Increased immunosuppressive function of CD4+CD25+Foxp3+GITR+ T regulatory cells from NFATc2(−/−) mice controls allergen-induced experimental asthma

Karwot, Roman; Übel, Caroline; Bopp, Tobias; Schmitt, Edgar; Finotto, Susetta

doi:10.1016/j.imbio.2012.01.004

Cited by 19 publications

(22 citation statements)

References 22 publications

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“…Upon T-cell receptor stimulation, cytoplasmic NFATC2 is dephosphorylated and translocated to the nucleus where it participates in gene regulation. 24 The role of NFATC2 on the risk of drug-induced allergy is unknown, yet studies have shown that NFATC2 can influence the development and function of regulatory T cells and can have either a negative 25 or positive 26 regulatory influence on the immune response, depending on the antigen. Nevertheless, several studies using NFAT inhibitors for different immune-related disease models support that inhibition of the NFAT pathway can attenuate an immune response.…”

Section: Discussionmentioning

confidence: 99%

Genome-wide analysis links NFATC2 with asparaginase hypersensitivity

Fernandez

Smith

Yang

et al. 2015

Blood

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Section: Discussionmentioning

confidence: 99%

Genome-wide analysis links NFATC2 with asparaginase hypersensitivity

Fernandez

Smith

Yang

et al. 2015

Blood

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“…3G). Because we and others reported previously that NFAT-deficient Foxp3 + Tregs are fully suppressive in vitro and in vivo (11,12,20), we assessed the specific protective function of NFAT-deficient thymus-derived naturally occurring regulatory T cells (nTregs) in our GvHD model. First, we assessed the necessity of Tregs by depleting them during the course of GvHD using WT and Nfat1 −/− mice backcrossed to depletion of regulatory T cell (DEREG) mice expressing a diphtheria toxin (DTx) receptor-enhanced green , Nfat2 fl/fl Cd4cre, and DKO T cells plus 5 × 10 6 BM cells.…”

Section: Whereas Both Cd4mentioning

confidence: 99%

“…An intrinsic inability to activate effector functions, however, is mostly evident in DKO Tcons (Fig. S5 D and E) (11,12,20). Because few Tregs can be sufficient to confer protection from GvHD (23), we cotransferred a suboptimal number (ratio Tcon:Treg = 2:1) of luc …”

Section: Whereas Both Cd4mentioning

confidence: 99%

“…Regrettably, methodologies for isolation of pure and sufficient numbers of donor Tregs or for their expansion in vitro are costly and inefficient, whereas in vitro expanded Tregs might even perturb their suppressive capacities (17)(18)(19). Because of the essential role of NFAT for Tcons, but not Tregs (11,12,20), we studied the specific contribution of individual NFAT family members to the immune pathogenesis of GvHD and, vice versa, their impact on antitumor activity of donor T cells. Allogenic donor T cells deficient in NFAT showed not only reduced proliferation, target tissue homing, and impaired effector function, but in contrast, increased Foxp3 + Treg frequencies following allo-HCT.…”

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confidence: 99%

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Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity

Vaeth

Bäuerlein

Pusch

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Graft-versus-host disease (GvHD) is a life-threatening immunological complication after allogenic hematopoietic stem cell transplantation (allo-HCT). The intrinsic graft-versus-leukemia (GvL) effect, however, is the desirable curative benefit. Patients with acute GvHD are treated with cyclosporine A (CsA) or tacrolimus (FK506), which not only often causes severe adverse effects, but also interferes with the anticipated GvL. Both drugs inhibit calcineurin, thus at first suppressing activation of the nuclear factor of activated T cells (NFAT). Therefore, we explored the specific contribution of individual NFAT factors in donor T cells in animal models of GvHD and GvL. Ablation of NFAT1, NFAT2, or a combination of both resulted in ameliorated GvHD, due to reduced proliferation, target tissue homing, and impaired effector function of allogenic donor T cells. In contrast, the frequency of Foxp3+ regulatory T (Treg) cells was increased and NFAT-deficient Tregs were fully protective in GvHD. CD8+ T-cell recall response and, importantly, the beneficial antitumor activity were largely preserved in NFAT-deficient effector T cells. Thus, specific inhibition of NFAT opens an avenue for an advanced therapy of GvHD maintaining protective GvL.

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“…Upon T-cell receptor stimulation, cytoplasmatic NFATC2 is dephosphorylated and traslocated to the nucleus where it participates in gene regulation. So far, diverse studies have shown that NFATC2 can influence the development and function of regulatory T cells and can have either negative or positive regulatory influence on the immune response, depending on the antigen [72,73]. Nevertheless, other studies have demonstrated that inhibition of the NFAT pathway can attenuate an immune response [74][75][76][77][78][79].…”

Section: Pharmacogeneticsmentioning

confidence: 99%

Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene

Lopez-Santillan

Iparraguirre

Martín-Guerrero

et al. 2017

Drug Metabolism and Personalized Therapy

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Acute lymphoblastic leukemia (ALL) is a major pediatric cancer in developed countries. Although treatment outcome has improved owing to advances in chemotherapy, there is still a group of patients who experience severe adverse events. L-Asparaginase is an effective antineoplastic agent used in chemotherapy of ALL. Despite its indisputable indication, hypersensitivity reactions are common. In those cases, discontinuation of treatment is usually needed and anti-asparaginase antibody production may also attenuate asparaginase activity, compromising its antileukemic effect. Till now, six pharmacogenetic studies have been performed in order to elucidate possible genetic predisposition for inter-individual differences in asparaginase hypersensitivity. In this review we have summarized the results of those studies which describe the involvement of four different genes, being polymorphisms in the glutamate receptor, ionotropic, AMPA 1 (GRIA1) the most frequently associated with asparaginase hypersensitivity. We also point to new approaches focusing on epigenetics that could be interesting for consideration in the near future.

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Increased immunosuppressive function of CD4+CD25+Foxp3+GITR+ T regulatory cells from NFATc2(−/−) mice controls allergen-induced experimental asthma

Cited by 19 publications

References 22 publications

Genome-wide analysis links NFATC2 with asparaginase hypersensitivity

Genome-wide analysis links NFATC2 with asparaginase hypersensitivity

Selective NFAT targeting in T cells ameliorates GvHD while maintaining antitumor activity

Review of pharmacogenetics studies of L-asparaginase hypersensitivity in acute lymphoblastic leukemia points to variants in the GRIA1 gene

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