Vitamin E and Immunity, Part 2 of 2

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The role that tocotrienols play in inflammation, immunity, and lung health

In addition to the tocopherol members of the vitamin E family, of which α-tocopherol dominates research, α-, β-, γ- and δ-tocotrienols also exist. Numerous studies suggest that tocotrienols have superior antioxidant and anti-inflammatory properties. However, they account for less than 5% of vitamin E research thus far, as they were discovered in more recent years and are less common in nature.^[1]

Palm oil is rich in tocotrienols and also contains approximately 30% tocopherols, while annatto oil contains 100% tocotrienols with a 90:10 δ:γ ratio. Tocotrienols have been shown to deliver numerous benefits particularly for metabolic, cardiovascular, and central nervous system health.^[2] In regard to immune function and respiratory health, we also have multiple human and animal studies showing they may be of benefit.

Tocotrienols and immune function. In mice, daily supplementation with tocotrienol-rich palm oil significantly improved the response to vaccination, increasing levels of interferon (IFN)-γ (a cytokine of particular importance to our response against viral invaders) and lymphocyte proliferation.^[3] In a four-arm animal study comparing the effects of a tocotrienol-rich blend (TRB) of α-, γ-, and δ-tocotrienols (including α-tocopherol as well) to δ-tocotrienols, α-tocopherol, and placebo, only the groups receiving the TRB or δ-tocotrienols had a significant increase in antibodies to tetanoid toxin (TT) after vaccination.^[4] Although IFN-γ levels were higher in all mice receiving the different forms of vitamin E than the control, they were highest in those given δ-tocotrienols followed by the TRB. Production of tumor necrosis factor (TNF)-α (a cytokine that can trigger substantial inflammation) was suppressed in all vitamin E groups compared to control.

In young, healthy humans, daily supplementation with 400 mg of a blend of tocotrienols with α-tocopherol for one month prior to and after vaccination with tetanoid toxin significantly enhanced the vaccine response.

In young, healthy humans, daily supplementation with 400 mg of a TRB also containing α-tocopherol for one month prior to and after vaccination with TT also significantly enhanced TT-stimulated leukocyte IFN-γ production as well as anti-TT IgG production one month after vaccination compared to the placebo group.^[5]

Studies have also shown that supplementation with a palm-sourced tocotrienol and tocopherol blend significantly increases lymphocyte proliferation in older mice compared to those receiving α-tocopherol only.^[6] A parallel in vitro study showed that α-tocotrienol had the greatest effect of stimulating lymphocyte proliferation. No changes in lymphocyte proliferation were seen in younger mice in this study, suggesting that supplemental vitamin E is of greater importance in an aging population, as discussed in Part 1.

Tocotrienols and inflammation. One unique aspect of protection that tocotrienols have demonstrated, but α-tocopherol has not, is reduction of NLRP3 inflammasome activation. Inflammasomes are protein complexes found in the cytosol of cells of the innate immune system and epithelial barrier tissues, such as the airway, intestines, and skin.^[7],[8] The NLRP3 inflammasome plays a role in numerous conditions, including the many facets of metabolic syndrome, neurodegenerative disease, respiratory disease, stroke and cardiovascular disease, and certain infectious diseases.^{[9],[10],[11],[12]} Air pollution and allergies are both factors that can push the NLRP3 inflammasomes of the airway epithelium to a “tipping point” upon which subsequent insults, such as an infection, can have a cascade effect of excessive cytokine production.^{[13],[14],[15],[16]} In animals, systemic inflammatory response syndrome has been shown in multiple conditions to be related to activation of the NLRP3 inflammasome.^[17],[18]

Multiple studies have shown that γ- and δ-tocotrienols, or a γ-/δ-tocotrienol blend, helps protects against NLRP3 inflammasome-related inflammation and development of disease.

Multiple studies have shown that γ- and δ-tocotrienols, or a γ-/δ-tocotrienol blend, significantly suppress NLRP3 inflammasome activation, and helps protects against NLRP3 inflammasome-related inflammation and development of disease.^{[19],[20],[21],[22],[23]} In critically ill patients, thrice daily administration of a combination of 400 IU of a tocotrienol blend with 500 mg of vitamin C (taken by nasogastric or oral administration) was shown clinically to improve numerous parameters associated with systemic inflammatory response syndrome, with better outcomes seen with the tocotrienol blend than in the group receiving α-tocopherol with vitamin C.^[24]

Tocotrienols and asthma. Due to their high antioxidant and anti-inflammatory potential, studies have also investigated tocotrienols as therapies for asthma and smoking-related respiratory disease, both conditions in which oxidative stress and inflammation contribute to the pathology. In animals, treatment with tocotrienols was shown to reduce allergen-triggered inflammatory cell infiltration and multiple markers of inflammation.^[25] While the lung histology of non-treated animals showed severe edema and inflammatory cell infiltration, the lungs of the tocotrienol-treated mice were healthy and normal appearing.

Multiple cellular studies have also shown that γ-tocotrienol inhibits smooth muscle cell proliferation, migration, and phenotype changes that contribute to airway remodeling in asthma.

In a study comparing vitamin E isoforms, similar findings related to inflammation and lung histology were shown, with γ-tocotrienol performing better than α-tocopherol and the other tocotrienol isoforms.^[26] Multiple cellular studies have also shown that γ-tocotrienol inhibits human airway smooth muscle cell proliferation, migration, and phenotype changes that contribute to airway remodeling in asthma.^[27],[28]

Tocotrienols and smoking. In mice, γ-tocotrienol has also been shown to significantly attenuate the inflammation, oxidative stress, neutrophil infiltration, and lung histology changes caused by cigarette smoke.^[29] A dose-dependent effect was seen with regard to the recovery of antioxidant and antioxidant enzyme capacity. After two months of exposure to cigarette smoke, with γ-tocotrienols provided in the final three weeks only, the mice receiving tocotrienols at the highest dose were observed to have very little changes in the bronchial epithelium thickness and alveolar diameter – even better than those receiving prednisone. All aspects of lung function were significantly improved with the highest dose of tocotrienols, and again, many parameters improved to a greater extent with tocotrienols than they did with prednisone.

It is currently under investigation if tocotrienols may ameliorate lung fibrosis of an inflammatory etiology as several pathways implicated in these tissue changes are similar to hepatic fibrosis,^[30] which multiple studies have shown tocotrienols improve.^[31],[32]

Clearly, there are many reasons to consider both α-tocopherol and a blend of tocotrienols as a part of a protocol to support normal, healthy immune function and the management of related inflammation and oxidative stress. As α-tocopherol is well established to ameliorate vitamin E deficiency, it would be prudent to consider its inclusion in a supplement routine to prevent the immune-related changes caused by deficiency, while the tocotrienols offer additional antioxidant and inflammation protection.

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