Taiyo International, Minneapolis, MN), and epigallocatechin gallate (EGCG; Sunphenon®, Taiyo International, Minneapolis, MN, standardized at 50%). The placebo capsules contained microcrystalline cellulose, dextrose, dicalcium phosphate, magnesium stearate, silicon dioxide, FD&C red #40, yellow #6, and blue #1. Each participant was given a bottle containing 180 capsules and was instructed to take 2 capsules every day (one in the morning and one in the evening, preferably with meals) for 12 weeks.

Subjects were given an illness log to record any cold and flu symptoms during the 12 week experimental period. Primary outcomes were defined as the number of subjects experiencing any symptoms, and the mean number of symptom days. For example, if a subject had a cough and a sore throat on the same day, this was counted as two symptom days. For analysis of illness frequency, illness was defined as having one or more symptoms for at least two consecutive days. The symptoms assessed were: runny nose, congested or stuffy nose, headache, cough, sore throat, fever, nausea/vomiting, and diarrhea. Subjects were also asked to report if they sought medical treatment and were prescribed any medications as a result of seeking treatment. The exit questionnaire included questions to determine if subjects experienced any side effects and/or experienced any changes in feelings of stress or anxiety, or took any additional dietary supplements during the study. Finally, subjects were asked to report whether they thought they had taken the active or the placebo capsules.

Blood Collection
Blood was obtained from fasting subjects on Days 0 (baseline), and 21. Blood was collected into one 10mL sodium heparin tubes for peripheral blood mononuclear cell (PBMC) separation, and one 10mL SST^TM tube (Vacutainer, Becton Dickinson, Franklin Lakes, NJ) for serum. Tubes for PBMC were maintained at room temperature (RT), while tubes for serum were kept at 4°C. All tubes were processed within 1 hr of blood collection. Blood cell separation and culture procedures were carried out under sterile conditions.

Serum Collection and Treatment
Serum was removed from SST^TM tubes after centrifugation (1000g, 10min, 4°C) and frozen at –80°C.

Blood Cell Separation
Whole blood was diluted and placed on a gradient to separate PBMC. Briefly, 7mL of whole, anti-coagulated blood (RT) was diluted 1:1 with 0.9% NaCl. Diluted blood (6mL) was layered over 3mL of Nycoprep 1-Step^TM 1.077 (Axis-Shield, Oslo, Norway) and centrifuged (800g, 20 min, 20°C). The mononuclear cell layer was removed, washed twice with 10% FBS-RPMI 1640 (Cellgro; Mediatech, Herndon, VA) complete (100U/mL Penicillin; 100µg/mL Streptomycin; 0.25µg/mL Fungizone; 50µg/mL Gentamycin; 2mM 1-glutamine; 25mM HEPES) by centrifugation (400g, 10min, 4°C). Individual cell pellets were resuspended in 2mL RPMI 1640 complete, without serum, and counted on a Z-2 Coulter Counter (3.8 µ setting for the 100µm aperture tube, Beckman Coulter, Inc., Fullerton, CA).

Culture of Peripheral Blood Mononuclear Cells (PBMC) for T-Cell Expansion and Cytokine Production
On Day 0, 1.0 x 10⁶ PBMC in 10% FBS-RPMI 1640 complete medium containing 50µM 2-ME, were seeded into each of two wells of duplicate 24-well tissue culture plates (Costar, Corning, NY). Ethylamine (1mM/mL, Sigma) in the same medium was added to one set of wells on each plate, while the other set was mock treated with 1mL medium. The plate was incubated in a humidified 5% CO₂ atmosphere at 37°C. On Day 1, cells and supernatant fluids from one plate were harvested and centrifuged (1500, 10min, 4°C). The supernatant fluids were removed and frozen at –80°C for cytokine analysis, while the cell pellets were re-suspended in 0.1mL PBS and 0.5mL RNAlater^TM (Ambion, Austin, TX) and frozen at –80°C. On Day 3, 30U/mL of recombinant human IL-2 (BD Biosciences, San Diego, CA) were added to all wells of the remaining plate, which was incubated until Day 10 when cells were harvested. Total cell counts were obtained on a Coulter Counter (4.5µ setting) and dead cells enumerated via trypan blue exclusion on a hemocytometer, and cells processed for flow cytometry.

Flow Cytometry
The ratio of ß and T cells in PBMC suspensions and cultures was determined by flow cytometry, using cell surface markers for identification on Days 0 and 10 of culture.

Antibodies.
Phycoerythrin (PE)-conjugated anti-human CD3⁺ (pan-T cell marker), and fluorescein isothiocyanate (FITC)-conjugated anti-human T cell surface markers ßTCR (pan-ß T cell marker) and TCR (pan- T cell marker; eBioscience, San Diego, CA) were used to stain PBMC.

Staining/Fixation.
PBMC in staining buffer (PBS + 0.1% NaN₃ + 2% FBS) were stained on ice in the dark for 30min, with PE anti-human CD3⁺ antibody and one of the two FITC-conjugated TCR specific antibodies. Cells were washed (PBS + 0.1% NaN₃) by centrifugation (1000g, 10 min, 20°C). Cells were fixed with 1% paraformaldehyde in PBS + 0.1% NaN₃. Cells were analyzed within 24 hours on a FACScan (Becton-Dickinson, San Jose, CA). Data was analyzed using WinMDI Software (Scripps Institute, build 1301-19-2000). Data collected was from gated CD3⁺ cells (events). Final data is reported as the mean percentage of cells expressing the specific cell surface marker, ± the standard deviation (SD).

Cytokine Level Determination in Supernatants from Cell Proliferation
Levels of human IFN- from PBMC culture supernatants were quantified using enzyme linked-immunosorbent assay (ELISA) kits, according to the manufacturer's directions (BD Biosciences Pharmingen, San Diego, CA). Human cytokine standards provided with each kit were used for a standard curve. Supernatants were analyzed undiluted for IFN-. Plates were read at 450nm (with correction of 570nm) on a SPECTRAmax 340PC plate reader (Molecular Devices, Menlo Park, CA). Cytokine concentrations were calculated as the mean value obtained for values within the range of the standard curve. The limits of detection of the cytokine ELISA kits were: IFN- -300pg/mL.

Statistical Analysis
For analysis of illness and symptom frequency, the z-test for two proportions, with two-tailed probability was used. Two-way ANOVA, with 2-tailed probability, was used for T cell proliferation studies and IFN- secretion.

	RESULTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Study Subjects
One hundred and twenty-four subjects were enrolled in the study. Six subjects withdrew from the study (three Camellia sinensis formulation; CSF, and three placebo). Adverse events were mild, infrequent, and transient. Bloating, gastric upset, dizziness, skin rash, and constipation were reported, and were not different between experimental and control groups. Two subjects taking CSF withdrew with mild skin rashes. One subject said she thought the rash was related to a seafood allergy, and the other thought it might be from the capsule. Neither subject sought medical attention. Such food allergies for green tea have been described previously, mostly in tea factory workers, and the causative agent in green tea is EGCG [38]. However, other reports in the literature describe EGCG as beneficial for asthma and atopic dermatitis [39, 40].

One placebo subject withdrew due to an unrelated urinary tract infection. One placebo individual withdrew because traveling interfered. One placebo individual withdrew because he could not return. One placebo subject withdrew because he just stopped taking the capsules (Table 1). Five more subjects (two CSF and three placebo) were excluded from all data because they were less than 70% compliant. One more CSF subject was excluded when they reported in their logs that they were ill when the study began, which was an exclusion criterion. Two more CSF subjects and one more placebo subject entered incomplete log data, and were excluded from the analysis. Fifty-five subjects in the supplement group and 53 subjects in the placebo group completed the study with 70% or greater compliance, and their data were included in all clinical results and analyses. Three week blood samples were obtained from 52 CSF and 56 placebo subjects who were complaint over that time period, and were included in the immune function analysis.

View larger version (8K): [in this window] [in a new window]   Fig. 1. The percentage of 55 CSF subjects and 53 placebo subjects who had at least one symptom during the 12-week study period.

Taken together, these results show that CSF is effective in preventing cold and flu symptoms in this group of healthy volunteers. The data suggest that CSF may also decrease the duration of symptoms and the need for medical treatment.

Ingestion of Camellia sinensis Formulation Enhanced Proliferation and IFN- Secretion by T Cells
Our previous study showed that PBMC taken from subjects who started drinking daily five to six cups of tea, containing L-theanine, for as little as one week secreted significantly more IFN- in response to T cell antigens, as compared to before [10]. To determine if ingestion of CSF, containing L-theanine, could enhance IFN- production, we isolated PBMC taken from subjects three weeks after they started taking CSF or placebo, and cultured them for 24 hours with media alone, or with media containing ethylamine, which is a T cell antigen that is a byproduct of L-theanine catabolism. It is important to note that only T cells respond to ethylamine [9, 41], and that CSF ingestion had no effect on IFN- secretion or T cell proliferation in response to a non-specific T cell mitogen, phytohemagglutinin (data not shown). PBMC from CSF and placebo subjects secreted only 2.8 and 2.3 ng/mL IFN-, respectively. As expected, PBMC from placebo subjects secreted more IFN- in response to 5 mM ethylamine as compared to media alone (13.6 ng/mL). However PBMC from CSF subjects secreted 18.4 ng/mL IFN- in response to ethylamine. This response was 26% higher than that from placebo PMBC (P = 0.046; Table 4).

View this table: [in this window] [in a new window]   Table 4. Interferon- (ng/mL) Secreted into the Culture Medium after 24h

View this table: [in this window] [in a new window]   Table 5. % -T Cells in Baseline Blood Sample and after 10d of Culture

	DISCUSSION

The results show that the ingestion of two capsules daily decreased by about a third the number of subjects who experienced cold and flu symptoms. Also seen were decreases in the number of days subjects had symptoms, and the number of subjects needing medical treatment. The magnitude of reduction of these symptoms in a preventive manner has enormous implications for public health.

There was a significantly increased cluster of symptom days, and a suggestion of an increased cluster of illness in February as compared to March and April/May. This is consistent with a colder climate in northern Florida during February, and this decreased temperature might be expected to be associated with more cold and flu activity. There was an unexpected decrease in the efficacy of CSF during April/May. This decrease may be due to waning compliance with a twice daily regimen at the end of the trial, or waning efficacy of the CSF. While overall compliance was measured by pill counts, we did not measure compliance month by month, so this end of trial decrease in compliance remains speculative. Further studies will be necessary to examine the cause of this decreased CSF effect.

The CSF benefits seen were not related to sex, gender, race, or BMI. CSF was well-tolerated. There were no significant differences in adverse events, or withdrawls due to adverse events.

In addition to its effect on the incidence of cold and flu symptoms, CSF ingestion enhanced proliferation of, and IFN- secretion by, T cells challenged in vitro with ethylamine. These findings are consistent with our previous study showing that subjects who drank tea containing L-theanine, but not coffee, increased their T cell function by up to 15-fold [10]. It is important to point out that T cell numbers or serum IFN- levels were not increased in subjects taking CSF, but that their T cells were primed in vivo by CSF to respond more vigorously to antigenic challenge ex vivo. Constitutive increases in T cell numbers and serum IFN- titers in the absence of pathogen exposure may actually increase symptoms due to inflammation. Such increased symptoms occur after ingestion of high doses of nitrogen-containing bisphosphonates (which activate T cells) for treatment of osteoporosis [43].

The mechanism of action of symptom reduction has not been determined with certainty. However, T lymphocytes are an important first line of defense against microbes [25]. L-theanine is known to prime human T lymphocytes to secrete IFN-, a powerful antimicrobial cytokine [9, 10]. In the early stages of infection, EGCG may aid in the activation of T cells by enhancing secretion of IL-12, a very important factor in T cell activation [10, 44]. EGCG also kills viruses and bacteria directly [26–29], and can decrease virus titers in vivo during chronic viral infection [45]. If infection does establish itself by evading the first-line T cell response, EGCG may decrease cold and flu symptoms due its anti-inflammatory activity [35]. Studies in our laboratory are now underway to address these mechanistic questions.

This study has several limitations. Symptom data were collected by self-reporting, so an actual medical diagnosis of cold or flu was not possible. Other illnesses, such as pneumonia, bronchitis, or allergy might have caused similar symptoms. The study was comprised of only healthy adult subjects, so it was not possible to assess the effect of CSF on children, or subjects with chronic illnesses who have increased susceptibility to acute illness.

Cold and flu symptoms can be perennial sources of misery and lost productivity for most healthy adults, and the introduction of a safe, effective, and natural capsule that can prevent such symptoms represents a significant breakthrough in preventive medicine.

	CONCLUSION

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
This proprietary Camellia sinensis formulation (CSF) is an effective preventative for cold and flu symptoms, and for enhancing the innate immune response. Widespread use of this CSF could have enormous beneficial effects in decreasing morbidity in healthy populations.

	ACKNOWLEDGMENTS

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
The authors thank Alberto Azeredo, Jillian Lozada, and Laura Marano for their assistance throughout the study. This study was funded in part by Nutraceutical Holdings, LLC, Orlando, FL, and Taiyo, International, Minneapolis, MN.

	FOOTNOTES

TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 
Contribution by JFB was in his capacity as NSRI Director; he is also a consultant for Taiyo International.

Dr. Cheryl A. Rowe and Meri P. Nantz are equal contributors to the work.

Received August 31, 2006. Accepted February 2, 2007.

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TOP FOOTNOTES ABSTRACT INTRODUCTION MATERIALS AND METHODS RESULTS CONCLUSION ACKNOWLEDGMENTS REFERENCES

 

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