Death Receptor 5 (DR5) marks the highly pathogenic interacting GM-CSF+ T helper cells and IL-23+ macrophages rendering it as an attractive therapeutic target of autoimmunity (51.4)

Abstract

Abstract The highly pathogenic granulocyte-macrophage colony-stimulating factor (GM-CSF)+ IL-17+ CD4 T cells and IL-23+IRF5+M1 macrophages (MØ) exhibit a bidirectional interaction in autoimmunity. DR5 is a pro-apoptotic molecule upregulated by IRF5. DR5 deficient mice develop increased inflammation. We analyzed DR5 expression and apoptosis function of TRA-8, an anti-human DR5 antibody, in T cells and MØ in autoimmune conditions. Expression of DR5 was highly correlated with that of GM-CSF in CD4 T cells and that of IL-23 and IRF5 in MØ from synovia fluid or PBMC of rheumatoid arthritis and lupus subjects (p<0.01). In vitro treatment of these samples with TRA-8 for 48 hrs resulted in 23.4% and 35.9% depletion of GM-CSF+ CD4+ T cells and IL-23+ MØ, respectively. Similar DR5 expression pattern and TRA-8 depletion effects were observed in a 3kb mouse promoter/humanized DR5 Tg mouse crossed with the SHP-1- deficient viable motheaten mice which exhibit a profound activation of inflammatory MØ and Th17 cells. Three doses of TRA-8 (0.1 mg IP, weekly) lead to a 35.7% reduction of GM-CSF+ CD4+ T cells and 45.1% reduction of IL-23+IRF5+ MØ in the draining LN, 74.4% and 94.7% decrease of Csf-2 and p19 in joints, resulting in amelioration of pneumonitis and arthritis, reduction of autoantibodies, and increase of the lifespan. Our study indicated that DR5 is highly correlated with GM-CSF in CD4+ T cells and IL-23 in MØ, and demonstrated the high therapeutic efficacy of an anti-human DR5 antibody.