AUTHOR=Duecker Ruth , Baer Patrick C. , Buecker Aileen , Huenecke Sabine , Pfeffermann Lisa-Marie , Modlich Ute , Bakhtiar Shahrzad , Bader Peter , Zielen Stefan , Schubert Ralf TITLE=Hematopoietic Stem Cell Transplantation Restores Naïve T-Cell Populations in Atm-Deficient Mice and in Preemptively Treated Patients With Ataxia-Telangiectasia JOURNAL=Frontiers in Immunology VOLUME=10 YEAR=2019 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2019.02785 DOI=10.3389/fimmu.2019.02785 ISSN=1664-3224 ABSTRACT=

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 (CD62L^highCD44^low) and memory (CD62L^lowCD44^high) 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.