B-cell reconstitution after lentiviral vector–mediated gene therapy in patients with Wiskott-Aldrich syndrome Maria Carmina Castiello, PhD, Samantha.

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Presentation transcript:

B-cell reconstitution after lentiviral vector–mediated gene therapy in patients with Wiskott-Aldrich syndrome Maria Carmina Castiello, PhD, Samantha Scaramuzza, PhD, Francesca Pala, MS, Francesca Ferrua, MD, Paolo Uva, PhD, Immacolata Brigida, PhD, Lucia Sereni, MS, Mirjam van der Burg, PhD, Giorgio Ottaviano, MD, Michael H. Albert, MD, Maria Grazia Roncarolo, MD, Luigi Naldini, MD, PhD, Alessandro Aiuti, MD, PhD, Anna Villa, MD, Marita Bosticardo, PhD Journal of Allergy and Clinical Immunology Volume 136, Issue 3, Pages 692-702.e2 (September 2015) DOI: 10.1016/j.jaci.2015.01.035 Copyright © 2015 The Authors Terms and Conditions

Fig 1 WASp expression in B cells after GT. WASp-expressing B cells in PB (A) and BM (B). Asterisks define the difference between pre-GT and post-GT samples. ***P ≤ .0005, **P ≤ .005, and *P < .05. Journal of Allergy and Clinical Immunology 2015 136, 692-702.e2DOI: (10.1016/j.jaci.2015.01.035) Copyright © 2015 The Authors Terms and Conditions

Fig 2 Expression of WASp among B-cell populations. A, WASp mean fluorescence intensity (MFI) in PB B-cell subsets of pediatric HDs (pHDs). Bars indicate means and SEMs. **P < .005 and *P < .05. B, WASp MFI in B-cell subsets of treated patients is reported in individual graphs, with the time of the analysis indicated as months after GT between parentheses. All MFI values are normalized to the MFI of the negative control stained only with secondary antibody. Journal of Allergy and Clinical Immunology 2015 136, 692-702.e2DOI: (10.1016/j.jaci.2015.01.035) Copyright © 2015 The Authors Terms and Conditions

Fig 3 B-cell differentiation and in vitro migratory ability of B cells after GT. A, Proportion of pre-B-II large (CD10intCD20int), pre-B-II small (CD10intCD20−), and immature B cells (CD10intCD20+) determined on CD34−CD19+ cells and calculated on total BM precursor B cells, excluding recirculating mature B cells (CD10−CD20+). B-E, Proportion of B-cell subsets in PB (gated on CD19+; HD <3 years, n = 26; HD 3-12 years, n = 20). Box plots show medians, 25th and 75th percentiles, minimums, and maximums. Asterisks above horizontal lines indicate significant differences between patients with WAS and HDs. Asterisks without lines define differences between pre-GT and post-GT samples. **P ≤ .005 and *P < .05. F-H,In vitro migration of CD20+ cells isolated from age-matched HDs (white bars, n = 10) and patients with WAS before (black bars) and after (gray bars) GT (n = 2, Pt2 and Pt3) in the presence of SDF-1α (+) or medium alone (−). Percentages of migrated CD19+ cells (Fig 3, F), transitional cells (Fig 3, G), and mature naive B cells (Fig 3, H) were determined by using flow cytometric analysis. Journal of Allergy and Clinical Immunology 2015 136, 692-702.e2DOI: (10.1016/j.jaci.2015.01.035) Copyright © 2015 The Authors Terms and Conditions

Fig 4 Normalization of phenotypic alterations of B cells from patients with WAS and BAFF levels after GT. A and B, CD21 and CD35 expression on CD19+ cells in patients with WAS before and after GT and in HDs (n = 16). C and D, CD21low B cells in patients with WAS before and after GT and in HDs (n = 45). E, BAFF levels before and after GT and in HDs (n = 24). Asterisks above horizontal lines indicate significant differences between patients with WAS and HDs. Asterisks without lines define differences between pre-GT and post-GT samples. **P ≤ .005 and *P < .05. Journal of Allergy and Clinical Immunology 2015 136, 692-702.e2DOI: (10.1016/j.jaci.2015.01.035) Copyright © 2015 The Authors Terms and Conditions

Fig 5 Decreased autoantibody production in patients with WAS after GT. IgG reactivities against 123 antigens were tested by using an autoantigen array. P values resulting from paired t tests of differential expression between pre-GT and matched post-GT samples are shown in the left panel. Blue and green bars refer to autoantibodies with higher expression in pre-GT and post-GT samples, respectively. The vertical line indicates a P value of less than .05. Data are represented as a heat map (right panel), with values mean centered and colors scaled from −2 to +2 SD. The legend shows z scores. Journal of Allergy and Clinical Immunology 2015 136, 692-702.e2DOI: (10.1016/j.jaci.2015.01.035) Copyright © 2015 The Authors Terms and Conditions

Fig E1 WASp expression and transduction levels after GT. A, Histogram plots showing WASp expression measured by means of cytofluorimetric analysis in different hematopoietic cells of Pt4 before and 2 years after GT and an HD. Negative controls are shown as gray histograms. B and C, Transduction levels are shown in the graph as VCNs per genome evaluated by means of quantitative PCR at different time points after GT in B cells purified either from PB (Fig E1, B) or BM (Fig E1, C). Journal of Allergy and Clinical Immunology 2015 136, 692-702.e2DOI: (10.1016/j.jaci.2015.01.035) Copyright © 2015 The Authors Terms and Conditions