Anti-CD3ε mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications
- Marrella, Veronica Humanitas Clinical and Research Center, Rozzano, Italy;
- Poliani, Pietro L. Department of Pathology, University of Brescia, Brescia, Italy;
- Fontana, Elena Department of Pathology, University of Brescia, Brescia, Italy;
- Casati, Anna Institute for Research in Biomedicine, Bellinzona, Switzerland;
- Maina, Virginia Humanitas Clinical and Research Center, Rozzano, Italy;
- Cassani, Barbara Humanitas Clinical and Research Center, Rozzano, Italy;
- Ficara, Francesca Humanitas Clinical and Research Center, Rozzano, Italy;
- Cominelli, Manuela Department of Pathology, University of Brescia, Brescia, Italy;
- Schena, Francesca Laboratory of Immunology and Rheumatic Disease, Istituto Giannina Gaslini, Genoa, Italy;
- Paulis, Marianna Humanitas Clinical and Research Center, Rozzano, Italy;
- Traggiai, Elisabetta Laboratory of Immunology and Rheumatic Disease, Istituto Giannina Gaslini, Genoa, Italy;
- Vezzoni, Paolo Humanitas Clinical and Research Center, Rozzano, Italy;
- Grassi, Fabio Dipartimento di Biologia e Genetica per le Scienze Mediche, Università di Milano, Milan, Italy; and
- Villa, Anna Telethon Institute for Gene Therapy, Hospital San Raffaele, Milan, Italy
Published in:
- Blood. - American Society of Hematology. - 2012, vol. 120, no. 5, p. 1005-1014
English
Abstract
Omenn syndrome (OS) is an atypical primary immunodeficiency characterized by severe autoimmunity because of activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T-cell receptor complex in immature thymocytes, which is crucial for an efficient development of the thymic epithelial component. Anti-CD3ε monoclonal antibody (mAb) treatment in RAG2−/− mice was previously shown to mimic pre-TCR signaling promoting thymic expansion. Here we show the effect of anti-CD3ε mAb administration in the RAG2R229Q mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator, displayed a significant amelioration in thymic epithelial compartment and an important reduction of peripheral T-cell activation and tissue infiltration. Furthermore, by injecting a high number of RAG2R229Q progenitors into RAG2−/− animals previously conditioned with anti-CD3ε mAb, we detected autoimmune regulator expression together with the absence of peripheral immunopathology. These observations indicate that improving epithelial thymic function might ameliorate the detrimental behavior of the cell-autonomous RAG defect. Our data provide important therapeutic proof of concept for future clinical applications of anti-CD3ε mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity.
- Language
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- English
- Open access status
- bronze
- Identifiers
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- DOI 10.1182/blood-2012-01-406827
- ISSN 0006-4971
- Persistent URL
- https://sonar.ch/global/documents/139653
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