1. B-cell development and functions and therapeutic options in adenosine deaminase–deficient patients
- Author
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Brigida, Immacolata, Sauer, Aisha V, Ferrua, Francesca, Giannelli, Stefania, Scaramuzza, Samantha, Pistoia, Valentina, Castiello, Maria Carmina, Barendregt, Barbara H, Cicalese, Maria Pia, Casiraghi, Miriam, Brombin, Chiara, Puck, Jennifer, Müller, Klaus, Notarangelo, Lucia Dora, Montin, Davide, van Montfrans, Joris M, Roncarolo, Maria Grazia, Traggiai, Elisabetta, van Dongen, Jacques JM, van der Burg, Mirjam, and Aiuti, Alessandro
- Subjects
Regenerative Medicine ,Genetics ,Pediatric ,Stem Cell Research ,Transplantation ,Stem Cell Research - Nonembryonic - Non-Human ,Gene Therapy ,2.1 Biological and endogenous factors ,5.2 Cellular and gene therapies ,Aetiology ,Development of treatments and therapeutic interventions ,Inflammatory and immune system ,Adenosine Deaminase ,Adolescent ,B-Cell Activating Factor ,B-Lymphocytes ,Child ,Child ,Preschool ,Enzyme Replacement Therapy ,Genetic Therapy ,Hematopoietic Stem Cell Transplantation ,Humans ,Infant ,Gene therapy ,adenosine deaminase-deficient severe combined immunodeficiency ,B-cell development ,antibodies ,adenosine deaminase–deficient severe combined immunodeficiency ,Immunology ,Allergy - Abstract
BackgroundAdenosine 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.ObjectiveWe 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.MethodsFlow 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.ResultsDespite 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.ConclusionsADA-deficient patients show specific defects in B-cell development and functions that are differently corrected after ERT and HSC-GT.
- Published
- 2014