B-cell reconstitution after lentiviral vector-mediated gene therapy in patients with Wiskott-Aldrich syndrome

Autor: Paolo Uva, Mirjam van der Burg, Anna Villa, Immacolata Brigida, Francesca Ferrua, Lucia Piceni Sereni, Michael H. Albert, Giorgio Ottaviano, Marita Bosticardo, Alessandro Aiuti, Maria Carmina Castiello, Francesca Pala, Maria Grazia Roncarolo, Luigi Naldini, Samantha Scaramuzza
Přispěvatelé: Castiello, Mc, Scaramuzza, S, Pala, F, Ferrua, F, Uva, P, Brigida, I, Sereni, L, van der Burg, M, Ottaviano, G, Albert, Mh, Grazia Roncarolo, M, Naldini, Luigi, Aiuti, Alessandro, Villa, A, Bosticardo, M., Immunology
Rok vydání: 2015
Předmět:
Male
VCN
Vector copy number
Transplantation Conditioning
Wiskott–Aldrich syndrome
medicine.medical_treatment
Gene Expression
Hematopoietic stem cell transplantation
Bone Marrow
Transduction
Genetic
B-Cell Activating Factor
Immunology and Allergy
Child
BM
Bone marrow
B cell
Wiskott-Aldrich syndrome
Hematopoietic Stem Cell Transplantation
Hematopoietic stem cell
gene therapy
3. Good health
medicine.anatomical_structure
Child
Preschool
SDF-1α
Stromal cell–derived factor 1α
Stem cell
Wiskott-Aldrich Syndrome Protein
BAFF
B cell–activating factor
Recombinant Fusion Proteins
Genetic Vectors
Immunology
B-Lymphocyte Subsets
Immunoglobulins
Biology
primary immunodeficiency
Transplantation
Autologous
CD19
Immunophenotyping
Immune Deficiencies
Infection
and Systemic Immune Disorders
WASp
Wiskott-Aldrich syndrome protein
medicine
Humans
Progenitor cell
Autoantibodies
IVIg
Intravenous immunoglobulin
GT
Gene therapy
Gene Expression Profiling
Lentivirus
lentiviral vector
Infant
PB
Peripheral blood
Genetic Therapy
HSC
Hematopoietic stem cell
Hematopoietic Stem Cells
medicine.disease
WAS
Wiskott-Aldrich syndrome
biology.protein
Bone marrow
HD
Healthy donor
Zdroj: Journal of Allergy and Clinical Immunology, 136(3), 692-+. Mosby Inc.
The Journal of Allergy and Clinical Immunology
ISSN: 0091-6749
DOI: 10.1016/j.jaci.2015.01.035
Popis: Background Wiskott-Aldrich syndrome (WAS) is a severe X-linked immunodeficiency characterized by microthrombocytopenia, eczema, recurrent infections, and susceptibility to autoimmunity and lymphomas. Hematopoietic stem cell transplantation is the treatment of choice; however, administration of WAS gene–corrected autologous hematopoietic stem cells has been demonstrated as a feasible alternative therapeutic approach. Objective Because B-cell homeostasis is perturbed in patients with WAS and restoration of immune competence is one of the main therapeutic goals, we have evaluated reconstitution of the B-cell compartment in 4 patients who received autologous hematopoietic stem cells transduced with lentiviral vector after a reduced-intensity conditioning regimen combined with anti-CD20 administration. Methods We evaluated B-cell counts, B-cell subset distribution, B cell–activating factor and immunoglobulin levels, and autoantibody production before and after gene therapy (GT). WAS gene transfer in B cells was assessed by measuring vector copy numbers and expression of Wiskott-Aldrich syndrome protein. Results After lentiviral vector-mediated GT, the number of transduced B cells progressively increased in the peripheral blood of all patients. Lentiviral vector-transduced progenitor cells were able to repopulate the B-cell compartment with a normal distribution of B-cell subsets both in bone marrow and the periphery, showing a WAS protein expression profile similar to that of healthy donors. In addition, after GT, we observed a normalized frequency of autoimmune-associated CD19 + CD21 − CD35 − and CD21 low B cells and a reduction in B cell–activating factor levels. Immunoglobulin serum levels and autoantibody production improved in all treated patients. Conclusions We provide evidence that lentiviral vector-mediated GT induces transgene expression in the B-cell compartment, resulting in ameliorated B-cell development and functionality and contributing to immunologic improvement in patients with WAS.
Databáze: OpenAIRE
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