In vitro and in vivo evidence that the switch from calcineurin to mTOR inhibitors may be a strategy for immunosuppression in Epstein–Barr virus–associated post-transplant lymphoproliferative disorder

Thieme, Constantin J.; Schulz, Malissa; Wehler, Patrizia; Anft, Moritz; Amini, Leila; Blázquez-Navarro, Arturo; Stervbo, Ulrik; Hecht, Jochen; Nienen, Mikalai; Stittrich, Anna-Barbara; Choi, Mira; Zgoura, Panagiota; Viebahn, Richard; Schmueck-Henneresse, Michael; Reinke, Petra; Westhoff, Timm H.; Roch, Toralf; Babel, Nina

doi:10.1016/j.kint.2022.08.025

Cited by 4 publications

(1 citation statement)

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“…106 The same may apply for BK-viremia, EBV-, and HHV8-associated Kaposi sarcoma. 107,108 mTOR is a serine-threonine kinase that regulates diverse cellular processes such as proliferation and differentiation and belongs to the phosphoinositide 3-kinase (PI3K)– related kinase (PIKK) family. 109 Initially, it was thought that, as with CNIs, the main effect is mediated through the IL-2 signaling pathway, 110 but recent evidence shows that the mechanism of action is much more complex.…”

Section: Mtor Inhibitorsmentioning

confidence: 99%

Cellular Immunobiology and Molecular Mechanisms in Alloimmunity—Pathways of Immunosuppression

et al. 2023

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Current maintenance immunosuppression commonly comprises a synergistic combination of tacrolimus as calcineurin inhibitor (CNI), mycophenolic acid, and glucocorticoids. Therapy is often individualized by steroid withdrawal or addition of belatacept or inhibitors of the mechanistic target of rapamycin. This review provides a comprehensive overview of their mode of action, focusing on the cellular immune system. The main pharmacological action of CNIs is suppression of the interleukin-2 pathway that leads to inhibition of T cell activation. Mycophenolic acid inhibits the purine pathway and subsequently diminishes T and B cell proliferation but also exerts a variety of effects on almost all immune cells, including inhibition of plasma cell activity. Glucocorticoids exert complex regulation via genomic and nongenomic mechanisms, acting mainly by downregulating proinflammatory cytokine signatures and cell signaling. Belatacept is potent in inhibiting B/T cell interaction, preventing formation of antibodies; however, it lacks the potency of CNIs in preventing T cell-mediated rejections. Mechanistic target of rapamycin inhibitors have strong antiproliferative activity on all cell types interfering with multiple metabolic pathways, partly explaining poor tolerability, whereas their superior effector T cell function might explain their benefits in the case of viral infections. Over the past decades, clinical and experimental studies provided a good overview on the underlying mechanisms of immunosuppressants. However, more data are needed to delineate the interaction between innate and adaptive immunity to better achieve tolerance and control of rejection. A better and more comprehensive understanding of the mechanistic reasons for failure of immunosuppressants, including individual risk/benefit assessments, may permit improved patient stratification.

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Section: Mtor Inhibitorsmentioning

confidence: 99%

Cellular Immunobiology and Molecular Mechanisms in Alloimmunity—Pathways of Immunosuppression

et al. 2023

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Umstellung auf einen mTOR-Inhibitor zur Verringerung von CMV-Rezidiven bei Nierentransplantatempfängern unter präventiver Behandlung

Kanzelmeyer

2023

Nephrologie

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Immunotherapy in hematologic malignancies: achievements, challenges and future prospects

Tang,

Huang,

Mei

et al. 2023

Sig Transduct Target Ther

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The immune-cell origin of hematologic malignancies provides a unique avenue for the understanding of both the mechanisms of immune responsiveness and immune escape, which has accelerated the progress of immunotherapy. Several categories of immunotherapies have been developed and are being further evaluated in clinical trials for the treatment of blood cancers, including stem cell transplantation, immune checkpoint inhibitors, antigen-targeted antibodies, antibody-drug conjugates, tumor vaccines, and adoptive cell therapies. These immunotherapies have shown the potential to induce long-term remission in refractory or relapsed patients and have led to a paradigm shift in cancer treatment with great clinical success. Different immunotherapeutic approaches have their advantages but also shortcomings that need to be addressed. To provide clinicians with timely information on these revolutionary therapeutic approaches, the comprehensive review provides historical perspectives on the applications and clinical considerations of the immunotherapy. Here, we first outline the recent advances that have been made in the understanding of the various categories of immunotherapies in the treatment of hematologic malignancies. We further discuss the specific mechanisms of action, summarize the clinical trials and outcomes of immunotherapies in hematologic malignancies, as well as the adverse effects and toxicity management and then provide novel insights into challenges and future directions.

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In vitro and in vivo evidence that the switch from calcineurin to mTOR inhibitors may be a strategy for immunosuppression in Epstein–Barr virus–associated post-transplant lymphoproliferative disorder

Cited by 4 publications

References 100 publications

Cellular Immunobiology and Molecular Mechanisms in Alloimmunity—Pathways of Immunosuppression

Cellular Immunobiology and Molecular Mechanisms in Alloimmunity—Pathways of Immunosuppression

Umstellung auf einen mTOR-Inhibitor zur Verringerung von CMV-Rezidiven bei Nierentransplantatempfängern unter präventiver Behandlung

Immunotherapy in hematologic malignancies: achievements, challenges and future prospects

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