Anti-CD3ε 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-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, 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 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.
Milan Unit, Istituto di Ricerca Genetica e Biomedica, Consiglio Nazionale delle Ricerche, Milan, Italy.
Veronica
V
Marrella
Pietro L
PL
Poliani
Elena
E
Fontana
Anna
A
Casati
Virginia
V
Maina
Barbara
B
Cassani
Francesca
F
Ficara
Manuela
M
Cominelli
Francesca
F
Schena
Marianna
M
Paulis
Elisabetta
E
Traggiai
Paolo
P
Vezzoni
Fabio
F
Grassi
Anna
A
Villa
D000818:Animals; D000831:Animals, Newborn; D000911:Antibodies, Monoclonal / Q000494:pharmacology* / Q000627:therapeutic use*; D001327:Autoimmune Diseases / Q000517:prevention & control*; D015551:Autoimmunity / Q000187:drug effects / Q000235:genetics; D017252:CD3 Complex / Q000276:immunology*; D004268:DNA-Binding Proteins / Q000235:genetics; D004195:Disease Models, Animal; D055879:Gene Knock-In Techniques; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009929:Organ Size / Q000187:drug effects; D016511:Severe Combined Immunodeficiency / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D013950:Thymus Gland / Q000187:drug effects* / Q000276:immunology / Q000473:pathology / Q000648:ultrastructure
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; C485468:Cd3e protein, mouse; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse