Hematopoietic stem cell transplantation restores naïve t-cell populations in atm-deficient mice and in preemptively treated patients with ataxia-telangiectasia

  • Background: Ataxia-telangiectasia (A-T) is a multisystem disorder with progressive cerebellar ataxia, immunodeficiency, chromosomal instability, and increased cancer susceptibility. Cellular immunodeficiency is based on naïve CD4+ and CD8+ T-cell lymphopenia. Hematopoietic stem cell transplantation (HSCT) offers a potential to cure immunodeficiency and cancer due to restoration of the lymphopoietic system. The aim of this investigation was to analyze the effect of HSCT on naïve CD4+ as well as CD8+ T-cell numbers in A-T. Methods: We analyzed total numbers of peripheral naïve (CD45RA+CD62L+) and memory (CD45RO+CD62L−) CD4+ and CD8+ T-cells of 32 A-T patients. Naïve (CD62LhighCD44low) and memory (CD62LlowCD44high) T-cells were also measured in Atm-deficient mice before and after HSCT with GFP-expressing bone marrow derived hematopoietic stem cells. In addition, we analyzed T-cells in the peripheral blood of two A-T patients after HLA-identic allogeneic HSCT. Results: Like in humans, naïve CD4+ as well as naïve CD8+ lymphocytes were decreased in Atm-deficient mice. HSCT significantly inhibited thymic lymphomas and increased survival time in these animals. Donor cell chimerism increased up to more than 50% 6 months after HSCT accompanied by a significant increase of naïve CD4 and CD8 T-cell subpopulations, but not of memory T-cells. This finding was also identified in the blood of the A-T patients after HSCT. Conclusion: HSCT seems to be a feasible strategy to overcome immunodeficiency and might be a conceivable strategy to avoid T-cell driven cancer in A-T at higher risk for malignancy. Naïve CD4 and CD8 T-cells counts are suitable markers for monitoring immune reconstitution post-HSCT. However, risks and benefits of HSCT in A-T have to be properly weighted.

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Author:Ruth Pia DückerORCiDGND, Patrick C. BaerORCiDGND, Aileen Bücker, Sabine HüneckeGND, Lisa-Marie PfeffermannGND, Ute Modlich, Shahrzad BakhtiarGND, Peter BaderORCiDGND, Stefan ZielenORCiDGND, Ralf SchubertORCiDGND
Pubmed Id:https://pubmed.ncbi.nlm.nih.gov/31849966
Parent Title (English):Frontiers in immunology
Publisher:Frontiers Media
Place of publication:Lausanne
Contributor(s):Sudhir Gupta
Document Type:Article
Year of Completion:2019
Date of first Publication:2019/11/27
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/02/03
Tag:ATM; CD45RA naïve lymphocytes; ataxia telangiectasia; immune deficiency; stem cell transplantation
Issue:Art. 2785
Page Number:10
First Page:1
Last Page:10
Copyright © 2019 Duecker, Baer, Buecker, Huenecke, Pfeffermann, Modlich, Bakhtiar, Bader, Zielen and Schubert. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
Institutes:Medizin / Medizin
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0