Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2021 Aug;21(8):2662-2674.
doi: 10.1111/ajt.16505. Epub 2021 Feb 19.

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

Grégory Ehx  1 , Caroline Ritacco  1 , Muriel Hannon  1 , Sophie Dubois  1 , Loic Delens  1 , Evelyne Willems  2 , Sophie Servais  1   2 , Pierre Drion  3 , Yves Beguin  1   2 , Frédéric Baron  1   2
Affiliations
Free article

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

Grégory Ehx et al. Am J Transplant. 2021 Aug.
Free article

Abstract

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 as GVHD prophylaxis after nonmyeloablative allo-HCT. We demonstrate that RAPA mitigates GVHD by decreasing T cell engraftment and differentiation, inhibiting CD8+ T cell activation and increasing the long-term IL-2 secretion, thereby supporting regulatory T cell (Treg) proliferation. In contrast, graft-versus-leukemia effects were not abrogated, as RAPA-treated T cells had increased resistance to apoptosis and retained their effector function and proliferative capacity upon re-stimulation. Importantly, we found that RAPA impact on Treg and CD8+ T cells was closely dependent upon IL-2 signaling and that therapeutic options interfering with IL-2, such as calcineurin inhibitors, antagonize the IL-2-dependent promotion of Treg mediated by RAPA. Our results suggest that RAPA immunological efficacy could be improved in combination with drugs having possible synergistic effects such as the hypomethylating agent 5-azacytidine.

Keywords: T cell biology; basic (laboratory) research/science; bone marrow/hematopoietic stem cell transplantation; flow cytometry; graft-versus-host disease (GVHD); graft-versus-leukemia (GVL)/graft versus tumor; hematology / oncology; immunosuppressant - mechanistic target of rapamycin: sirolimus; immunosuppression/immune modulation; translational research/science.

PubMed Disclaimer

References

REFERENCES

    1. Baron F, Storb R. Allogeneic hematopoietic cell transplantation as treatment for hematological malignancies: a review. Springer Semin Immunopathol. 2004;26(1-2):71-94.
    1. Zeiser R, Socie G, Blazar BR. Pathogenesis of acute graft-versus-host disease: from intestinal microbiota alterations to donor T cell activation. Br J Haematol. 2016;175(2):191-207.
    1. Storb R, Antin JH, Cutler C. Should methotrexate plus calcineurin inhibitors be considered standard of care for prophylaxis of acute graft-versus-host disease? Biol Blood Marrow Transplant. 2010;16(1 Suppl):S18-S27.
    1. Bacigalupo A, Vitale V, Corvò R, et al. The combined effect of total body irradiation (TBI) and cyclosporin A (CyA) on the risk of relapse in patients with acute myeloid leukaemia undergoing allogeneic bone marrow transplantation. Br J Haematol. 2000;108(1):99-104.
    1. Craddock C, Nagra S, Peniket A, et al. Factors predicting long-term survival after T-cell depleted reduced intensity allogeneic stem cell transplantation for acute myeloid leukemia. Haematologica. 2010;95(6):989-995.

Publication types

MeSH terms