Successful treatment of systemic de novo sarcoidosis with cyclosporine discontinuation and provision of rapamune after liver transplantation

Manzia, Tommaso Maria; Bellini, Maria Irene; Corona, Lauren E.; Toti, Luca; Fratoni, Stefano; Cillis, Annagrazia; Orlando, Giuseppe; Tisone, Giuseppe

doi:10.1111/j.1432-2277.2011.01256.x

Cited by 29 publications

(19 citation statements)

References 8 publications

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“…Our findings point to the evaluation of mTOR inhibitors in this patient group. Indeed, successful treatment of a sarcoidosis patient with the mTOR inhibitor rapamycin has been reported49. Finally, our results warrant the assessment of whether mTORC1-dependent macrophage proliferation and granuloma formation contributes to disease outcomes in other non-infectious and infectious granulomatous diseases.…”

Section: Discussionsupporting

confidence: 56%

Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression

et al. 2017

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Aggregation of hypertrophic macrophages constitutes the basis of all granulomatous diseases such as tuberculosis or sarcoidosis and is decisive for disease pathogenesis. However, macrophage-intrinsic pathways driving granuloma initiation and maintenance remain elusive. Here we show that activation of the metabolic checkpoint kinase mTORC1 in macrophages by deletion of Tsc2 was sufficient to induce hypertrophy and proliferation resulting in excessive granuloma formation in vivo. TSC2-deficient macrophages formed mTORC1-dependent granulomatous structures in vitro and showed constitutive proliferation mediated by the neo-expression of cyclin-dependent kinase 4 (CDK4). Moreover, mTORC1 promoted metabolic reprogramming via CDK4 towards increased glycolysis, while simultaneously inhibiting NF-κB signaling and apoptosis. Inhibition of mTORC1 induced apoptosis and completely resolved granulomas in myeloid TSC2-deficient mice. In human sarcoidosis patients mTORC1 activation, macrophage proliferation, and glycolysis were identified as hallmarks that correlated with clinical disease progression. Collectively, TSC2 maintains macrophage quiescence and prevents mTORC1-dependent granulomatous disease with clinical implications for sarcoidosis.

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Section: Discussionsupporting

confidence: 56%

Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression

et al. 2017

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“…Research into this field will help determine whether improvement of Treg survival, e.g. by other immunosuppressive drugs, such as rapamycin [ 36 , 37 ], holds a promising new therapeutic approach for chronic sarcoidosis patients.…”

Section: Discussionmentioning

confidence: 99%

Impaired survival of regulatory T cells in pulmonary sarcoidosis

et al. 2015

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BackgroundImpaired regulatory T cell (Treg) function is thought to contribute to ongoing inflammatory responses in sarcoidosis, but underlying mechanisms remain unclear. Moreover, it is not known if increased apoptotic susceptibility of Tregs may contribute to an impaired immunosuppressive function in sarcoidosis. Therefore, the aim of this study is to analyze proportions, phenotype, survival, and apoptotic susceptibility of Tregs in sarcoidosis.MethodsPatients with pulmonary sarcoidosis (n = 58) were included at time of diagnosis. Tregs were analyzed in broncho-alveolar lavage fluid and peripheral blood of patients and healthy controls (HC).ResultsIn sarcoidosis patients no evidence was found for a relative deficit of Tregs, neither locally nor systemically. Rather, increased proportions of circulating Tregs were observed, most prominently in patients developing chronic disease. Sarcoidosis circulating Tregs displayed adequate expression of FoxP3, CD25 and CTLA4. Remarkably, in sarcoidosis enhanced CD95 expression on circulating activated CD45RO+ Tregs was observed compared with HC, and proportions of these cells were significantly increased. Specifically sarcoidosis Tregs - but not Th cells - showed impaired survival compared with HC. Finally, CD95L-mediated apoptosis was enhanced in sarcoidosis Tregs.ConclusionIn untreated patients with active pulmonary sarcoidosis, Tregs show impaired survival and enhanced apoptotic susceptibility towards CD95L. Increased apoptosis likely contributes to the insufficient immunosuppressive function of sarcoidosis Tregs. Further research into this field will help determine whether improvement of Treg survival holds a promising new therapeutic approach for chronic sarcoidosis patients.Electronic supplementary materialThe online version of this article (doi:10.1186/s12931-015-0265-8) contains supplementary material, which is available to authorized users.

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“…The occurrence of relapses on discontinuation or the reduction in treatment is frequent (14% to 74%) [ 31 ]. Treatment advances would benefit from innovative research models as revealed with mTOR inhibitors [ 127 ]. Alternatively, research models could be developed in order to practice a more “personalized medicine”.…”

Section: Discussionmentioning

confidence: 99%

“…These results were supported by additional studies showing an increased expression of mTORC1 in cutaneous sarcoidosis patients [ 125 ] and an enrichment of the TOR signaling ( DDIT4 , MLST8 , DDIT4L , MTOR ) familial cases of sarcoidosis [ 126 ]. Interestingly, in a case report of a patient who had developed a systemic de novo sarcoidosis after liver transplantation, the use of rapamune, an immunosuppressor that binds to the specific cytosolic protein FKPB-12 inhibiting mTOR activation, improved dramatically the patient status with both normal chest imaging and liver biopsy [ 127 ].…”

Section: In Vivo Modelsmentioning

confidence: 99%

Models Contribution to the Understanding of Sarcoidosis Pathogenesis: “Are There Good Models of Sarcoidosis?”

Besnard

Jeny

2020

JCM

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Sarcoidosis is a systemic, granulomatous, and noninfectious disease of unknown etiology. The clinical heterogeneity of the disease (targeted tissue(s), course of the disease, and therapy response) supports the idea that a multiplicity of trigger antigens may be involved. The pathogenesis of sarcoidosis is not yet completely understood, although in recent years, considerable efforts were put to develop novel experimental research models of sarcoidosis. In particular, sarcoidosis patient cells were used within in vitro 3D models to study their characteristics compared to control patients. Likewise, a series of transgenic mouse models were developed to highlight the role of particular signaling pathways in granuloma formation and persistence. The purpose of this review is to put in perspective the contributions of the most recent models in the understanding of sarcoidosis.

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Successful treatment of systemic de novo sarcoidosis with cyclosporine discontinuation and provision of rapamune after liver transplantation

Cited by 29 publications

References 8 publications

Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression

Chronic signaling via the metabolic checkpoint kinase mTORC1 induces macrophage granuloma formation and marks sarcoidosis progression

Impaired survival of regulatory T cells in pulmonary sarcoidosis

Models Contribution to the Understanding of Sarcoidosis Pathogenesis: “Are There Good Models of Sarcoidosis?”

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