Utilizzo di molecole pro-glutatione per modulare la risposta immunitaria Th1/Th2 durante le infezioni virali

It is known that several diseases are characterized by an imbalance of glutathione (GSH). Moreover, the glutathione-redox balance in antigen presenting cells (APC) has a critical role for developing innate immune responses. More precisely, low levels of GSH decrease the secretion of interleukin (IL)-12 and lead to the polarization from the Th1 cytokine profile towards Th2 response patterns; on the contrary, high levels of GSH favor Th1 response. The shift from a Th1 to a Th2 immune response has been described in many viral infections as well as during aging. In this study, the capacity of two pro-GSH molecules to modulate the immune response in C57BL/6 (B6) mice infected with LP-BM5 murine leukemia virus mixture was investigated. The selected molecules were GSH-C4, an N-butanoyl GSH derivative, and I-152 [N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine], a pro-drug of N-acetylcysteine (NAC) and beta-mercaptoethylamine (cysteamine), that can be used for GSH synthesis. LP-BM- infected mice develop a profound and broad immunodeficiency, known as murine AIDS (MAIDS), with a shift in cytokine profiles from a Th1 to Th2 phenotype. Therefore, preliminary studies were performed to establish the role of GSH in influencing the immune response in these animals. To this aim, Th1/Th2 cytokine profile and GSH levels in spleen, lymph nodes, pancreas and brain, were analyzed. The results obtained show that LP-BM5 infection was characterized by a prevalent Th2 immune response at every time point analyzed (2, 5 and 9 weeks post-infection), as revealed by the expression of Th1/Th2 cytokines both at protein and mRNA level. The prevalent Th2 response was also supported by IgE production which is the most distinctive effect of IL-4 in vivo. Besides, the disease was affected by redox unbalance as shown by the depletion of GSH and/or cysteine in spleen, lymph nodes, pancreas and brain. There is no doubt that there are multiple factors that can affect either Th1 or Th2 cytokines, but the general conclusion that can be drawn from these results is that an important factor that could affect MAIDS progression and Th1/Th2 cytokine disequilibrium is the redox unbalance. Moreover, the treatment with I-152 or GSH-C4 strengthened Th1 immune response increasing the production of Th1 cytokines and/or inhibiting the Th2 cytokines. In parallel experiments conducted on elderly Balb-c mice infected with influenza A PR8/H1N1 virus it has been study the ability of GSH-C4 to modulate the immune response. The results obtained showed that treatment whit GSH-C4 inhibited the viral replication and reinforced Th1 immune response increasing the production of IL-12 and IgG2a. These results suggest that GSH-replenishing molecules could be used to re-establish a correct intracellular redox state and a balanced Th1/Th2 immune response. Hence, the immunotherapy based on the use of pro-GSH molecules would permit to combat more efficiently all those viral infections characterized by a Th1/Th2 disequilibrium.