Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years

Oaks, Zachary; Winans, Thomas; Huang, Nick; Bánki, Katalin; Perl, András

doi:10.1007/s11926-016-0622-8

Cited by 62 publications

(36 citation statements)

References 64 publications

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“…In a recent trial of NAC in SLE, the drug was well-tolerated and reduced disease activity via the mTOR pathway [82]. Indeed, mTOR pathway modulators appear to be viable therapies, and the use of rapamycin as a therapeutic option has also been tested animal models of lupus and in humans ([34,76,83,84]; Trial ID: NCT00779194). The role of the PPARγ-agonist pioglitazone is currently being investigated in proof-of-concept trials.…”

Section: Immunometabolism Therapeutic Targets and Slementioning

confidence: 99%

Metabolic abnormalities and oxidative stress in lupus

Lightfoot

Blanco

Kaplan

2017

Current Opinion in Rheumatology

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Purpose of review Upon antigen exposure, immune cells rely on cell-specific metabolic pathways to mount an efficient immune response. In autoimmunity, failure in critical metabolic checkpoints may lead to immune cell hyper-activation and tissue damage. Oxidative stress in autoimmune patients can also contribute to immune dysregulation and injury to the host. Recent insights into the immune cell metabolism signatures specifically associated with systemic lupus erythematosus (SLE) and the consequences of heightened oxidative stress in patients are discussed herein. Recent findings Glucose metabolism inhibitors, mTOR pathway modulators, and PPARγ-activating compounds demonstrate therapeutic benefit in experimental models of lupus. Mitochondrial-derived reactive oxygen species (ROS) and molecular modifications induced by oxidative stress appear to be detrimental in lupus. Effective therapies tailored towards the reconfiguration of metabolic imbalances in lupus immune cells and the reduction of mitochondrial ROS production/availability are currently being tested. Summary A paucity of knowledge exists regarding the metabolic needs of a number of immune cells involved in the pathogenesis of SLE, including myeloid cells and B cells. Nonetheless, SLE-specific metabolic signatures have been identified and their specific targeting, along with mitochondrial ROS inhibitors/scavengers, could show therapeutic advantage in lupus patients.

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Section: Immunometabolism Therapeutic Targets and Slementioning

confidence: 99%

Metabolic abnormalities and oxidative stress in lupus

Lightfoot

Blanco

Kaplan

2017

Current Opinion in Rheumatology

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“…Intense efforts to develop pharmacological mTOR inhibitors in addition to the allosteric inhibitor rapamycin (also known as sirolimus) and its analogs, resulted in the development of ATP-competitive inhibitors such as Torin. In addition to its use in transplant recipients, mTOR inhibitors are now being utilized, or are proposed to be utilized, in treatment regimens for many diseases including cancers such as lymphoma and renal carcinomas [12]; autoimmune disease such as systemic lupus erythematosus [13]; neurodegenerative diseases including Alzheimer’s and Parkinson’s [14]; lysosomal storage diseases [15]; and for the extension of a healthy lifespan [16]. The increased and widespread use of rapamycin and other mTOR inhibitors highlights the need to more fully understand the molecular mechanisms of how mTOR functions, the potential toxicities of mTOR inhibitors, and the biological and molecular consequences of inhibiting mTOR in many different cell types.…”

Section: Introductionmentioning

confidence: 99%

Control of B lymphocyte development and functions by the mTOR signaling pathways

Iwata

Ramírez-Komo

Park

et al. 2017

Cytokine & Growth Factor Reviews

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Mechanistic target of rapamycin (mTOR) is a serine/threonine kinase originally discovered as the molecular target of the immunosuppressant rapamycin. mTOR forms two compositionally and functionally distinct complexes, mTORC1 and mTORC2, which are crucial for coordinating nutrient, energy, oxygen, and growth factor availability with cellular growth, proliferation, and survival. Recent studies have identified critical, non-redundant roles for mTORC1 and mTORC2 in controlling B cell development, differentiation, and functions, and have highlighted emerging roles of the Folliculin-Fnip protein complex in regulating mTOR and B cell development. In this review, we summarize the basic mechanisms of mTOR signaling; describe what is known about the roles of mTORC1, mTORC2, and the Folliculin/Fnip1 pathway in B cell development and functions; and briefly outline current clinical approaches for targeting mTOR in B cell neoplasms. We conclude by highlighting a few salient questions and future perspectives regarding mTOR in B lineage cells.

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“…Our study was confined to cells from healthy subjects that might constitute a major limitation as it remains unclear whether CD71 or CD98 expression is altered significantly on ex vivo T cells in subjects with infectious and autoimmune diseases, malignancies, or immunodeficiencies. For example, it has been observed that CD71 upregulation on activated T cells is dependent on the mammalian target of rapamycin (mTOR) (32), and as mTOR signaling is elevated in autoimmune diseases such as systemic lupus erythematosus (SLE) (33), it is expected that CD71 is upregulated on ex vivo T cells in SLE patients as has been reported elsewhere (34). Further studies are needed to explore CD71 and CD98 expression on T cells from nonhealthy subjects and to carefully evaluate the validity of our approach in acute or chronic diseases.…”

Section: Discussionmentioning

confidence: 99%

“…For example, it has been observed that CD71 upregulation on activated T cells is dependent on the mammalian target of rapamycin (mTOR) (32), and as mTOR signaling is elevated in autoimmune diseases such as systemic lupus erythematosus (SLE) (33), it is expected that CD71 is upregulated on ex vivo T cells in SLE patients as has been reported elsewhere (34). For example, it has been observed that CD71 upregulation on activated T cells is dependent on the mammalian target of rapamycin (mTOR) (32), and as mTOR signaling is elevated in autoimmune diseases such as systemic lupus erythematosus (SLE) (33), it is expected that CD71 is upregulated on ex vivo T cells in SLE patients as has been reported elsewhere (34).…”

Section: Cd71 Upregulation Can Be Used For Magnetic Enrichment Of In mentioning

confidence: 99%

Tracking Dye‐Independent Approach to Identify and Isolate In Vitro Expanded T Cells

Ogunjimi

Tendeloo

2019

Cytometry Pt A

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T cell proliferation is routinely identified in vitro using tracking dyes or through detecting intracellular upregulation of the nuclear protein, Ki-67. However, labeling with tracking dyes is cumbersome, associated with cellular toxicity, while Ki-67 cannot be used to identify and isolate viable T cells, and both techniques are incompatible with MACS technology. Here, we introduce a simple tool to identify and isolate in vitro T cell expansion that is tracking dye-independent and allows for sorting of viable T cells. We show that CD71, a transferrin receptor, and CD98, a heterodimer glycoprotein involved in both integrin signaling and amino-acid transport, are both highly upregulated on proliferating T cells upon in vitro stimulation, and that CD71 expression is maximal on the more recent progeny T cells, while CD98 upregulation remains stable across different generations of progeny T cells. Moreover, we demonstrate that the upregulation of CD71 and CD98 identifies CFSE low T cells and provides further proof of the antigenspecificity of T cells identified by CD71 and CD98 dual upregulation based on tetramer staining. We further show that CD71 can be used to enrich for in vitro expanding T cells using MACS technology. In conclusion, we show that CD71 and CD98 can be used to identify and isolate expanded T cells following in vitro stimulation and that CD71 is an MACS-compatible alternative to tracking dyes or Ki-67 detection.Priming of naïve T cells, upon their activation with a specific peptide-MHC complex and in the presence of appropriate co-signals, initiates the proliferation program that leads to a clonal expansion of T cells. T cell capability to expand is at the center of the clonal selection paradigm of adaptive immunity, in which clones that engage antigenic determinants through T cell receptors (TCRs) clonally expand during the effector phase of the immune response and surviving cells constitute the bulk of the memory T cells. Memory T cells respond more vigorously upon a second encounter and this forms the basis of recall responses and vaccination (1). Cell proliferation results from progression through the cell cycle wherein regulatory proteins direct the cell through a specific set of events that results in mitosis and the production of two daughter cells (2).T cell proliferation after in vitro stimulation with antigen or peptide is a measure of T cell immunity to natural infection, vaccination, or tumors. Proliferation of T cells has historically been assessed using a nucleoside analog incorporation assay, namely the 3 H-thymidine assay, but this, once gold standard, was disadvantageous as it relied on the use of a radioactive nucleoside, and the nature of the technique did not allow for the phenotype and functionality of the proliferating T cells to be identified simultaneously. Another common nucleoside analog incorporation assay employs 5-bromo-2 0 -deoxyuridine (BrdU), in which incorporated BrdU is detected by a specific monoclonal antibody conjugated to a fluorescent tag and measured

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Activation of the Mechanistic Target of Rapamycin in SLE: Explosion of Evidence in the Last Five Years

Cited by 62 publications

References 64 publications

Metabolic abnormalities and oxidative stress in lupus

Metabolic abnormalities and oxidative stress in lupus

Control of B lymphocyte development and functions by the mTOR signaling pathways

Tracking Dye‐Independent Approach to Identify and Isolate In Vitro Expanded T Cells

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