The Ups and Downs of TORKinibs in Transplantation

Fantus, Daniel; Thomson, Angus W.

doi:10.1097/tp.0000000000000803

Cited by 3 publications

(3 citation statements)

References 6 publications

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“…Short-term exposure to RAPA inhibits mTORC1 complex but enhances the mTORC2 signal, while prolonged exposure to RAPA is necessary to inhibit both signals [84]. Zeng et al .…”

Section: Discussionmentioning

confidence: 99%

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Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

et al. 2017

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Adoptive transfer of CD4+CD25+FOXP3+ regulatory T cells (Treg cells) has been successfully utilized to treat graft versus host disease and represents a promising strategy for the treatment of autoimmune diseases and transplant rejection. The aim of this study was to evaluate the effects of all-trans retinoic acid (atRA) and rapamycin (RAPA) on the number, phenotype, homing markers expression, DNA methylation, and function of induced human Treg cells in short-term cultures. Naive T cells were polyclonally stimulated and cultured for five days in the presence of different combinations of IL-2, TGF-β1, atRA and RAPA. The resulting cells were characterized by the expression of FOXP3, activation, surface and homing markers. Methylation of the Conserved Non-coding Sequence 2 was also evaluated. Functional comparison of the different culture conditions was performed by suppression assays in vitro. Culturing naive human T cells with IL-2/TGFβ1 resulted in the generation of 54.2% of Treg cells (CD4+CD25+FOXP3+) whereas the addition of 100 nM atRA increased the yield of Treg cells to 66% (p = 0.0088). The addition of RAPA did not increase the number of Treg cells in any of these settings. Treg cells generated in the presence of atRA had an increased expression of the β7 integrin to nearly 100% of the generated Treg cells, while RAPA treated cells showed enhanced expression of CXCR4. The differential expression of homing molecules highlights the possibility of inducing Treg cells with differential organ-specific homing properties. Neither atRA nor RAPA had an effect on the highly methylated CNS2 sites, supporting reports that their contribution to the lineage stability of Treg cells is not mediated by methylation changes in this locus. Treg cells generated in the presence of RAPA show the most potent suppression effect on the proliferation of effector cells.

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“…Short-term exposure to RAPA inhibits mTORC1 complex but enhances the mTORC2 signal, while prolonged exposure to RAPA is necessary to inhibit both signals [84]. Zeng et al .…”

Section: Discussionmentioning

confidence: 99%

“…These results are apparently in contrast with the widely accepted Treg-promoting effect of RAPA, and highlight the complexities of mTOR inhibition [ 83 ]. Short-term exposure to RAPA inhibits mTORC1 complex but enhances the mTORC2 signal, while prolonged exposure to RAPA is necessary to inhibit both signals [ 84 ]. Zeng et al .…”

Section: Discussionmentioning

confidence: 99%

Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

et al. 2017

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“…While rapamycin and its analogues, or ‘rapalogs’, almost completely inhibit mTORC1, mTORC2 is affected only after long exposure . Specific deletion of genes encoding mTORC1 or mTORC2, and the use of new‐generation dual mTOR kinase inhibitors, known as ‘TORKinibs’ , have opened up new possibilities to investigate the discrete functions of each mTOR subunit in immune cells, with implications for their roles in transplantation. Comprehensive review of the role of mTOR in the regulation of immune responses , pharmacokinetic and dynamic aspects of rapamycin in transplantation , and the advantages and disadvantages of mTOR inhibitors in renal transplantation have been published.…”

Section: Introductionmentioning

confidence: 99%

New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation

Waldner

Fantus

Solari

et al. 2016

Brit J Clinical Pharma

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The macrolide rapamycin and its analogues (rapalogs) constitute the first generation of mammalian target of rapamycin (mTOR) inhibitors. Since the introduction of rapamycin as an immunosuppressant, there has been extensive progress in understanding its complex mechanisms of action. New insights into the function of mTOR in different immune cell types, vascular endothelial cells and neoplastic cells have opened new opportunities and challenges regarding mTOR as a pharmacological target. Currently, the two known mTOR complexes, mTOR complex (mTORC) 1 and mTORC2, are the subject of intense investigation, and the introduction of second‐generation dual mTORC kinase inhibitors (TORKinibs) and gene knockout mice is helping to uncover the distinct roles of these complexes in different cell types. While the pharmacological profiling of rapalogs is advanced, much less is known about the properties of TORKinibs. A potential benefit of mTOR inhibition in transplantation is improved protection against transplant‐associated viral infections compared with standard calcineurin inhibitor‐based immunosuppression. Preclinical and clinical data also underscore the potentially favourable antitumour effects of mTOR inhibitors in regard to transplant‐associated malignancies and as a novel treatment option for various other cancers. Many aspects of the mechanisms of action of mTOR inhibitors and their clinical implications remain unknown. In this brief review we discuss new findings and perspectives of mTOR inhibitors in transplantation.

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TLR-4 Agonist Induces IFN-γ Production Selectively in Proinflammatory Human M1 Macrophages through the PI3K-mTOR– and JNK-MAPK–Activated p70S6K Pathway

Gajanayaka

Dong

Ali

et al. 2021

The Journal of Immunology

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IFN-γ, a proinflammatory cytokine produced primarily by T cells and NK cells, activates macrophages and engages mechanisms to control pathogens. Although there is evidence of IFN-γ production by murine macrophages, IFN-γ production by normal human macrophages and their subsets remains unknown. Herein, we show that human M1 macrophages generated by IFN-γ and IL-12– and IL-18–stimulated monocyte-derived macrophages (M0) produce significant levels of IFN-γ. Further stimulation of IL-12/IL-18–primed macrophages or M1 macrophages with agonists for TLR-2, TLR-3, or TLR-4 significantly enhanced IFN-γ production in contrast to the similarly stimulated M0, M2a, M2b, and M2c macrophages. Similarly, M1 macrophages generated from COVID-19–infected patients’ macrophages produced IFN-γ that was enhanced following LPS stimulation. The inhibition of M1 differentiation by Jak inhibitors reversed LPS-induced IFN-γ production, suggesting that differentiation with IFN-γ plays a key role in IFN-γ induction. We subsequently investigated the signaling pathway(s) responsible for TLR-4–induced IFN-γ production in M1 macrophages. Our results show that TLR-4–induced IFN-γ production is regulated by the ribosomal protein S6 kinase (p70S6K) through the activation of PI3K, the mammalian target of rapamycin complex 1/2 (mTORC1/2), and the JNK MAPK pathways. These results suggest that M1-derived IFN-γ may play a key role in inflammation that may be augmented following bacterial/viral infections. Moreover, blocking the mTORC1/2, PI3K, and JNK MAPKs in macrophages may be of potential translational significance in preventing macrophage-mediated inflammatory diseases.

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The Ups and Downs of TORKinibs in Transplantation

Cited by 3 publications

References 6 publications

Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

Single and combined effect of retinoic acid and rapamycin modulate the generation, activity and homing potential of induced human regulatory T cells

New perspectives on mTOR inhibitors (rapamycin, rapalogs and TORKinibs) in transplantation

TLR-4 Agonist Induces IFN-γ Production Selectively in Proinflammatory Human M1 Macrophages through the PI3K-mTOR– and JNK-MAPK–Activated p70S6K Pathway

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