BD-02 Blockade of the mechanistic target of rapamycin elicits rapid and lasting improvement of disease activity through restraining pro-inflammatory T cell lineage specification in patients with active SLE

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:10.1136/lupus-2018-lsm.26

Cited by 6 publications

(9 citation statements)

References 3 publications

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“…In 2018, a single-arm, open-label trial further verified the role of mTOR inhibition by sirolimus in treating SLE to recover mitochondrial dysfunction (60). Both the off-label drug use and subsequent open-label phase 1/2 clinical trial revealed that sirolimus effectively reduced SLE disease activity (60,158), and could be an effective therapeutic medication for SLE. Nonetheless, further randomized controlled trials of sirolimus in SLE are warranted.…”

Section: Sirolimusmentioning

confidence: 98%

“…This demonstrates that recovery of mitochondrial dysfunction caused by insufficient mitophagy and mROS overproduction normalizes the phenotypes of T cells in SLE. Furthermore, few clinical trials have demonstrated that either inhibiting mTORC1 by rapamycin (sirolimus) (60) or supplementing Nacetylcysteine (NAC), a glutathione precursor and an antioxidant (58), is therapeutically effective and improved systemic inflammation in patients with SLE. Interestingly, mitochondrial accumulation depletes memory T cells and regulatory T (Tregs) cells in SLE (60).…”

Section: Mitochondrial Dysfunction In Adaptive Immune Cellsmentioning

confidence: 99%

“…Furthermore, few clinical trials have demonstrated that either inhibiting mTORC1 by rapamycin (sirolimus) (60) or supplementing Nacetylcysteine (NAC), a glutathione precursor and an antioxidant (58), is therapeutically effective and improved systemic inflammation in patients with SLE. Interestingly, mitochondrial accumulation depletes memory T cells and regulatory T (Tregs) cells in SLE (60). Indeed, decreased number of Treg cells fail to maintain self-tolerance and immunosuppressive function in SLE, whereas supplementation of Treg cells normalizes the inflammatory response and SLE pathology in lupus mice (61).…”

Section: Mitochondrial Dysfunction In Adaptive Immune Cellsmentioning

confidence: 99%

“…Sirolimus blocks both mTORC1 activation and T-cell hyperactivity, and its effectiveness has been demonstrated in lupus mice by normalizing proteinuria, protecting renal function, reducing anti-dsDNA titers and inhibiting antiphospholipid antibody production (156,157). In 2018, a single-arm, open-label trial further verified the role of mTOR inhibition by sirolimus in treating SLE to recover mitochondrial dysfunction (60). Both the off-label drug use and subsequent open-label phase 1/2 clinical trial revealed that sirolimus effectively reduced SLE disease activity (60,158), and could be an effective therapeutic medication for SLE.…”

Section: Sirolimusmentioning

confidence: 99%

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Mitochondrial impairment and repair in the pathogenesis of systemic lupus erythematosus

Zhao

Xiao

et al. 2022

Front. Immunol.

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Nucleic acid autoantibodies, increase type I interferon (IFN-α) levels, and immune cell hyperactivation are hallmarks of systemic lupus erythematosus (SLE). Notably, immune cell activation requires high level of cellular energy that is predominately generated by the mitochondria. Mitochondrial reactive oxygen species (mROS), the byproduct of mitochondrial energy generation, serves as an essential mediator to control the activation and differentiation of cells and regulate the antigenicity of oxidized nucleoids within the mitochondria. Recently, clinical trials on normalization of mitochondrial redox imbalance by mROS scavengers and those investigating the recovery of defective mitophagy have provided novel insights into SLE prophylaxis and therapy. However, the precise mechanism underlying the role of oxidative stress-related mitochondrial molecules in skewing the cell fate at the molecular level remains unclear. This review outlines distinctive mitochondrial functions and pathways that are involved in immune responses and systematically delineates how mitochondrial dysfunction contributes to SLE pathogenesis. In addition, we provide a comprehensive overview of damaged mitochondrial function and impaired metabolic pathways in adaptive and innate immune cells and lupus-induced organ tissues. Furthermore, we summarize the potential of current mitochondria-targeting drugs for SLE treatment. Developing novel therapeutic approaches to regulate mitochondrial oxidative stress is a promising endeavor in the search for effective treatments for systemic autoimmune diseases, particularly SLE.

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Section: Sirolimusmentioning

confidence: 98%

Section: Mitochondrial Dysfunction In Adaptive Immune Cellsmentioning

confidence: 99%

Section: Mitochondrial Dysfunction In Adaptive Immune Cellsmentioning

confidence: 99%

Section: Sirolimusmentioning

confidence: 99%

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Mitochondrial impairment and repair in the pathogenesis of systemic lupus erythematosus

Zhao

Xiao

et al. 2022

Front. Immunol.

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“…During the development of SLE, the mTOR signaling is activated, and blocking the mTOR pathway using rapamycin has emerged as a new strategy for treating SLE in animal models and patients (117-119). A phase 1/2 clinical trial of rapamycin showed the improvement in disease in SLE patients over a 12month treatment period (120). Inhibition of mTOR by rapamycin prevented IFN-I production by SLE monocytes and promoted autophagy-mediated degradation of STING (121).…”

Section: Other Cgas-sting Related Autoimmune Diseases 431 Systemic Lu...mentioning

confidence: 99%

Inhibitory targeting cGAS-STING-TBK1 axis: Emerging strategies for autoimmune diseases therapy

et al. 2022

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The cGAS-STING signaling plays an integral role in the host immune response, and the abnormal activation of cGAS-STING is highly related to various autoimmune diseases. Therefore, targeting the cGAS-STING-TBK1 axis has become a promising strategy in therapy of autoimmune diseases. Herein, we summarized the key pathways mediated by the cGAS-STING-TBK1 axis and various cGAS-STING-TBK1 related autoimmune diseases, as well as the recent development of cGAS, STING, or TBK1 selective inhibitors and their potential application in therapy of cGAS-STING-TBK1 related autoimmune diseases. Overall, the review highlights that inhibiting cGAS-STING-TBK1 signaling is an attractive strategy for autoimmune disease therapy.

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Dysregulation and chronicity of pathogenic T cell responses in the pre-diseased stage of lupus

et al. 2022

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In the normal immune system, T cell activation is tightly regulated and controlled at several levels to ensure that activation occurs in the right context to prevent the development of pathologic conditions such as autoimmunity or other harmful immune responses. CD4+FoxP3+ regulatory T cells (Treg) are crucial for the regulation of T cell responses in the peripheral lymphatic organs and thus for the prevention and control of autoimmunity. In systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disease with complex etiology, a disbalance between Treg and pathogenic effector/memory CD4+ T cells develops during disease progression indicating that gradual loss of control over T cell activation is an important event in the immune pathogenesis. This progressive failure to adequately regulate the activation of autoreactive T cells facilitates chronic activation and effector/memory differentiation of pathogenic T cells, which are considered to contribute significantly to the induction and perpetuation of autoimmune processes and tissue inflammation in SLE. However, in particular in humans, little is known about the factors which drive the escape from immune regulation and the chronicity of pathogenic T cell responses in an early stage of autoimmune disease when clinical symptoms are still unapparent. Here we briefly summarize important findings and discuss current views and models on the mechanisms related to the dysregulation of T cell responses which promotes chronicity and pathogenic memory differentiation with a focus on the early stage of disease in lupus-prone individuals.

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BD-02 Blockade of the mechanistic target of rapamycin elicits rapid and lasting improvement of disease activity through restraining pro-inflammatory T cell lineage specification in patients with active SLE

Cited by 6 publications

References 3 publications

Mitochondrial impairment and repair in the pathogenesis of systemic lupus erythematosus

Mitochondrial impairment and repair in the pathogenesis of systemic lupus erythematosus

Inhibitory targeting cGAS-STING-TBK1 axis: Emerging strategies for autoimmune diseases therapy

Dysregulation and chronicity of pathogenic T cell responses in the pre-diseased stage of lupus

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