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Because of the known functions and increased disease risk with a decline of GSH, systematic efforts are needed to quantify the difference between the available GSH and the amount needed. One approach is to consider how much GSH is present in a natural diet. GSH content has been measured in more than 100 common foods37 and provides the basis to estimate dietary intake. The best diets contain about 150 milligrams of GSH per day; the worst diets contain as little as 3 milligrams per day. GSH is present in essentially all raw and freshly prepared foods; the best sources are fresh fruits and vegetables, nuts, and whole-cut meats, including poultry and fish. GSH can also be increased by supplements, such as the increase in hepatic GSH following ingestion of silymarin, found in milk thistle. GSH is lost during most food processing procedures, with the exception of fresh-frozen foods. Processed, cured, and canned meat products have essentially no GSH. Similarly, canned or dried fruits and canned vegetables are not good sources. Cereal and grain products are largely deficient, and almost all dairy products, beverages, sweeteners, and condiments lack GSH. Thus, a simple conclusion is that modern processed foods are deficient in GSH compared to natural, freshly prepared foods. In quantitative terms, up to 150 mg of daily intake of GSH can be lost due to food processing.

Many foods also contain reactive chemicals that remove GSH through the GSH transferase reaction associated with the lining of the small intestines. Measurement of a broad range of foods show that milk, prunes, tea, blueberries, and bottled apple juice have high contents of GSH-reactive chemicals.38 Recently, there has been interest in the potent neurotoxicant acrylamide, because this has been found to be relatively high in french fries. The daily intake of GSH-reactive equivalents can range from almost zero to values exceeding the maximum naturally available 150 milligrams GSH.38 Thus, the sum of the amount of GSH needed to eliminate reactive chemicals and the amount of GSH lost by food processing can be greater than 300 mg of GSH per day.
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Measurement of a broad range of foods show that milk, prunes, tea, blueberries, and bottled apple juice have high contents of GSH-reactive chemicals.

The extent to which environmental exposures, alcohol consumption, smoking, inflammation, infection, etc., further increases this dietary GSH gap is not known. Similarly, the magnitude of the GSH gap due to disease is not known. This could be greater than 300 mg—perhaps as high as the GSH equivalent of the RDA for sulfur amino acids (ie, 3 g/day). The RDA for sulfur amino acids is about 1.1 g/day for women and 1.4 g/day for men; these values are equivalent to 2.7 and 3.3 g/day of GSH. Because the body contains 15 g of GSH, values in this range represent up to 20% of the amount of GSH in the body. There are conditions, such as severe burns, in which the sulfur amino acid requirement is increased. Consequently, there may be conditions in which the functional need for GSH is relatively high, but this upper limit is currently unknown.

GSH is depleted by elimination of reactive chemicals dependent upon abundant GSH transferases. These enzymes increase in response to toxic challenge, and trials have been conducted to determine whether continuous elevation of these enzymes can protect against cancer. In protection against cancer, GSH reacts with cancer-causing chemicals at rates that are faster than the chemical can react with DNA, thereby preventing mutations. To date, however, practical approaches to reduce cancer by increasing GSH transferase have not been established. In addition to cellular activities, GSH transferase is associated with mucus and provides a detoxifying barrier in the small intestines. Animal studies showed that provision of GSH to the GSH transferase associated with the mucus provides a defense mechanism to eliminate ingested toxic chemicals, such as oxidation products from polyunsaturated fatty acids, acrylein, acrylamide, and other reactive chemicals, prior to absorption by the body. This defense depends upon GSH supply outside of the cells, either from the bile, from food, or from a supplement. The finding that oral and pharyngeal cancer is decreased in association with intake of foods high in GSH25 could reflect the function of this mechanism in protection against cancer-causing chemicals or a better function of the immune system. Studies with human cells in culture further show that added GSH protects cells even in the absence of GSH uptake, apparently due to protection of proteins on the surface of cells. Recent studies show that cell surface thiols function as redox sensors, signaling processes such as platelet activation and early events of atherosclerosis. As indicated above, in vitro experiments have demonstrated that addition of GSH to the media improved killing of bacteria by pulmonary macrophages and decreased production of infectious influenza virus by human small airway epithelial cells.
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How Big is the Functional Need for GSH?

In addition to the age-related decline mentioned above, GSH levels are inversely associated with environmental exposures and disease risk. GSH is decreased in the epithelial lining fluid of human lung in individuals who abuse alcohol. This example is illustrative of the hidden risks of low GSH in that these individuals have no apparent lung disease and yet are at considerably increased risk of acute lung injury and death from adult respiratory death syndrome. Oxidation of GSH occurs in association with increased carotid intima media thickness, an indicator of cardiovascular disease risk. GSH redox balance (ie, the GSH/ GSSG ratio) favors oxidation in cigarette smokers and type 2 diabetics. Direct evidence that the decrease and oxidation of GSH occurs due to toxic chemical exposures is available from studies in individuals following chemotherapy. The extensive evidence that GSH status is decreased in association with disease and recognized risk factors for disease implies that maintenance of this protective system could reduce risk of disease development.

Homeostatic mechanisms prevent the hepatic GSH content from falling too low. During fasting and starvation, GSH and its precursors are derived from muscle and other tissues. Simple calculations show that the entire human body has no more than a 4-day reserve of GSH so that loss of GSH can become critical in catabolic illness or whenever there is a prolonged period of protein/energy insufficiency. Importantly, GSH declines with age and has a diurnal variation with lowest values in the morning and early afternoon. The diurnal variation is linked to cysteine, and cysteine variation increases in individuals over 60 years. Thus, older individuals have increased vulnerability in cell injury due to both a decline in total amount of GSH and a decline in its homeostatic control.

Most research has focused on tissue levels of GSH, but the difference between GSH needs and availability may be equally important in the extracellular fluids, which bathe cells. GSH is found in all extracellular biological fluids, including plasma, interstitial fluid, cerebrospinal fluid, alveolar lining fluid, saliva, bile, pancreatic fluid, tears, sweat. and urine. The concentration of GSH in body fluids can be up to 1,000-fold lower than found in the tissues, yet all cells appear to release GSH, suggesting a universal requirement for extracellular GSH to protect cell surfaces. In addition, specific functions of extracellular GSH are well described. Bile has a high content of GSH to support detoxification of reactive chemicals in the lumen of the small intestines and to enhance iron absorption. Lipid peroxides are toxic species in the diet that are eliminated by supplemental GSH. GSH in the lining fluid of the lungs eliminates airborne oxidants and helps maintain fluidity of the mucus lining the airways. Elimination of bacteria by pulmonary macrophages in vitro is stimulated by added GSH, but this experiment has not been done in humans in vivo. GSH also protects human lung cells (in vitro) from influenza virus and protects against influenza in mice. One should note that controlled, double-blind studies of these effects have not been done in vivo in humans.

How is GSH Maintained in Tissues and Body Fluids?

GSH is maintained by a continuous cycle of turnover at a rate equivalent to the entire body pool of GSH being made and degraded daily. GSH is synthesized from the precursor amino acids (ie, glutamine, glycine, cysteine) in all tissues. Cells in certain organs (ie, intestines, lung, kidney) can utilize exogenous GSH by a secondary active transport mechanism. Supply of GSH from tissue to extracellular fluids occurs through two types of transporters, classified as MRP and OAT transport proteins. The molecular nature of the systems that allow transport in the opposite direction (from extracellular spaces into cells) is not known. The cycle of GSH release, conversion to precursor amino acids, and resynthesis is termed the “GSH cycle.” Although it was earlier proposed that a “γ-glutamyl cycle” functioned in amino acid uptake, this was found to not be an important mechanism. Disulfide forms of GSH include low molecular weight chemicals and protein-bound forms; under many circumstances, the balance between GSH and these disulfide forms (ie, GSH redox balance) can be more important than the absolute amount of GSH.

GSH is a simple molecule, composed of 3 common amino acids: glutamate, cysteine, and glycine, which are also found in protein throughout the body. The amino acids are connected in a unique way so that GSH can be made and broken down independently of the body’s protein. The structure controls the reactivity of a sulfur atom in the cysteine, which is critical for function. GSH reacts with toxic oxygen radicals to form GSH radicals and glutathione disulfide (GSSG), thereby protecting against oxidative damage to DNA and proteins. Living organisms depend on controlled reactions in which chemicals share and transfer electrons to maintain physical and chemical organization. Reactive chemicals with a high affinity for electrons destroy the organization and function because they interfere with the normal processes of sharing and donating electrons. The body is constantly exposed to damaging reactive chemicals, and GSH provides a general biological solution because the electron properties of the sulfur of GSH are ideally suited to protect against such chemicals.

In protection against an imbalance in electron transfer reactions, termed “oxidative stress,” GSH donates electrons to chemicals known as “oxidants.” Oxidants avidly accept electrons, and this disrupts normal electron flow. The electron-donating property of GSH protects against this; in the process, two molecules of GSH are converted to GSSG, an oxidized (disulfide) form. The balance of GSH and GSSG is quantified as the “GSH redox balance,” a measure of the status of the GSH system to protect against such oxidative challenges. In this expression, more reduced (more negative) “redox” values are generally healthy, while more oxidized (more positive) “redox” values are unhealthy. Values measured in blood are a reflection of tissue values because cells have transport systems for both GSH and GSSG. However, oxidation also occurs outside of cells, so under a normal, healthy state, the extracellular balance is oxidized relative to that in cells. Many diseased states have excessively oxidized extracellular GSH redox values.
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Where is GSH found in the body?
GSH is found in all tissues and body fluids. A healthy balance requires an unequal distribution of GSH and GSSG among these locations,6 similar to the need for sodium and potassium to differ between plasma and cells. In general, the concentrations of GSH within cells are much higher than outside of cells. Nonetheless, the amounts of GSH in the fluids surrounding cells are important because they provide a chemical-defense barrier to protect the cell surfaces.

The total amount of GSH in the body is about 15 grams, of which the cysteine component represents 5 grams. The organs principally responsible for detoxification (ie, the liver and kidneys), have the highest amounts, but the 15 grams are distributed among all major organ systems, including brain, heart, skeletal muscle, intestines, lungs, skin, and the immune system. The liver (6% of the body) has about 4 grams of GSH (25% of the body’s total), which is part of an important homeostatic mechanism. Liver GSH varies as a function of diet, time of day, and body needs. The cysteine content of liver GSH is similar to the RDA for sulfur amino acids (methionine plus cysteine), which is 1.4 g for a reference 70 kg individual. Thus, the GSH in the liver is equivalent to a 1-day reserve for the cysteine needed for the body’s protein synthesis.

Abstract
Glutathione (GSH) is a naturally occurring chemical used by the human body to protect against chemical and environmental threats. As a consequence of aging, lifestyle, diet, and disease, a gap can develop between the needs and availability of GSH. GSH decreases in association with risk factors for disease and undergoes a diurnal variation with lowest values beginning in the morning and extending through midday. Decreased GSH has been associated with specific diseases, including cardiovascular disease and diabetes, and has been implicated in many others. Abundant biochemical data support a direct causal link between low GSH, impaired defenses, and cellular susceptibility in model systems. Emerging personalized health strategies utilize GSH as a quantitative indicator of health with the expectation that diet selection, GSH supplementation, and lifestyle approaches can be used to manage GSH status, thereby providing a health dividend by protecting against disease development.

Introduction
More than 100 years of research and 81,000 scientific papers have established glutathione (GSH) as one of the most important protective molecules in the human body. The present article provides a brief overview of GSH and its functions in health and disease. Low GSH has been implicated in neuronal, hepatic, renal, pulmonary, cardiac, musculoskeletal, pancreatic, gastrointestinal, visual, auditory, and infectious diseases. Accumulating data have established that poor diet and age-related disease can create a functional disparity between the body’s natural GSH defenses and the levels needed for optimal health. The purpose of this article is to provide practical considerations for health professionals concerning the evolving use of GSH as a strategy for maintenance of health.

What is Glutathione?
GSH is a component of defenses for both acute and chronic health challenges. Acute deficiency can be caused by exposure to toxic chemicals and endogenous oxidative reactions. Under acute GSH deficiency, cells cannot maintain normal cell functions, lose ability to divide normally, and can undergo either necrotic or apoptotic cell death. Under chronic conditions, variations in GSH levels occur due to nutrition, environmental exposures, and activation of the immune system. These variations affect risk of chronic and age-related diseases by limiting protective functions. The protective functions include elimination of cancer-causing chemicals, enhancement of antioxidant defenses, and maintenance of homeostatic conditions of the epithelial barriers. GSH protects against hundreds of cancer-causing chemicals. GSH is at the apex of a group of protective chemicals, including vitamins C and E, which guard against oxidative damage to tissues. Interorgan transport of GSH is part of a homeostatic control system3 that maintains a “redox” environment essential for life. The term “redox” refers to chemical reactions involving electron transfer. Adenosine triphosphate (ATP) is obtained from redox reactions in the mitochondria. In this process, most electron transfer occurs with reduction of O2 to water, but a small fraction is reduced to hydrogen peroxide and toxic oxygen radical species. GSH is critical for elimination of these oxidants.

Michael Traub of Ho’o Lokahi clinic in Kailua Kona, HI, also praises the NERC model, saying the residency program improves the services his clinic can offer the community:

Having a resident helps …increase patient care services through the resident’s private practice hours and clinical skill set; provide coverage for my patients when I am out of town; provide assistance for clinical research projects conducted at the clinic; give educational lectures to the public; and volunteer at a variety of health fairs and events, including senior health fairs, free skin cancer screenings, and the Ironman Triathlon World Championship.

Without NERC’s role as facilitator, doctors and students must organize residencies or mentorship opportunities on their own, and the clinic or practitioner must come up with funding for the resident’s salary. And if the residency is to be official, the clinic must have staff on hand to interact with one of the CNME-approved residency programs. All this strains the limits of what small practices can often accomplish. By joining the consortium, partner clinics benefit from NERC’s network of funders and practitioners, relationships with sponsors, and administrative contacts with residency oversight bodies.

At its core, NERC provides member clinics with direct funding for residencies. This support is possible thanks to NERC’s relationships with companies whose natural products NERC clinics dispense. “Sponsors fund our community-based residencies. Without them, we would not have NERC,” says Beeson. To this end, NERC seeks out corporate partners that share NERC’s commitment to advance the practice and promise of naturopathic medicine. Sponsors are companies with whom member clinics already have relationships, not unknown companies that approach NERC looking for a distribution outlet.

Beeson points out that many supplement companies “are founded and run by NDs who value the concept of residencies and furthering the profession.” Such professionals bring proven commitment to the “profession and to the principles of naturopathic medicine.” By approaching companies whose products are already in use in NERC clinics, or whose products or services are of interest to the NERC clinic network, the consortium creates a powerful microeconomy in which effective products can be discounted and clinical capabilities can be improved and enhanced by bringing residents into the clinic and community.

Looking ahead, NERC’s ambition is to help make residencies possible for all naturopathic graduates.
Looking ahead, NERC’s ambition is to help make residencies possible for all naturopathic graduates. Asked about the future, Hudson offers NERC’s vision statement: A healthcare system where naturopathic physicians are optimally educated and prepared for clinical practice; patients are able to become healthier by working with highly skilled clinicians; naturopathic physicians are able to contribute the full scope of their training to all communities, age groups, and socioeconomic classes; and naturopathic physicians have many more job opportunities.

Beeson looks to her and Hudson’s own experiences to postulate about NERC’s potential. “I studied with Dr. Bastyr, and Dr. Hudson studied with Dr. Turska. Through the NERC residency program, we have the opportunity to pass the core principles of the naturopathic art on to the next generation of physicians, and that’s very exciting.”

The Naturopathic Education and Research Consortium (NERC) is a small nonprofit organization making a big impact on the future of naturopathic medicine. Dedicated to increasing postgraduate residency and training opportunities for naturopathic doctors, NERC work has been with clinics across the country to provide official residencies for naturopathic physicians since 2005. Founded by Tori Hudson, ND, and Margaret Beeson, ND, NERC partners with clinics from Maine to Hawaii to create one- and two-year residency opportunities for new naturopathic doctors (NDs).

While students of naturopathic medicine are required to complete as many as 1,500 hours of clinical training in medical school,1 few formal opportunities exist after graduation to help new NDs continue to learn and grow professionally. In the mid-1990s, both Hudson and Beeson enjoyed the benefits of hosting residents in their clinics and saw a clear need for official and approved residency opportunities.
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Before the founding of NERC, two schools—the National College of Natural Medicine (NCNM) and Bastyr University—provided no more than eight positions for resident NDs, and those positions existed in only two or three locations. NERC’s collaboration with practitioners, clinics, schools, sponsors, and residents has created nine off-campus sites nationwide in which residents continue to train under professional supervision in conjunction with residency programs approved by the Council on Naturopathic Medical Education (CNME).2 In 2011, NERC will facilitate 12 off-campus residencies.

“Residencies are crucial to the advancement of our profession in terms of insurance reimbursement and loan repayment,at the very least. More importantly, graduates need paid opportunities to hone their skills in a supervised setting with seasoned naturopaths who can support and educate beyond medical school,” Beeson explains. “These types of relationships are the foundation for passing on the wisdom of medicine as both art and science.”

Besides the clinical competencies they bestow, residencies also foster community connections for clinics, doctors, and patients. Because CNME-approved residencies emphasize integrative medicine, NERC clinics bring together practitioners and clients seeking conventional and complementary health solutions. For evidence of the roles residents play in their practices and communities—and community appreciation for those roles—consider a recent resident experience at Seattle’s Institute of Complementary Medicine (ICM). Eileen Stretch, ND, of ICM reflects on a very positive integrative residency experience:

With support from NERC, we were able to employ JanciKarp, ND, LAc, as a resident for two years. During that time, Karp provided both naturopathic and acupuncture services to our patients, educated the community with a variety of talks and workshops, and built a successful practice of her own within our office. While a resident she rotated through a variety of medical practices, which benefited her education and also benefited the practitioners with whom she worked by being exposed to naturopathic medicine.

It was postulated that supplementation with these specific Lactobacillus strains could benefit patients with allergic diseases by reducing Th2 cytokine production. Other studies have shown that L. rhamnosus GG can reduce allergic disease symptoms in humans. Ingestion of therapeutic levels of L. rhamnosus GG by breast-feeding mothers and newborn babies resulted in a 50% inhibition of the risk of developing atopic eczema in babies. These studies provide an example of how administration of strainspecific probiotics can modulate the immune response and down-regulate the Th2 dominance associated with the development of allergies.
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Regulatory T cells
There are other subsets of T cells, termed type 1 T regulatory cells (Treg) or Type 3 T regulatory cells (Th3) that help regulate T-helper cell functions and maintain intestinal homeostasis. For example, Treg cells predominantly secret IL-10, a cytokine that down-regulates Th1 activity and, therefore, reduces Th1-associated inflammation. Adequately primed Th3 cells primarily secrete TGF-β, which helps modulate both Th1 and Th2 activity7 (see figure 1). There is increased understanding that Treg and Th3 cells are influential in the maintenance of mucosal immunity and, therefore, the prevention of pathology. Furthermore, certain probiotic strains can moderate these regulatory responses. For example, L. paracasei (NCC2461) stimulates in vitro regulatory T cells to produce TGF-beta and IL-10, cytokines implicated in the oral tolerance response to bovine betalactoglobulin in mice.14,15 Artificial induction of the oral tolerance response, via the administration of strain-specific probiotics, would help modulate hypersensitivity reactions.

Conclusions and future directions
There are convincing initial studies with animal models and humans to demonstrate that probiotics can reduce Th1 or Th2 skewed disorders, like gastrointestinal inflammation and allergic diseases. These initial studies are encouraging but future studies must be conducted to more clearly determine the impact that specific probiotic strains have on T cells and immunopathology. Further studies also are needed to determine the therapeutic dose and timing of probiotic administration needed to produce these immune responses in humans. This increased knowledge of the effect of specific strains of probiotics on immune-system modulation has widespread medical implications. For example, when a patient has a Th1-cell dominant disorder, such as Crohn’s disease, then administration of specific probiotic strains can be given to promote secretion of IL-10 and TGF-β cytokines and, therefore, down-regulate chronic Th1 cell-associated inflammation and promote a return to balanced immunity.

An increased understanding of the unique effects of strain-specific probiotics on the immune system will help healthcare professionals be more specific with their therapeutic intent and select certain probiotic supplements based on the diagnosed condition and the desired direction needed to positively influence the immune system. Nutraceutical companies also can formulate safe, effective probiotic supplements with unique effects on the immune system that can be more effectively used to reduce pathogenesis and maintain intestinal homeostasis. Currently, there are some multistrain probiotics that are known to affect Th1- or Th2-cell associated immunity. For example, NFH ProBio SAP-90 contains a blend of probiotic strains that will cause a more balanced Th1:Th2 response, whereas HMF forte more specifically activates the Th1 pathway and thus down-regulates overactive Th2 disorders. Conversely, the probiotic mixture VSL#3 promotes secretion of cytokines that drive a Th2 response and, therefore, will prevent and treat diseases associated with Th1 cell rigidity. With future clinical trials, there will be an increased understanding of how probiotic strains can regulate the production of T cell cytokines to produce a balanced T helper cell response (Th1=Th2=Th3/Tr1) and prevent imbalance (Th1>Th2 or Th2>Th1). Ideally, a more selective choice of probiotics by healthcare professionals can be used to prevent and treat certain immunopathologies and, therefore, maintain optimal health.

Certain probiotic strains can help down-regulate these Th1 dominant disorders and return balance to the immune response. For example, TNF-α plays a key role in the pathogenesis of intestinal inflammation in Crohn’s disease, a disease associated with Th1 polarization. Borruel et al. (2002) studied the effect of probiotic bacteria on TNF-α production by obtaining ileal specimens from ten patients with Crohn’s disease. They observed a significant reduction in the production of TNF-α by inflamed Crohn’s disease mucosa when cultured with L. casei or L. bulgaricus, but not with L. crispatus or E. coli. The authors concluded that these probiotic strains had the ability to attenuate the release of the pro-inflammatory cytokines that promote Th1 rigidity by interacting with the intestinal mucosal immunocompetent cells. Furthermore, in mouse studies it was found that a probiotic mixture of nine different bacterial strains ameliorated recurrent Th1-mediated murine colitis by inducing IL-10 secretion and promoting development of IL-10 dependent TGF-β bearing regulatory cells. Daily administration of 2 mg (approximately 3 billion bacteria) of this probiotic mixture for three weeks to mice during a remission period induced an immunoregulatory response involving TGF-β secreting cells and, therefore, resulted in a milder form of recurrent colitis. These two studies support the therapeutic use of certain strains of probiotics in different animal species to prevent and moderate diseases associated with chronic Th1 cell dominance.
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Th 2 Subse t
The Th2 cell pathway supports humoral immunity by activating specific B cells and promoting antibody class switching. Th2 cells release the cytokines IL-4, IL-13, IL-5 and IL-10 that activate antibody formation or release from immune cells like B cells, mast cells or eosinophils7 (see figure 1). Persistent, uncontrolled Th2 activation is associated with diseases like atopy (including allergies, eczema, asthma, and allergic rhinitis), chronic fatigue and immunodeficiency syndrome, eosinophilic rhinosinusitis, ulcerative colitis and possibly certain cancers. Many studies in the past decade have shown that specific probiotic strains can benefit allergic diseases characterized by this chronic expression of Th2 cell-related cytokines. For example, Pochard et al. (2002) in an in vitro study demonstrated that different Lactobacillus strains reduce IL-4 levels (a Th2 cytokine) and enhance production of Th2 cell-related cytokines, supporting a more balanced Th1/ Th2 response. More specifically, a three-hour incubation of L. plantarum, L. lactis, L. casei and L. rhamnosus GG (at a oncentration of ten bacteria per purified CD4+T cell) inhibited the production of IL-4 and IL-5 in a dose-dependent manner from human polymorphonuclear cells and stimulated the production of the pro Th1 cell cytokines, IFN-γ and IL- 12. In the same experiment, no significant inhibition of IL-4 and IL-5 secretion occurred when the cells were incubated with Escherichia coli TG1, demonstrating that the inhibition of cytokine secretion was specific to certain bacterial strains.

If APCs are challenged with blood-borne pathogens, cytokines like IL-4 are released to promote Th2 cell differentiation. Additional cytokines like IL-13 also are secreted under certain conditions, and further promote Th2 polarization and development in an IL-4 independent manner. Maturing Th2 cells continue to release IL-4, generating an autocrine feedback loop that further increases the differentiation of naive T cells to Th2 cells.7 Th2 cell dominant cytokines are continuously secreted until the blood-borne pathogens are removed or sufficiently reduced. When naive T cells become Th1 or Th2 polarized they are committed to that specific pathway and cannot be reversed. Cytokines secreted by Th2 cells activate specific B cells for antigen clearance as well as for antibody class switching. Cytokines secreted by the Th1 cells primarily promote inflammation and the activation of cytotoxic T cells. These Th1 and Th2 specific cytokines interact with each other to antagonize their respective maturation and actions. For example, Th1 cells secrete IFN-γ which inhibits proliferation of Th2 cells, whereas Th2 cells secrete the cytokine IL-4 that prevents Th1 cell differentiation.7 Further regulation of Th1 and Th2 cells occurs with additional subsets of T cells, termed regulatory T cells (Treg) or Th3 cells.7 Specific regulation of T cells by Th1, Th2 or Treg/Th3 cells will be discussed in the next sections.

Th 1 Subse t
The Th1 cell pathway supports cell-mediated immunity, preventing disease from intracellular pathogens like viruses, certain bacteria, yeast, fungi and protozoans. Th1 cellassociated immunity also has a major role in preventing tumor cell development. However, if naive T cells are chronically Th1 polarized, an overactive cell-mediated immune response can result. For example, persistently high secretion of IL-12 will cause Th1 cells to produce large amounts of pro-inflammatory cytokines like IFN-γ and TNF-α. These cytokines further activate macrophages to produce additional pro-inflammatory mediators (i.e. IL- 12 and IL-18) in a positive feedback loop that has potential pathological consequences.

Persistent Th1-mediated inflammation of the gastrointestinal tract is associated with pathologies like Crohn’s disease, H. pylori gastritis, cellular autoimmunity, chronic recurrent inflammation and possibly rheumatoid arthritis, multiple sclerosis and systemic lupus erythematosus. This Th1 rigidity and the potential pathological consequences can be moderated by upregulating the production of Th2 dominant cytokines, like IL- 4, IL-10 and IL-13. These cytokines inhibit the development of Th1 cells and macrophage activation and, therefore, can prevent inflammatory tissue damage resulting from an overabundance of Th1 cell stimulation.8 Furthermore, the immunosuppressive cytokines IL-10 and TGF-β, released by regulatory T cells, also down-regulate Th1 rigidity and help control colitis and other inflammatory diseases.

The intestinal mucosa has an extensive surface area (>300m2) that provides a physical and immunological barrier to infection. The physical barrier includes the mucous layer, the epithelial cells and the tight junctions between these cells. It acts as a structural separation between the lumen of the gastrointestinal tract (essentially part of the external environment) and the internal environment. The immunological barrier is part of the mucosal-associated lymphoid tissue (MALT) and is termed gut-associated lymphoid tissue (GALT). GALT contains one of the largest pools of immunocompetent cells in the body, with over 60- 80% of total immunoglobulins circulating at some point in their life through this tissue. GALT also has more than 10 lymphocytes/g tissue, making it a more concentrated source of lymphocytes than all of the other immune organs combined. The GALT can be separated into organized lymphoid tissue and diffuse lymphoid tissue. Organized lymphoid tissue includes mesenteric lymph nodes and Peyer’s patches, containing microfold (M) cells, dendritic cells (DC) and B cells. Dendritic cells are antigen-presenting cells (APC) that sample antigen, process it, modify it and present it to other immune cells, like naive T cells, to initiate specific immune functions. Diffuse lymphoid tissue is found primarily in the connective tissue of the lamina propria of the gastrointestinal tract layers. It contains lymphocytes like CD4+ T cells in the lamina propria, CD8+ T cells between the epithelial cells (intraepithelial lymphocytes (IEL)), B lymphocytes (memory and plasma cells that produce type A immunoglobins (IgA)), and natural killer (NK) cells. The intestinal mucosal barrier is a highly selective, intelligent system that protects us from pathogens.6 It must selectively exclude potentially toxic and infectious material from entering systemic circulation. It also must tolerate commensal bacteria and beneficial nutrients.

Hypo-responsiveness towards ingested substances is the predominate response of the GALT. This response is termed oral tolerance and can be both T- and B- cell mediated. Normally, oral tolerance prevents an immunogenic response, but if suboptimal oral tolerance is present, hypersensitivity responses to oral antigens can occur. For example, if a person does not tolerate milk proteins, a hypersensitivity reaction to dairy products can occur. This hypersensitivity response often begins with either Th1 or Th2 cell polarization.

Th 1/Th 2 Polari zation
The initial step in the polarization of naive T cells is the interaction of APCs, mostly DCs, with a non-self or “danger signaling” antigen. The physical nature of the antigen and the cytokines subsequently released by the APC encountering this antigen determines whether a Th1 or Th2 skewed immune response occurs. For example, when APCs are challenged with intracellular pathogens, like viruses, a common cytokine secreted is IL-12. This cytokine promotes the differentiation of naive T cells into Th1 cells. Maturing Th1 cells then produce the cytokine IFN-γ, which feeds back in an autocrine loop to trigger the development of more APCs as well as further promote the maturation of naive T cells into Th1 cells. Additional cytokines, like IL-18, also can be secreted to further influence Th1 development by enhancing IL-12 dependent Th1 cell differentiation and effector function.3 This self-perpetuating cycle of Th1 dominant cytokines persists until the immune challenge is sufficiently reduced.