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

作者：Marrella Veronica; Poliani Pietro L; Fontana Elena; Casati Anna; Maina Virginia; Cassani Barbara; Ficara Francesca; Cominelli Manuela; Schena Francesca; Paulis Marianna; Traggiai Elisabetta; Vezzoni Paolo; Grassi Fabio; Villa Anna^*

来源：Blood, 2012, 120(5): 1005-1014.

DOI：10.1182/blood-2012-01-406827

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-CD3 epsilon 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-CD epsilon 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, 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-CD3 epsilon 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-CD3 epsilon mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity. (Blood. 2012;120(5):1005-1014)

• 出版日期2012-8-2