Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial

Lai, Zhi-Wei; Kelly, Ryan L.; Winans, Thomas; Marchena, Ivan; Shadakshari, Ashwini; Yu, Julie; Dawood, Maha; García, Ricardo Juan Bosch; Tily, Hajra; Francis, Lisa; Faraone, Stephen V.; Phillips, Paul E. M.; Perl, András

doi:10.1016/s0140-6736(18)30485-9

Cited by 328 publications

(257 citation statements)

References 41 publications

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“…Metabolic reprogramming is cell type-specific; for example, pDC activation by type I IFN relying on FAO instead of glycolysis [61], a process that has not been found in other types of DCs. Furthermore, mTOR inhibitors and metformin show promising results in SLE [25,30]. In addition, some metabolites such as succinate or itaconate show previously unsuspected anti-inflammatory effects [122].…”

Section: Resultsmentioning

confidence: 99%

“…The metabolism of immune cells is already targeted by a drug commonly used by rheumatologists, methotrexate, which interferes with 1-Carbon metabolism [124]. Furthermore, mTOR inhibitors and metformin show promising results in SLE [25,30]. It would also be of great interest to explore the metabolic consequences of current treatments used or tested by rheumatologists to have a clearer understanding of the mechanisms by which drugs or biologics modulate the immune system effectively or not through altered metabolism.…”

Section: Resultsmentioning

confidence: 99%

“…The function and differentiation of follicular regulatory T cells (Tfr), a T reg subset that suppresses germinal center (GC) B cells and Tfh cells, is also mTORC1dependent [23]. Indeed, treatment with sirolimus, an mTOR inhibitor, reduced disease activity in refractory lupus patients [25]. CD4 + T cells from lupus patients present a high level of mTOR activation that is directly implicated in the disease process [24].…”

Section: The Yin and Yang Regulation Of Autoimmunity By Mtor And Ampkmentioning

confidence: 99%

“…CD4 + T cells from lupus patients present a high level of mTOR activation that is directly implicated in the disease process [24]. Indeed, treatment with sirolimus, an mTOR inhibitor, reduced disease activity in refractory lupus patients [25]. Intriguingly, the therapeutic response in these patients was best associated with a reduced number of effector memory CD8 + T cells, a subset whose role in lupus pathogenesis is as yet undefined.…”

Section: Review Series: Translating Immunometabolismmentioning

confidence: 99%

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Immune cell metabolism in autoimmunity

Teng

Cornaby

et al. 2019

Clinical and Experimental Immunology

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Immune metabolism is a rapidly moving field. While most of the research has been conducted to define the metabolism of healthy immune cells in the mouse, it is recognized that the overactive immune system that drives autoimmune diseases presents metabolic abnormalities that provide therapeutic opportunities, as well as a means to understand the fundamental mechanisms of autoimmune activation more clearly. Here, we review recent publications that have reported how the major metabolic pathways are affected in autoimmune diseases, with a focus on rheumatic diseases. mental Immunology 2019, 197: 141-142. T cell metabolism in chronic viral infection. Clinical and Experimental Immunology 2019, 197: 143-152. Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting. Clinical and Experimental Immunology 2019, 197: 153-160. Sensing between reactions -how the metabolic microenvironment shapes immunity. Clinical and Experimental Immunology 2019, 197: 161-169. Altered metabolic pathways regulate synovial inflammation in rheumatoid arthritis. OTHER ARTICLES PUBLISHED IN THIS REVIEW SERIES Translating immunometabolism: towards curing human diseases by targeting metabolic processes underpinning the immune response. Clinical and Experi

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: The Yin and Yang Regulation Of Autoimmunity By Mtor And Ampkmentioning

confidence: 99%

Section: Review Series: Translating Immunometabolismmentioning

confidence: 99%

See 2 more Smart Citations

Immune cell metabolism in autoimmunity

Teng

Cornaby

et al. 2019

Clinical and Experimental Immunology

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“…Lupus and Sjogren's syndrome occur when mTOR is activated, and its blockade with rapamycin is therapeutically effective [70]. Recent investigations have demonstrated that both mTOR and rapamycin have pivotal roles of antiaging, development, various diseases such as cancer, diabetes, obesity and also tissue injury [71][72][73][74][75][76].…”

Section: Discussionmentioning

confidence: 99%

Role of the mTOR signalling pathway in salivary gland development

et al. 2019

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Development of the salivary gland is characterized by extensive branching morphogenesis. Although various molecules have been implicated in salivary gland development, the role of the mammalian target of rapamycin (mTOR) signalling pathway, including both mTOR complexes 1 and 2 (mTORC1 and 2), in salivary gland development is unknown. Here, we examined protein expression levels related to the mTOR signalling pathway using an ex vivo submandibular salivary gland (SMG) organ culture. We showed that branching buds in the salivary glands were substantially decreased and phosphorylation of mTORC1 signalling pathway related proteins (mTOR, p70 ribosomal protein S6 kinase 1 and eukaryotic initiation factor 4E‐binding protein 1) was inhibited by rapamycin (an mTOR inhibitor). In addition, AKT, which is an upstream protein kinase of mTORC1 and is downstream of mTORC2, is inhibited by LY294002 (a phosphatidylinositol 3‐kinase inhibitor), but not by rapamycin. Moreover, rapamycin‐treated ICR neonatal mice exhibited a reduction in both body weight and salivary glands compared with vehicle‐treated neonatal mice. The present data indicate that the mTOR signalling pathway, including both mTORC1 and mTORC2, plays a critical role in salivary gland development both in ex vivo SMG organ culture and ICR neonatal mice in vivo.

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Redox Pathogenesis in Rheumatic Diseases

Laniak,

Winans,

Patel

et al. 2024

ACR Open Rheumatology

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Despite being some of the most anecdotally well‐known roads to pathogenesis, the mechanisms governing autoimmune rheumatic diseases are not yet fully understood. The overactivation of the cellular immune system and the characteristic development of autoantibodies have been linked to oxidative stress. Typical clinical manifestations, such as joint swelling and deformities and inflammation of the skin and internal organs, have also been connected directly or indirectly to redox mechanisms. The differences in generation and restraint of oxidative stress provide compelling evidence for the broad variety in pathology among rheumatic diseases and explain some of the common triggers and discordant manifestations in these diseases. Growing evidence of redox mechanisms in pathogenesis has provided a broad array of new potential therapeutic targets. Here, we explore the mechanisms by which oxidative stress is generated, explore its roles in autoimmunity and end‐organ damage, and discuss how individual rheumatic diseases exhibit unique features that offer targets for therapeutic interventions.

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Sirolimus in patients with clinically active systemic lupus erythematosus resistant to, or intolerant of, conventional medications: a single-arm, open-label, phase 1/2 trial

Abstract: Pfizer, the National Institutes of Health, and the Central New York Community Foundation.

Cited by 328 publications

References 41 publications

Immune cell metabolism in autoimmunity

Immune cell metabolism in autoimmunity

Role of the mTOR signalling pathway in salivary gland development

Redox Pathogenesis in Rheumatic Diseases

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