Th17 cells and IL-17 A—Focus on immunopathogenesis and immunotherapeutics,☆☆,

https://doi.org/10.1016/j.semarthrit.2013.04.006Get rights and content

abstract

Importance

Accumulating evidence suggests that IL-17 A has broad pathogenic roles in multiple autoimmune and immune-mediated inflammatory diseases, including psoriasis and rheumatoid arthritis (RA). The development of new therapies that inhibit IL-17 pathway signaling is of clinical significance.

Objectives

This review aims to summarize the current preclinical evidence on the role of Th17 cells and IL-17 and related cytokines in immune-mediated disease pathophysiology, with a focus on psoriasis and rheumatoid arthritis, as well as to summarize recent clinical trials in these indications with newly developed IL-17 pathway inhibitors.

Methods

A systematic literature search was conducted of PubMed using relevant keywords. Studies were assessed according to recent relevance to IL-17-mediated pathophysiology and clinical IL-17 inhibition. Experimental animal models of autoimmune disease and clinical studies that focused on IL-17 pathway inhibitors were included.

Results

Preclinical studies suggest that IL-17A is an attractive therapeutic target. Several IL-17A inhibitors have advanced into clinical trials, including the anti-IL-17A monoclonal antibodies, secukinumab and ixekizumab, and the anti-17RA monoclonal antibody brodalumab. Each has shown variable and sometimes favorable results in proof-of-concept and phase II clinical trials and is currently undergoing further clinical evaluation in a range of immune-mediated diseases.

Conclusion

Targeting the IL-17 pathway shows promise as strategy to treat immune-mediated diseases ranging from skin to joints.

Introduction

Interleukin (IL)-17-producing helper T (Th17) cells are broadly associated with development of a large number of autoimmune and immunoinflammatory diseases, including psoriasis and rheumatoid arthritis (RA) [1], [2]. Our understanding of the roles of Th17 cells and their cytokine/chemokine products, particularly IL-17A, continues to evolve at a rapid pace [3], [4]. The identification of immunotherapeutics that target cytokines involved in Th17 cell differentiation and effector function has provided important insights into the immunopathogenesis of autoimmune diseases. IL-17A is now considered to be a key driver of chronic inflammatory reactions in multiple immune-mediated diseases, and blocking this cytokine is seen as a potentially viable approach for treating these disorders while preserving key functions of the adaptive immune system [4], [5].

Section snippets

Th cell differentiation

Cytokines produced by cells of the innate immune system direct the differentiation of naïve CD4+ T cells into effector T-helper cells. This process was initially classified according to a Th1–Th2 paradigm, in which IL-12 (with IL-18) drives differentiation via the Th1 pathway and IL-4 (with IL-33) drives differentiation via the Th2 pathway [6]. These T-helper subsets produce different cytokines that act on cellular targets to mediate host defenses against specific types of pathogenic organisms.

IL-17A: A proinflammatory cytokine

Initially termed cytotoxic T-lymphocyte antigen 8 (CTLA8), IL-17A was first identified from a clone of activated murine T cells in 1993 [26], and subsequently cloned from a human CD4+ T-cell library [27]. The human sequence predicted a glycoprotein with 155 amino acids and 63% homology to murine CTLA8 [27]. IL-17A is now recognized as a member of a unique cytokine family that includes five other members (designated IL-17B–IL-17F) [28], [29]. IL-17A and IL-17F are secreted by Th17 cells as

IL-17A receptor biology

The IL-17 receptor family consists of five subunits (termed IL-17RA–IL-17RE), which contain a single transmembrane domain and certain conserved structural motifs, including an extracellular fibronectin III-like domain and a cytoplasmic SEF/IL-17R (SEFIR) domain [28], [29]. Although the SEFIR domain is highly homologous with Toll/IL-1R (TIR) domains found in receptors involved in innate immune responses, it lacks motifs necessary for interacting with adapter proteins involved in TIR-mediated

Biology of IL-17A

IL-17A is a pleiotropic cytokine that acts on multiple cell types, including macrophages, dendritic cells, chondrocytes, neutrophils, osteoblasts, fibroblasts, endothelial cells, epithelial cells, keratinocytes, and lymphocytes A (Table 1) [3], [43].

Synergistic effects with TNF-α

The effects of IL-17A should not be considered in isolation at the functional biological level, particularly due to its ability to synergize with other cytokines that are involved in inflammatory reactions. TNFα, like IL-17A, promotes joint inflammation, cartilage destruction, and bone erosion in experimental arthritis models. IL-17A acts in an additive, and sometimes synergistic, manner with TNFα to enhance cytokine, chemokine, and MMP production and, as noted previously, to enhance arthritis

Animal studies as a model for use of IL-17A inhibitors

IL-17 family members have been extensively targeted in vivo. We focus herein upon those models of articular and skin disease.

Concluding remarks

IL-17A, the principal cytokine effector of Th17 cells, plays an important pathogenic role in autoimmune and immunoinflammatory diseases, including RA and psoriasis. IL-17A is produced in rheumatoid synovial tissue and psoriatic plaques and acts on multiple cell types to promote pathological changes inherent to RA and psoriasis. Many of the effects of IL-17A may be augmented through synergistic interactions with other proinflammatory cytokines, and disease pathology may be sustained through

Acknowledgments

This review was supported by Novartis Pharma AG.

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  • Cited by (0)

    Source of support: Dr. van den Berg did not receive any funding for IL-17-related research over the last 3 years. Dr. McInnes received grant funding from Wellcome Trust, MRC, Arthritis Research UK, and research grants from Astra Zeneca, Novo Nordisk, Pfizer, and Roche within the last year.

    ☆☆

    Disclaimers: Dr. van den Berg is listed on the IL-17 patent issued to Novartis but did not receive any funding for IL-17-related research over the last 3 years. Dr. McInnes received honoraria from Novartis for consulting on development of IL-17-targeted approaches in inflammatory diseases.

    Role of the funding source: Editorial support was provided by Barry Weichman, PhD, and Catherine Fontana of BioScience Communications, New York, NY, and was funded by Novartis Pharma AG, Basel, Switzerland.

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