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Rheumatoid arthritis (RA) affects about 1% of the population and is characterized by joint pain and tissue destruction, and in seropositive cases, is characterized by the presence of antibodies against post-translationally modified proteins and IgM (rheumatoid factor)
.
Cells involved in RA inflammation include not only lymphocytes, but also neutrophils, macrophages, osteoclasts, and synovial fibroblasts
rheumatoid arthritis
Systemic lupus erythematosus (SLE) is also a systemic disease mediated by autoantibodies, characterized by tissue inflammation and damage to multiple organ systems including joints, skin, and kidneys
.
Defects in the clearance of apoptotic and necrotic cells have been demonstrated, allowing autoantibodies to acquire nuclear antigens
immunity
Interleukin 1 receptor-activated kinase 4 (IRAK4) is a central regulator of innate immune responses
.
IRAK4 induces signaling through IRAK1 and IRAK2 by binding to the adaptor protein myeloid differentiation factor 88 (MyD88), thereby transmitting signals from T cell-like receptors (TLRs) and interleukin 1 receptor (IL-1R)
We have recently developed potent and selective IRAK4 inhibitors with little activity on IRAK1
.
In the current study, we demonstrate that PF-06650833, a small-molecule inhibitor of IRAK4, reduces responses to disease-related stimuli in human cells as well as in animal models of rheumatoid arthritis and systemic lupus erythematosus
Objective: To investigate the role of PF-06650833, a highly active and selective small molecule inhibitor of interleukin 1-related kinase 4 (IRAK4), in autoimmune pathophysiology
.
Methods to simulate the pathophysiology of rheumatoid arthritis (RA) inflammation in vitro include: 1) primary human macrophages stimulated by anti-citrullinated protein antibody immune complex (IC); 2) Toll-like receptor (TLR) ligand stimulation RA fibroblast-like synoviocytes (FLS) culture; 3) in vitro culture of primary cells exposed to inflammatory stimuli
.
Modeling the pathophysiological changes of neutrophils, dendritic cells, B cells, and peripheral blood mononuclear cells in systemic lupus erythematosus (SLE) patients stimulated by TLR ligands and IC in SLE patients
In vitro, PF-06650833 inhibits the inflammatory response of primary human cells to physiologically relevant stimuli produced in plasma from patients with rheumatoid arthritis and systemic lupus erythematosus
.
In vivo, PF-06650833 reduced circulating autoantibody levels in Pristane-induced and MRL/lpr lupus mouse models and protected protection against CIA in rats
These data demonstrate that inhibition of IRAK4 kinase activity reduces levels of inflammatory markers in humans and provide confidence in the rationale for the clinical development of IRAK4 inhibitors for rheumatic indications
Source: Aaron Winkler, Weiyong Sun, Saurav DeThe , Interleukin- 1 Receptor– Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial, Arthritis & Rheumatology.
Aaron Winkler, Weiyong Sun, Saurav DeThe , Interleukin- 1 Receptor– Associated Kinase 4 Inhibitor PF-06650833 Blocks Inflammation in Preclinical Models of Rheumatic Disease and in Humans Enrolled in a Randomized Clinical Trial, Arthritis & Rheumatology.
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