Omenn Syndrome (OS) is an atypical primary immunodeficiency (PID) characterized by severe autoimmunity due to activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T cell receptor (TCR) 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 RAG2(R229Q) mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator (AIRE), 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 RAG2(R229Q) progenitors into RAG2(-/-) animals previously conditioned with anti-CD3ε mAb, we detected AIRE 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-CD3εmAb treatment in severe combined immunodeficiency (SCID) forms characterized by poor thymus function and autoimmunity

Anti-CD3{epsilon} mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications / Marrella, V; Poliani, Pietro Luigi; Fontana, Elena; Casati, A; Maina, V; Cassani, B; Ficara, F; Cominelli, Manuela; Schena, F; Paulis, M; Traggiai, E; Vezzoni, P; Grassi, F; Villa, A.. - In: BLOOD. - ISSN 0006-4971. - 120:5(2012), pp. 1005-1014. [10.1182/blood-2012-01-406827]

Anti-CD3{epsilon} mAb improves thymic architecture and prevents autoimmune manifestations in a mouse model of Omenn syndrome: therapeutic implications

POLIANI, Pietro Luigi;
2012-01-01

Abstract

Omenn Syndrome (OS) is an atypical primary immunodeficiency (PID) characterized by severe autoimmunity due to activated T cells infiltrating target organs. The impaired recombinase activity in OS severely affects expression of the pre-T cell receptor (TCR) 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 RAG2(R229Q) mouse model, which closely recapitulates human OS. These animals, in spite of the inability to induce the autoimmune regulator (AIRE), 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 RAG2(R229Q) progenitors into RAG2(-/-) animals previously conditioned with anti-CD3ε mAb, we detected AIRE 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-CD3εmAb treatment in severe combined immunodeficiency (SCID) forms characterized by poor thymus function and autoimmunity
2012
thymic architecture
autoimmunity
mouse model of Omenn syndrome
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11768/162551
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