Anti-CD3{epsilon} 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 (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