One of the first indications that glutathione influences aspects of immune function, which are related to T lymphocytes, came from a study in which the GSH content of these cells was measured in a group of healthy volunteers (65). The numbers of helper (CD4+) and cytotoxic (CD8+) T cells increased in parallel with intracellular GSH concentrations up to 30 nmol/mg of protein. However, the relationship between cellular glutathione concentrations and cell numbers was complex, with numbers of both subsets declining at intracellular glutathione concentrations between 30 and 50 nmol/mg of protein. The study also revealed that cell numbers were responsive to long-term changes in GSH content. When the subjects engaged in a program of intensive physical exercise daily for 4 weeks, a fall in glutathione concentrations occurred. Individuals with gluta-thione concentrations in the optimal range before exercise, who experienced a fall in concentration after exercise, showed a 30% fall in CD4+ T cell numbers. The decline in T cell number was prevented by administration of N-acetyl cysteine (NAC is metabolized to cysteine, see later section). This study suggests that immune cell function may be sensitive to a range of intracellular sulfhydryl compounds including glutathione and cysteine. In HIV+ individuals and patients with AIDS, a reduction in cellular and plasma glutathione has been noted (15). At present, it is unclear whether the depletion in lymphocyte population that occurs in these subjects is related to this phenomenon. However, in a large randomized, double-blind, placebo-controlled trial, administration of 600 mg/day of NAC for 7 months, resulted in both anti-inflammatory and immunoenhancing effects (6). A decrease in plasma IL-6 concentration occurred, together with an increase in lymphocyte count and in the stimulation index of T lymphocytes in response to tetanus toxin. The precise mechanism underlying the complex effects of changes in cellular glutathione content are not clear, and whether they are related to GSH function as an anti-oxidant or to some other property, such as the effect of GSH on thioredoxin, is not apparent. However, a recent study suggests that glutathione promotes IL-12 production by antigen-presenting cells so driving T helper cells along the Th1 pathway of differentiation (66). Paradoxically, when GSH is processed by glutathione-S-transferases (GST), in pathogens, suppressive effect on immune function are achieved. The enzyme in Faciola hepatica in rat is responsible for inhibition of T cell function and downregulation of nitric oxide production thereby allowing the parasite to evade the animals immune defenses. Likewise, the human parasites Onchocerca volvulus and Trapanozoma cruzi may also, via GST, interfere with immune function in the host. On the basis of these observations, a hypothesis has been proposed that some pathogens via release of GST interfere with the functions of cells of the immune system through their ability to scavenge GSH (67).
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