ABSTRACT
IL-1 receptor-activated kinase 1 (IRAK1) is involved in signal transduction downstream of many TLRs and the IL-1R. Its potential as a drug target for chronic inflammatory diseases is underappreciated. To study its functional role in joint inflammation, we generated a mouse model expressing a functionally inactive IRAK1 (IRAK1 kinase deficient, IRAK1KD), which also displayed reduced IRAK1 protein expression and cell type-specific deficiencies of TLR signaling. The serum transfer model of arthritis revealed a potentially novel role of IRAK1 for disease development and neutrophil chemoattraction exclusively via its activity in nonhematopoietic cells. Consistently, IRAK1KD synovial fibroblasts showed reduced secretion of neutrophil chemoattractant chemokines following stimulation with IL-1ß or human synovial fluids from patients with rheumatoid arthritis (RA) and gout. Together with patients with RA showing prominent IRAK1 expression in fibroblasts of the synovial lining, these data suggest that targeting IRAK1 may be therapeutically beneficial. As pharmacological inhibition of IRAK1 kinase activity had only mild effects on synovial fibroblasts from mice and patients with RA, targeted degradation of IRAK1 may be the preferred pharmacologic modality. Collectively, these data position IRAK1 as a central regulator of the IL-1ß-dependent local inflammatory milieu of the joints and a potential therapeutic target for inflammatory arthritis.
Subject(s)
Arthritis, Rheumatoid , Interleukin-1 Receptor-Associated Kinases , Neutrophils , Synovial Membrane , Animals , Arthritis, Rheumatoid/metabolism , Cells, Cultured , Disease Models, Animal , Interleukin-1 Receptor-Associated Kinases/metabolism , Interleukin-8/metabolism , Mice , Neutrophils/metabolism , Synovial Membrane/metabolismABSTRACT
The CD40-CD154 costimulatory pathway is essential for T cell-dependent immune responses, development of humoral memory, and antigen presenting cell function. These immune functions have been implicated in the pathology of multiple autoimmune diseases as well as allograft rejection. We have generated CFZ533, a fully human, pathway blocking anti-CD40 monoclonal antibody that has been modified with a N297A mutation to render it unable to mediate Fcγ-dependent effector functions. CFZ533 inhibited CD154-induced activation of human leukocytes in vitro, but failed to induce human leukocyte activation. Additionally, CFZ533 was unable to mediate depletion of human CD40 expressing B cells. In vivo, CFZ533 blocked primary and recall T cell-dependent antibody responses in nonhuman primates and abrogated germinal formation without depleting peripheral blood B cells. We also established a relationship between plasma concentrations of CFZ533 and CD40 pathway-relevant pharmacodynamic effects in tissue. Collectively these data support the scientific rationale and posology for clinical utility of this antibody in select autoimmune diseases and solid organ transplantation.
