B-cell development and functions and therapeutic options in adenosine deaminase-deficient patients

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• 作者：Immacolata Brigida ; PhD^a ; Aisha V. Sauer ; PhD^a ; Francesca Ferrua ; MD^c ; Stefania Giannelli ; PhD^a ; Samantha Scaramuzza ; PhD^a ; Valentina Pistoia ; MSc^a ; Maria Carmina Castiello ; PhD^a ; ^d ; Barbara H. Barendregt ; BSc^e ; Maria Pia Cicalese ; MD^c ; Miriam Casiraghi ; RCN^c ; Chiara Brombin ; PhD^f ; Jennifer Puck ; MD^g ; Klaus Mü ; ller ; MD ; PhD^h ; Lucia Dora Notarangelo ; MDⁱ ; Davide Montin ; MD^j ; Joris M. van Montfrans ; MD ; PhD^k ; Maria Grazia Roncarolo ; MD^a ; ^d ; Elisabetta Traggiai ; PhD^l ; Jacques J.M. van Dongen ; MD ; PhD^e ; Mirjam van der Burg ; PhD^e ; Alessandro Aiuti ; MD ; PhD^a ; ^b ; ^{aiuti.alessandro@hsr.it" class="auth_mail}
• 关键词：Gene therapy ; adenosine deaminase&ndash ; deficient severe combined immunodeficiency ; B-cell development ; antibodies
• 刊名：Journal of Allergy and Clinical Immunology
• 出版年：March, 2014
• 年：2014
• 卷：133
• 期：3
• 页码：799-806.e10
• 全文大小：1369 K

文摘

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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聽B-cell development and functions that are differently corrected after ERT and HSC-GT.