Comprehensive analysis of the immunomodulatory effects of rapamycin on human T cells in graft‐versus‐host disease prophylaxis

@article{Ehx2021ComprehensiveAO,
  title={Comprehensive analysis of the immunomodulatory effects of rapamycin on human T cells in graft‐versus‐host disease prophylaxis},
  author={Gr{\'e}gory Ehx and Caroline Ritacco and Muriel Hannon and Sophie Dubois and Lo{\"i}c Delens and {\'E}velyne Willems and Sophie Servais and Pierre V Drion and Yves Beguin and Fr{\'e}d{\'e}ric Baron},
  journal={American Journal of Transplantation},
  year={2021},
  volume={21}
}
Graft‐versus‐host disease (GVHD) is a major cause of toxicity after allogeneic hematopoietic cell transplantation (allo‐HCT). While rapamycin (RAPA) is commonly used in GVHD prophylaxis in combination with a calcineurin inhibitor (CNI), the understanding of its mechanism of action on human T cells is still incomplete. Here, we performed an extensive analysis of RAPA effects on human T cells in a humanized mouse model of GVHD, in ex‐vivo T cell cultures and in patients given RAPA plus tacrolimus… 

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References

SHOWING 1-10 OF 57 REFERENCES

Transient antibody targeting of CD45RC inhibits the development of graft-versus-host disease.

TLDR
The results show the potential of a prophylactic treatment with anti-human CD45RC mAbs in combination with rapamycin as a new therapy to treat aGVHD without abolishing the antitumor effect.

Rapamycin‐resistant effector T‐cell therapy

  • D. Fowler
  • Biology, Medicine
    Immunological reviews
  • 2014
TLDR
Use of ex vivo rapamycin to modulate effector T‐cell function represents a promising new approach to transplantation therapy.

Azacytidine prevents experimental xenogeneic graft-versus-host disease without abrogating graft-versus-leukemia effects

TLDR
It is demonstrated that AZA prevents xGVHD without abrogating graft-vs-leukemia effects, and could serve as basis for further studies of GVHD prevention by AZA in acute myeloid leukemia patients offered an allogeneic transplantation.

Rapamycin, not cyclosporine, permits thymic generation and peripheral preservation of CD4+CD25+FoxP3+ T cells

TLDR
It is demonstrated in a mouse model that in contrast to rapamycin, cyclosporine compromises not only the thymic generation of CD4+CD25+FoxP3+ T cells but also their homeostatic behavior in peripheral immune compartments, which has potential clinical relevance.

Mechanisms of Graft-versus-Host Disease Prevention by Post-transplantation Cyclophosphamide: An Evolving Understanding

TLDR
The history of cyclophosphamide's use in preventing murine skin allograft rejection and the evolving new understanding of the mechanisms underlying its efficacy in preventing GVHD after HCT are reviewed.

Human T cells depend on functional calcineurin, tumour necrosis factor‐α and CD80/CD86 for expansion and activation in mice

TLDR
Insight is provided into the mechanisms used by human T cells during expansion and activation in mice, and it is speculated that PBMC‐injected mice may be useful to study intrinsic human T cell functions in vivo and to test T cell‐targeting compounds.

Ex Vivo Rapamycin Generates Donor Th2 Cells That Potently Inhibit Graft-versus-Host Disease and Graft-versus-Tumor Effects via an IL-4-Dependent Mechanism1

TLDR
Ex vivo rapamycin generates enhanced donor Th2 cells for attempts to balance GVHD and GVT effects.

Inhibition of CD4+CD25+ regulatory T-cell function by calcineurin-dependent interleukin-2 production.

TLDR
The data indicate that RAPA and MMF rather than CSA preserve function of Treg cells in pathologic immune responses such as GVHD without weakening the GVT effect.

High number of memory t cells is associated with higher risk of acute graft-versus-host disease after allogeneic stem cell transplantation.

  • M. LoschiR. Porcher G. Socié
  • Biology, Medicine
    Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation
  • 2015

New perspectives on the use of mTOR inhibitors in allogeneic haematopoietic stem cell transplantation and graft-versus-host disease.

TLDR
The need for prospective registration trials to reduce off label use and improve patient safety by optimizing dosing and enhancing pharmacovigilance is stressed and the future role of mTOR inhibitors in allogeneic haematopoietic stem cell transplantation is speculated on.
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