Targeting mTOR in sarcoid granulomas: where the rubber meets the road

Notwithstanding the efforts of Team Science, the mechanisms underlying granuloma formation remain incompletely understood and the granuloma remains the final frontier for developing targeted therapeutics in sarcoidosis. Until recently, passage through this frontier was an uncertain prospect. Thanks to several recent discoveries, however, there is a realistic possibility of developing these therapies in sarcoidosis. The development of in vitro 1 Locke LW Schlesinger LS Crouser ED Current sarcoidosis models and the importance of focusing on the granuloma. Front Immunol. 2020; 111719 Crossref Scopus (22) Google Scholar and murine models of granuloma formation 2 Linke M Fritsch SD Sukhbaatar N Hengstschlager M Weichhhart T Regulation of innate immune cell function by mTOR. Nat Rev Immunol. 2015; 15: 599-614 Crossref PubMed Scopus (545) Google Scholar and the identification of potential pathogenic antigens 3 Chen ES Wahlstrom J Song Z et al. T cell responses to mycobacterial catalase-peroxidase profile a pathogenic antigen in systemic sarcoidosis. J Immunol. 2008; 181: 8784-8796 Crossref PubMed Google Scholar , 4 Greaves SA Ravindran A Santos RG et al. CD4+ T cells in the lungs of acute sarcoidosis patients recognize an Aspergillus nidulans epitope. J Exp Med. 2021; 218e20210785 Crossref PubMed Scopus (24) Google Scholar provide a template for recapitulating sarcoid immunopathogenesis. The mechanistic data that emerge from these studies are likely to unveil therapeutic targets that hold great promise for patients with sarcoidosis and this is, indeed, where the rubber meets the road. Efficacy and safety of mTOR inhibition in cutaneous sarcoidosis: a single-centre trialShort-term treatment with systemic sirolimus might be an effective and safe treatment option for patients with persistent glucocorticoid-refractory sarcoidosis with a long-lasting disease-modulating effect. The effect of sirolimus in granulomatous inflammation should be investigated further in large, multi-centre, randomised clinical trials. Full-Text PDF