Contrasting Contributions Of Tnf From Distinct Cellular Sources In Arthritis

Objectives Neutralisation of tumour necrosis factor (TNF) is widely used as a therapy for rheumatoid arthritis (RA). However, this therapy is only effective in less than a half of patients and is associated with several side effects. We hypothesised that TNF may possess non-redundant protective and immunomodulatory functions in vivo that cannot be blocked without a cost. The present work aimed to identify cellular sources of protective and pathogenic TNF, and its molecular forms during autoimmune arthritis.Methods Mice lacking TNF expression by distinct cell types, such as myeloid cells and T or B lymphocytes, were subjected to collagen-induced arthritis (CIA) and collagen antibody-induced arthritis. Mice lacking soluble TNF production were also employed. The severity and incidence of the disease, as well as humoral and cellular responses were assessed.Results Myeloid cell-derived TNF contributes to both induction and pathogenesis of autoimmune arthritis. Conversely, T cell-derived TNF is protective during the induction phase of arthritis via limiting of interleukin-12 production by dendritic cells and by subsequent control of autoreactive memory T cell development, but is dispensable during the effector phase of arthritis. B cell-derived TNF mediates severity of CIA via control of pathogenic autoantibody production.Conclusions Distinct TNF-producing cell types may modulate disease development through different mechanisms, suggesting that in arthritis TNF ablation from restricted cellular sources, such as myeloid cells, while preserving protective TNF functions from other cell types may be superior to pan-anti-TNF therapy.