B-cell development and functions and therapeutic options in adenosine deaminase–deficient patients - 01/03/14
Abstract |
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.
Le texte complet de cet article est disponible en PDF.Key words : Gene therapy, adenosine deaminase–deficient severe combined immunodeficiency, B-cell development, antibodies
Abbreviations used : ADA, ANA, APC, BAFF, BAFF-R, BCR, BM, BMT, CD40L, CFSE, ERT, FACS, FITC, GT, HSC, IVIg, LME, PB, PE, qPCR, SCID, TLR, Treg
Plan
| Supported by the Italian TELETHON foundation (TIGET Core grant A1), the European Commission: Advanced Cell–based Therapies for the treatment of Primary Immuno-Deficiency (HEALTH-F5-2010-261387, CELL-PID), and Italian Ministero della Salute (RF-2009-1485896 conv.055). J.P. acknowledges support from the UCSF CTSI, NIH NCATS 1UL1 RR024131. |
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| Disclosure of potential conflict of interest: J. Puck has received research support from the National Institutes of Health. M. van der Burg has received research support from ZonMW (Vidi grant 91712323). The rest of the authors declare that they have no relevant conflicts of interest. |
Vol 133 - N° 3
P. 799 - mars 2014 Retour au numéro
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