Modulation of Th1/Th2 immune responses to HIV-1 Tat by new pro-GSH molecules

Fraternale, Alessandra; Paoletti, Maria Filomena; Dominici, Sabrina; Buondelmonte, Costantina; Caputo, Antonella; Castaldello, Arianna; Tripiciano, Antonella; Cafaro, Aurelio; Palamara, Anna Teresa; Sgarbanti, Rossella; Garaci, Enrico; Ensoli, Barbara; Magnani, Mauro

doi:10.1016/j.vaccine.2011.07.101

Cited by 25 publications

(21 citation statements)

References 31 publications

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“…Consistent with the well-known reciprocal relationship between the production of IFN-␥ and IL-4 (64), the increase in IFN-␥ levels by splenocytes from infected I-152-treated mice was accompanied by decreased IL-4 levels in splenocytes from such mice. Hence, in agreement with previous in vitro and in vivo works showing that GSH levels influence IL-12 production and Th response patterns (17,18,38,39), we can conclude that in MAIDS Th1/Th2 cytokines can also be influenced by the redox state. Moreover, the molecules able to increase the intracellular GSH content can favor and inhibit Th1 and Th2 cytokines, respectively, thus reestablishing a Th1/Th2 balance.…”

Section: Discussionsupporting

confidence: 92%

“…Moreover, a prevalent Th2 immune response associated with an alternative pathway of macrophage activation was found to characterize LP-BM5 infection. The treatment of LP-BM5-infected mice with N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine (I-152), a prodrug of N-acetyl-cysteine (NAC) and beta-mercaptoethylamine (cysteamine), which was already successfully used both as an antiviral and as an immunomodulator (36)(37)(38)(39), could restore the intraorgan GSH content and a balanced Th1/Th2 response. These data show that, similarly to what happens in other viral infections (20,26,(40)(41)(42)(43)(44), a Th1/Th2 imbalance can be mediated by GSH-dependent mechanisms in MAIDS as well.…”

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confidence: 99%

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Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Brundu

Palma

Picceri

et al. 2016

J Virol

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Injection of the LP-BM5 murine leukemia virus into mice causes murine AIDS, a disease characterized by many dysfunctions of immunocompetent cells. To establish whether the disease is characterized by glutathione imbalance, reduced glutathione (GSH) and cysteine were quantified in different organs. A marked redox imbalance, consisting of GSH and/or cysteine depletion, was found in the lymphoid organs, such as the spleen and lymph nodes. Moreover, a significant decrease in cysteine and GSH levels in the pancreas and brain, respectively, was measured at 5 weeks postinfection. The Th2 immune response was predominant at all times investigated, as revealed by the expression of Th1/Th2 cytokines. Furthermore, investigation of the activation status of peritoneal macrophages showed that the expression of genetic markers of alternative activation, namely, Fizz1, Ym1, and Arginase1, was induced. Conversely, expression of inducible nitric oxide synthase, a marker of classical activation of macrophages, was detected only when Th1 cytokines were expressed at high levels. In vitro studies revealed that during the very early phases of infection, GSH depletion and the downregulation of interleukin-12 (IL-12) p40 mRNA were correlated with the dose of LP-BM5 used to infect the macrophages. Treatment of LP-BM5-infected mice with N-(N-acetyl-L-cysteinyl)-S-acetylcysteamine (I-152),an N-acetyl-cysteine supplier, restored GSH/cysteine levels in the organs, reduced the expression of alternatively activated macrophage markers, and increased the level of gamma interferon production, while it decreased the levels of Th2 cytokines, such as IL-4 and IL-5. Our findings thus establish a link between GSH deficiency and Th1/Th2 disequilibrium in LP-BM5 infection and indicate that I-152 can be used to restore the GSH level and a balanced Th1/Th2 response in infected mice. IMPORTANCEThe first report of an association between Th2 polarization and alteration of the redox state in LP-BM5 infection is presented. Moreover, it provides evidence that LP-BM5 infection causes a decrease in the thiol content of peritoneal macrophages, which can influence IL-12 production. The restoration of GSH levels by GSH-replenishing molecules can represent a new therapeutic avenue to fight this retroviral infection, as it reestablishes the Th1/Th2 balance. Immunotherapy based on the use of pro-GSH molecules would permit LP-BM5 infection and probably all those viral infections characterized by GSH deficiency and a Th1/ Th2 imbalance to be more effectively combated. Infection with the LP-BM5 murine leukemia virus causes a profound and broad immunodeficiency in susceptible mouse strains, such as C57BL/6 (B6) mice. This disease is known as murine AIDS (MAIDS) and is characterized by early polyclonal T-and B-cell activation, splenomegaly, lymphadenopathy, hypergammaglobulinemia, decreased T-and B-cell responses, increased susceptibility to opportunistic pathogens, and the development of terminal B-cell lymphomas and neurological dysfunctions (1-4). MAIDS is charact...

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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 99%

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Brundu

Palma

Picceri

et al. 2016

J Virol

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“…The randomized study, Promoting Maternal-Infant Survival Everywhere (PROMISE), is currently enrolling participants and aims to answer the question of whether there is a benefit to women with CD4 cell counts above current thresholds for treatment in continuing ART initiated for PMTCT [35]. If pregnancy-related immune modulation leads to an extended increase in inflammation postpartum (with associated adverse clinical outcomes), this would add evidence to support women remaining on ART after pregnancy, regardless of CD4 count, for their own health [36], [37].…”

Section: Discussionmentioning

confidence: 99%

Immune Activation Markers in Peripartum Women in Botswana: Association with Feeding Strategy and Maternal Morbidity

et al. 2014

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Hormone levels shift the immune state in HIV-uninfected pregnant and breastfeeding women away from Th1 responses and toward regulation to permit fetal tolerance. Limited data exist on inflammation during pregnancy or postpartum in HIV-infected women, though certain inflammatory markers are associated with adverse health outcomes among HIV-infected persons.We measured hsCRP, D-dimer, IFN-γ, IL-6, IL-10 and TNF-α at 34 weeks gestation and six months postpartum in HIV-infected women from the Botswana Mashi PMTCT trial who were randomized to breastfeeding or formula-feeding. Differences in inflammatory markers between gestation and postpartum periods, and by randomized feeding method, were estimated using generalized estimating equations, adjusting for baseline plasma HIV-1 viral load, CD4 count, calendar time, and antiretroviral treatment status. Additionally, we studied the association between marker concentrations at six months postpartum and major adverse clinical events over the following 4.5 years, using case-cohort sampling and adjusted Cox proportional hazards models.In 86 breastfeeding and 75 formula-feeding women, hsCRP and D-dimer decreased significantly between 34 weeks gestation and six months postpartum, while IFN-γ increased. There was no significant association between inflammatory marker change and randomized feeding method after adjusting for multiple comparisons and removing outliers. In univariate analysis, TNF-α, D-dimer, and IFN-γ concentrations at six months postpartum were significant predictors of subsequent clinical events, and TNF-α remained significant in multivariate analysis (HR = 4.16, p = 0.001).In young HIV-infected women in Botswana inflammatory marker concentrations did not differ significantly between women who breast- vs. formula-fed. However, postpartum TNF-α level was predictive of subsequent adverse clinical event.

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“…Whatever the mechanism responsible for low CSE expression in tolerated allografts, it is reminiscent of the TH-1 and IL-12 defects associated with HIV infection, 50 characterized by sulfur loss and CSE underexpression, 51 and for which administration of cysteine can increase anti-HIV responses. 52,53 BLOOD, 15 MARCH 2012 ⅐ VOLUME 119, NUMBER 11 For personal use only. on May 9, 2018. by guest www.bloodjournal.org From…”

Section: Discussionmentioning

confidence: 99%

Transplant tolerance is associated with reduced expression of cystathionine-γ-lyase that controls IL-12 production by dendritic cells and TH-1 immune responses

Silly

Coulon

Poirier

et al. 2012

Blood

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AbstractAntigen-activated T lymphocytes undergo an immune or tolerogeneic response in part according to the activation status of their antigen-presenting cells. However, factors controlling the activation of antigen-presenting cells are not fully understood. In this study, we demonstrate that immune tolerance after organ allotransplantation in the rat is associated with a repressed intragraft expression of several enzymes of the trans-sulfuration pathway, including cystathionine γ-lyase (CSE). The pharmacologic blockade of CSE with propargylglycine delayed heart allograft rejection and abrogated type IV hypersensitivity but did not modify antibody responses, and was associated with a selective inhibition of the TH-1 type factors T-bet, IL-12, and IFN-γ. IL-12 repression could also be induced by propargylglycine in vitro in monocytes and dendritic cells (DCs), a phenomenon not mediated by changes to nuclear factor-κ B or hydrogen sulfide but that occurred together with a modulation of intracellular cysteine content. Intracellular cysteine levels were predominantly controlled in DCs by CSE activity, together with extracellular import via the Xc− transporter. Our results indicate that CSE plays a critical role in regulating IL-12 in monocytes and DCs and is down-modulated in transplant tolerance, presumably participating in the maintenance of the tolerant state.

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Modulation of Th1/Th2 immune responses to HIV-1 Tat by new pro-GSH molecules

Cited by 25 publications

References 31 publications

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Glutathione Depletion Is Linked with Th2 Polarization in Mice with a Retrovirus-Induced Immunodeficiency Syndrome, Murine AIDS: Role of Proglutathione Molecules as Immunotherapeutics

Immune Activation Markers in Peripartum Women in Botswana: Association with Feeding Strategy and Maternal Morbidity

Transplant tolerance is associated with reduced expression of cystathionine-γ-lyase that controls IL-12 production by dendritic cells and TH-1 immune responses

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