Glutathione and glutathione derivatives in immunotherapy

Abstract

Reduced glutathione (GSH) is the most prevalent non-protein thiol in animal cells. Its de novo and salvage synthesis serves to maintain a reduced cellular environment, which is important for several cellular functions. Altered intracellular GSH levels are observed in a wide range of pathologies, including several viral infections, as well as in aging, all of which are also characterized by an unbalanced Th1/Th2 immune response. A central role in influencing the immune response has been ascribed to GSH. Specifically, GSH depletion in antigen-presenting cells (APCs) correlates with altered antigen processing and reduced secretion of Th1 cytokines. Conversely, an increase in intracellular GSH content stimulates IL-12 and/or IL-27, which in turn induces differentiation of naive CD4+ T cells to Th1 cells. In addition, GSH has been shown to inhibit the replication/survival of several pathogens, i.e. viruses and bacteria. Hence, molecules able to increase GSH levels have been proposed as new tools to more effectively hinder different pathogens by acting as both immunomodulators and antimicrobials. Herein, the new role of GSH and its derivatives as immunotherapeutics will be discussed.

Glutathione increase by the n‐butanoyl glutathione derivative (GSH‐C4) inhibits viral replication and induces a predominant Th1 immune profile in old mice infected with influenza virus

“… Moreover, we establish a link between the increased GSH content in the lungs and elevated production of IL‐12 in the BALF of influenza virus infected old mice treated with GSH‐C4. Hence, in agreement with previous works showing that GSH concentration influence IL‐12 production and Th response patterns, we can conclude that in old mice infected with influenza virus, Th1/Th2 cytokine production can be also influenced by the redox state. In summary, GSH‐C4 treatment, by enhancing intracellular GSH content, elicited strong IgA and cellular immune responses that resulted in reduced lung virus titers in old mice (Table ).…”

“…So, as widely reported, the results described in this paper, reinforce the conclusion that GSH exerts an important role in antiviral immunity, not simply as ROS scavenger, but by influencing the antiviral GSH‐dependent signaling pathways impaired by the virus. Therefore, the use of a molecule as GSH‐C4, equipped with both antiviral and immunomodulatory activity, may constitute a goal in the fighting influenza virus infection in aged people.…”

“…Reduced age‐associated IL‐12 production may be partly attributable to the decrease in GSH content within the aging macrophage . Therefore, restoring of GSH content in macrophages may be useful for enhancing the immune response and stimulating Th1 immunity during aging . Fraternale et al have reported that the N‐butanoyl GSH derivative (GSH‐C4), a molecule able to enter cells more easily than GSH, can shift the immune response toward Th1 type in different immunization models by modulating IL‐12 secretion …”

“…6 Therefore, restoring of GSH content in macrophages may be useful for enhancing the immune response and stimulating Th1 immunity during aging. 7 Fraternale et al have reported that the N-butanoyl GSH derivative (GSH-C4), a molecule able to enter cells more easily than GSH, can shift the immune response toward Th1 type in different immunization models by modulating IL-12 secretion. 8,9 Intracellular redox state plays also a pivotal role in regulating the life-cycle of influenza virus and a depletion of GSH was observed in infected cells.…”

New Insights into the Role of Glutathione in the Mechanism of Fever

“…One of the first steps in antigen degradation and processing is the reduction of disulfide bonds, which requires GSH [78,79]. The antigens then move to a more acidic environment, that facilitates further unfolding, cleavage by endopeptidases, and binding to MHC molecules [80].…”