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

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? 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-CD3? mAb administration in the RAG2 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 progenitors into RAG2 animals previously conditioned with anti-CD3? 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? mAb treatment in severe combined immunodeficiency forms characterized by poor thymus function and autoimmunity. © 2012 by The American Society of Hematology.