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Brigida, Immacolata, PhD; Sauer, Aisha V., PhD; Ferrua, Francesca, MD; Giannelli, Stefania, PhD; Scaramuzza, Samantha, PhD; Pistoia, Valentina, MSc; Castiello, Maria Carmina, PhD; Barendregt, Barbara H., BSc; Cicalese, Maria Pia, MD; Casiraghi, Miriam, RCN; Brombin, Chiara, PhD; Puck, Jennifer, MD; Müller, Klaus, MD, PhD; Notarangelo, Lucia Dora, MD; Montin, Davide, MD; van Montfrans, Joris M., MD, PhD; Roncarolo, Maria Grazia, MD; Traggiai, Elisabetta, PhD; van Dongen, Jacques J.M., MD, PhD; van der Burg, Mirjam, PhD; Aiuti, Alessandro, MD, PhD
Journal of allergy and clinical immunology, 03/2014, Letnik: 133, Številka: 3Journal Article
Background Adenosine deaminase (ADA) deficiency causes severe cellular and humoral immune defects and dysregulation because of metabolic toxicity. Alterations in B-cell development and function have been poorly studied. Enzyme replacement therapy (ERT) and hematopoietic stem cell (HSC) gene therapy (GT) are therapeutic options for patients lacking a suitable bone marrow (BM) transplant donor. Objective We sought to study alterations in B-cell development in ADA-deficient patients and investigate the ability of ERT and HSC-GT to restore normal B-cell differentiation and function. Methods Flow cytometry was used to characterize B-cell development in BM and the periphery. The percentage of gene-corrected B cells was measured by using quantitative PCR. B cells were assessed for their capacity to proliferate and release IgM after stimulation. Results Despite the severe peripheral B-cell lymphopenia, patients with ADA-deficient severe combined immunodeficiency showed a partial block in central BM development. Treatment with ERT or HSC-GT reverted most BM alterations, but ERT led to immature B-cell expansion. In the periphery transitional B cells accumulated under ERT, and the defect in maturation persisted long-term. HSC-GT led to a progressive improvement in B-cell numbers and development, along with increased levels of gene correction. The strongest selective advantage for ADA-transduced cells occurred at the transition from immature to naive cells. B-cell proliferative responses and differentiation to immunoglobulin secreting IgM after B-cell receptor and Toll-like receptor triggering were severely impaired after ERT and improved significantly after HSC-GT. Conclusions ADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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