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Journal of Hematology & Oncology
Published in: Journal of Hematology & Oncology 1/2017

Open Access 01-12-2017 | Research

Interleukin-21 promotes thymopoiesis recovery following hematopoietic stem cell transplantation

Authors: Aurélie Tormo, Fatemeh Khodayarian, Yun Cui, Edouard Al-Chami, Reem Kanjarawi, Beatriz Noé, Huijie Wang, Moutih Rafei

Published in: Journal of Hematology & Oncology | Issue 1/2017

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Abstract

Background

Impaired T cell reconstitution remains a major deterrent in the field of bone marrow (BM) transplantation (BMT) due to pre-conditioning-induced damages inflicted to the thymi of recipient hosts. Given the previously reported thymo-stimulatory property of interleukin (IL)-21, we reasoned that its use post-BMT could have a profound effect on de novo T cell development.

Methods

To evaluate the effect of IL-21 on de novo T cell development in vivo, BM derived from RAG2p-GFP mice was transplanted into LP/J mice. Lymphocyte reconstitution was first assessed using a hematological analyzer and a flow cytometer on collected blood samples. Detailed flow cytometry analysis was then performed on the BM, thymus, and spleen of transplanted animals. Finally, the effect of human IL-21 on thymopoiesis was validated in humanized mice.

Results

Using a major histocompatibility complex (MHC)-matched allogeneic BMT model, we found that IL-21 administration improves immune reconstitution by triggering the proliferation of BM Lin−Sca1+c-kit+ (LSK) subsets. The pharmacological effect of IL-21 also culminates in the recovery of both hematopoietic (thymocytes) and non-hematopoietic (stromal) cells within the thymi of IL-21-treated recipient animals. Although T cells derived from all transplanted groups proliferate, secrete various cytokines, and express granzyme B similarly in response to T cell receptor (TCR) stimulation, full regeneration of peripheral naïve CD4+ and CD8+ T cells and normal TCRvβ distribution could only be detected in IL-21-treated recipient mice. Astonishingly, none of the recipient mice who underwent IL-21 treatment developed graft-versus-host disease (GVHD) in the MHC-matched allogeneic setting while the graft-versus-tumor (GVT) effect was strongly retained. Inhibition of GVHD onset could also be attributed to the enhanced generation of regulatory B cells (B10) observed in the IL-21, but not PBS, recipient mice. We also tested the thymopoiesis-stimulating property of human IL-21 in NSG mice transplanted with cord blood (CB) and found significant improvement in de novo human CD3+ T cell development.

Conclusions

In sum, our study indicates that IL-21 represents a new class of unforeseen thymopoietin capable of restoring thymic function following BMT.
Appendix
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Metadata
Title
Interleukin-21 promotes thymopoiesis recovery following hematopoietic stem cell transplantation
Authors
Aurélie Tormo
Fatemeh Khodayarian
Yun Cui
Edouard Al-Chami
Reem Kanjarawi
Beatriz Noé
Huijie Wang
Moutih Rafei
Publication date
01-12-2017
Publisher
BioMed Central
Published in
Journal of Hematology & Oncology / Issue 1/2017
Electronic ISSN: 1756-8722
DOI
https://doi.org/10.1186/s13045-017-0490-3

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Treatment of localized gastric and gastroesophageal adenocarcinoma: the role of accurate staging and preoperative therapy

Rapid communication

Incorporation of a hinge domain improves the expansion of chimeric antigen receptor T cells

Research

Thrombospondin-2 promotes prostate cancer bone metastasis by the up-regulation of matrix metalloproteinase-2 through down-regulating miR-376c expression

Review

The crosstalk between autophagic and endo-/exosomal pathways in antigen processing for MHC presentation in anticancer T cell immune responses
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

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Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
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