RESUMO
To investigate whether dysregulated selection of autoreactive marginal zone (MZ) B cells is involved in autoimmune diseases, we examined MZ B cell profile in multiple strains of mice, and found that type II collagen (CII)-reactive autoreactive CD80high MZ B cells spontaneously developed in the DBA/1, but not in C57BL/6 mice. CD80high MZ B cells that were characteristically found in DBA/1 mice expressed higher levels of TACI, SLAM3, and SLAM6 than the usual CD80low MZ B cells. Notably, the CD80high MZ B cells were more sensitive to ibrutinib, a Bruton's tyrosine kinase inhibitor, than CD80low MZ or follicular B cells and their transient depletion via intravenous injection of ibrutinib significantly delayed the induction of collagen-induced arthritis (CIA). In summary, we suggest that the positive selection of CII-reactive CD80high MZ B cells is a critical homeostatic process predisposing the DBA/1 mice to the CIA induction.
Assuntos
Artrite Experimental/imunologia , Linfócitos B/imunologia , Colágeno Tipo II/imunologia , Adenina/análogos & derivados , Tirosina Quinase da Agamaglobulinemia , Animais , Autoimunidade/imunologia , Linfócitos B/efeitos dos fármacos , Linfócitos B/metabolismo , Antígeno B7-1/metabolismo , Sobrevivência Celular/imunologia , Modelos Animais de Doenças , Ensaio de Imunoadsorção Enzimática , ELISPOT , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos DBA , Piperidinas , Inibidores de Proteínas Quinases/farmacologia , Proteínas Tirosina Quinases/antagonistas & inibidores , Pirazóis/farmacologia , Pirimidinas/farmacologia , Família de Moléculas de Sinalização da Ativação Linfocitária/metabolismo , Proteína Transmembrana Ativadora e Interagente do CAML/metabolismoRESUMO
Elotuzumab (Empliciti™) is a humanised IgG1 monoclonal antibody developed by Bristol-Myers Squibb (BMS) and AbbVie that has been approved as combination therapy with lenalidomide and dexamethasone for relapsed/refractory multiple myeloma in the US. Elotuzumab binds to the cell surface receptor signalling lymphocytic activation molecule F7 (SLAMF7), which is selectively expressed on myeloma cells and natural killer cells, leading to antibody-dependent cellular cytotoxicity and direct natural killer cell activation. In a phase III clinical trial, addition of elotuzumab to lenalidomide and dexamethasone therapy in patients with relapsed/refractory multiple myeloma was associated with a significant improvement in progression-free survival and overall response rate. This article summarizes the milestones in the development of elotuzumab leading to this first approval for relapsed/refractory multiple myeloma.