Recombination-activating gene 1 (Rag1)–deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune.

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Recombination-activating gene 1 (Rag1)–deficient mice with severe combined immunodeficiency treated with lentiviral gene therapy demonstrate autoimmune Omenn- like syndrome Niek P. van Til, PhD, Roya Sarwari, MSc, Trudi P. Visser, BSc, Julia Hauer, MD, Chantal Lagresle-Peyrou, PhD, Guus van der Velden, BSc, Vidyasagar Malshetty, PhD, Patricia Cortes, PhD, Arnaud Jollet, PhD, Olivier Danos, PhD, Barbara Cassani, PhD, Fang Zhang, PhD, Adrian J. Thrasher, MD, PhD, Elena Fontana, PhD, Pietro L. Poliani, MD, PhD, Marina Cavazzana, MD, PhD, Monique M.A. Verstegen, PhD, Anna Villa, MD, PhD, Gerard Wagemaker, PhD Journal of Allergy and Clinical Immunology Volume 133, Issue 4, Pages 1116-1123 (April 2014) DOI: 10.1016/j.jaci.2013.10.009 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 T-cell development. A, Histologic features of the thymus in different experimental settings, highlighting CMD (hematoxylin and eosin [H&E] and TdT, left panels) or mTECs (AIRE+) and Treg cells (Foxp3+, right panels). Rag1−/− mice lack distinct CMD, mTECs, and Treg cells compared with WT and WT Tx–treated mice. Rag1−/− gene therapy–treated mice partially restored the presence of CMD, mTECs, and Treg cells. B, TCR repertoire analysis on spleen cDNA. SF-RAG1co and RAG1p-RAG1co indicate mice treated with the SF promoter and RAG1 promoter, respectively. Journal of Allergy and Clinical Immunology 2014 133, 1116-1123DOI: (10.1016/j.jaci.2013.10.009) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Autoimmune manifestations in Rag1−/− gene therapy–treated mice. A, Gene therapy (GT)–treated Rag1−/− mice had autoimmune reactions, with rashes and wasting from 2 months onward. Arrows indicate rashes (left) and disfigured earlobes (right). B, This resulted in reduced survival (WT Tx–treated mice, n = 8; SF-treated mice, n = 25; UP-treated mice, n = 24; and CP-treated mice, n = 27). C, Hematoxylin and eosin staining, with arrows indicating the cellular infiltrates. D, Percentage of gene therapy–treated mice with cellular tissue infiltrates. E and F, Percentages of CD4+ cells of total CD4+ and CD8+ T cells (Fig 2, E) and activated peripheral blood CD4+ and CD8+ T cells (Fig 2, F). G-J, Foxp3+ cells within the CD3+CD4+ population (Fig 2, G) were determined in peripheral blood 3 months after transplantation, increased IgE levels (Fig 2, H), anti-dsDNA IgM (GT-treated mice, n = 7; Rag1−/− mice, n = 1; WT Tx mice, n = 2; Fig 2, I), and IgG levels (GT-treated mice, n = 9; Rag1−/− mice, n = 1; WT Tx mice, n = 2; Fig 2, J). K, Increased BAFF levels in Rag1−/− and gene therapy–treated mice. Samples were obtained from 3 to 12 months after transplantation. *P < .05, **P < .01, and ***P < .001. Journal of Allergy and Clinical Immunology 2014 133, 1116-1123DOI: (10.1016/j.jaci.2013.10.009) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Journal of Allergy and Clinical Immunology 2014 133, 1116-1123DOI: (10.1016/j.jaci.2013.10.009) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Journal of Allergy and Clinical Immunology 2014 133, 1116-1123DOI: (10.1016/j.jaci.2013.10.009) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 Journal of Allergy and Clinical Immunology 2014 133, 1116-1123DOI: (10.1016/j.jaci.2013.10.009) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 Journal of Allergy and Clinical Immunology 2014 133, 1116-1123DOI: (10.1016/j.jaci.2013.10.009) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions