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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2019.01879

NIH-defined cGVHD in pediatric HSCT patients correlates with parameters of long-term immune reconstitution

 Anita Lawitschka1, 2*, Ece D. Gueclue1, Angela Januszko1, Ulrike Koermoeczi3, Arno Rottal3, Gerhard Fritsch1,  Dorothea Bauer1,  Christina Peters1,  Hildegard T. Greinix4,  Winfried F. Pickl3 and  Zoya Kuzmina1, 2
  • 1St. Anna Children’s Cancer Research Institute (CCRI), Austria
  • 2Medical University of Vienna, Austria
  • 3Institute of Immunology, Center for Pathophysiology, Infectiology and Immunology, Medical University of Vienna, Austria
  • 4Division of Hematology, Department of Internal Medicine, Medical University of Graz, Austria

Recent data revealed the importance of immune reconstitution (IR) for the evaluation of possible biomarkers in NIH-defined cGVHD and its clinical aspects. In this large pediatric study (n=146) we have analyzed whether cellular and humoral parameters of IR in the long-term follow-up (FU) with a special emphasis on B-cell reconstitution correlate with NIH-defined cGVHD criteria. HYPOTHESIS: We were especially interested, whether meaningful cGVHD biomarkers could be defined in a large pediatric cohort. We here demonstrate for the first time in a highly homogenous pediatric patient cohort that both cGVHD (n=38) and its activity were associated with the perturbation of the B-cell compartment including low frequencies of CD19+CD27+ memory B-cells and increased frequencies of circulating CD19+CD21low B-cells, a well-known hyperactivated B-cell subset frequently found elevated in chronic infection and autoimmunity. Notably, resolution of cGVHD correlated with expansion of CD19+CD27+ memory B-cells and normalization of CD19+CD21low B-cell frequencies. Moreover, we found that the severity of cGVHD had an impact on parameters of IR and that severe cGVHD was associated with increased CD19+CD21lowB-cell frequencies.
When comparing the clinical characteristics of the active and non active cGVHD patients (in detail at time of analyses) we found a correlation between activity and a higher overall severity of cGVHD, which means that in the active cGVHD patient group were more patients with a higher disease burden of cGVHD - despite similar risk profiles for cGVHD.
Our data also provide solid evidence that the time point of analysis regarding both HSCT-FU and cGVHD disease activity may be of critical importance for the detailed investigation of pediatric cohorts. Finally, we have proven that the differences in risk factors and patterns of IR, with cGVHD as its main confounding factor, between malignant and non-malignant diseases, are important to be considered in future studies aiming at identification of novel biomarkers for cGVHD.

Keywords: cGVHD, Pediatric HSCT, long-term immune reconstitution, B cells, biomarker

Received: 10 Apr 2019; Accepted: 24 Jul 2019.

Edited by:

Jacopo Peccatori, San Raffaele Hospital (IRCCS), Italy

Reviewed by:

Luiza Guilherme, University of São Paulo, Brazil
Maria-Teresa Lupo-Stanghellini, San Raffaele Hospital (IRCCS), Italy  

Copyright: © 2019 Lawitschka, Gueclue, Januszko, Koermoeczi, Rottal, Fritsch, Bauer, Peters, Greinix, Pickl and Kuzmina. 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.

* Correspondence: Dr. Anita Lawitschka, St. Anna Children’s Cancer Research Institute (CCRI), Vienna, 1090, Vienna, Austria,