Therapeutic antibodies that target inflammatory cytokines in autoimmune diseases

Abstract

Inflammatory cytokines are key regulators of immune responses. Persistent and excessive production of inflammatory cytokines underscores the development of autoimmune diseases. Therefore, neutralizing inflammatory cytokines or antagonizing their receptor function is considered as a useful therapeutic strategy to treat autoimmune diseases. To achieve the success of such a strategy, understanding of the complex actions of these cytokines and cytokine networks is required. In this review we focus on four inflammatory cytokines--tumor necrosis factor α (TNFα), interleukin-6 (IL-6), IL-23 and IL-17--and dissect how the dysregulation of these cytokines regulates autoimmune diseases. On the basis of pre-clinical and clinical data, we specifically discuss the therapeutic rationale for targeting these cytokines and describe the potential adverse effects.

Keywords: IL-17; IL-23; IL-6; TNFα; Th17; autoimmune diseases.

Fig. 1.

The inflammatory circuit of TNFα, IL-6, IL-23 and IL-17 in the pathogenesis of psoriasis. The persistent production of TNFα and other inflammatory cytokines activates DCs to produce IL-23, and IL-6, together with TGFβ, induces naive CD4⁺ T cells to differentiate into IL-17-producing T cells. IL-23 directly activates macrophages (Mϕ) to produce inflammatory cytokines such as TNFα and IL-1; IL-23 also promotes T_h17 cell differentiation into highly pathogenic T_h17 cells and activates γδ T cells, both cell types constantly produce IL-17A, IL-17F, IL-6 and TNFα. IL-17 activates epithelial cells (e.g. keratinocytes) and endothelial cells to produce a variety of inflammatory cytokines, chemokines and AMPs. The inflammatory cytokines induced by IL-17 promote the expansion of IL-17-producing γδ T or T_h17 cells whereas the chemokines recruit more neutrophils or IL-17-producing T cells to sites of inflammation in the skin, which produces a positive feed-forward mechanism and further amplifies local inflammatory responses to incite cytokine storms in psoriasis.