While autoimmune inflammation was long considered to be driven by Th1 T cell activation and associated cytokines (i.e. IFN-γ), the discovery of Th17 T cells and the causality of Th17 T cells in inducing experimental autoimmune encephalitis greatly altered this concept (44
In turn, it then raised the question whether Th17 T cells have an important pathogenic contribution in human immune- mediated inflammatory diseases. Psoriasis vulgaris is a strong candidate disease for pathogenic activity of Th17 cells based on several lines of evidence: genetic susceptibility controlled in part by IL-23 and IL-23 receptor gene variants; disease improvements associated with ustekinumab therapy (blocking the p40 subunit of this cytokine)(47
); increased skin infiltration by Th17 T-cells (3
); and over-expression of IL-17A/F transcripts in skin lesions, with strong up-regulation of many disease-related mRNAs that are induced by IL-17 signaling in skin cells (5
Even so, Th17 T-cells are a relatively small percentage of overall infiltrates, while Th1 cells producing gamma-interferon, and Th22 T-cells selectively producing IL-22 are major parts of the disease phenotype (6
). Pathogenic models have considered that combined actions of all these cytokines might be required to sustain pathogenic inflammation, and broad alterations in gene expression are best explained by activation of multiple cytokine receptors/cytokine pathways in this disease (32
). To the extent that individual cytokines have been proposed as major drivers of the disease phenotype, IL-22 has emerged as a “most likely” cytokine for regulating epidermal hyperplasia and associated skin inflammation in mouse models (23
). However, pathways of skin inflammation in humans may be significantly different from animal models, as most IL-22 produced by T-cells in humans are within a distinct subset termed “Th22,” whereas Th17 T-cells in mice co-produce IL-17 and IL-22.
The results of the study reported here, testing multiple doses of an IL-17 monoclonal antibody, ixekizumab, provide strong evidence linking IL-17 to a central role in disease pathogenesis in psoriasis. We observed significant clinical improvements in patients receiving ixekizumab with no unexpected safety signals, although the sample size was small and further clinical trials are needed to fully evaluate its safety and efficacy. In addition, histological and genetic analyses of lesional skin biopsies revealed the underlying collapse of inflammatory circuits with treatment that may explain the high magnitude of clinical efficacy and the long-lasting effect of treatment after the last dose. The translational science approach illustrated in this study demonstrate the power of detailed mechanistic studies in the drug development process for understanding disease pathogensis in psoriasis in particular and potentially for autoimmune diseases more broadly.
It seems likely that Th17 T-cells are the source of IL-17 in psoriatic skin, since antagonism of the p40 subunit or p19 subunit of IL-23 can produce marked disease clearing and suppression of the IL-17 pathway in diseased skin (49
). Clinical responses are not highly correlated with expression of IL-22 or interferon-response pathway genes, suggesting that IL-17 is the major “driver” cytokine for this complex disease phenotype. Accordingly, the psoriasis disease phenotype defined by dysregulation of over 1000 gene products, tissue infiltration by multiple leukocyte subsets, and associated keratinocyte hyperplasia/tissue patterning and the clinical disease appearance, was significantly reversed by treatment with ixekizumab, a monoclonal antibody to IL-17A. Given that IL-17A and IL-17F bind independently to the same receptor, it may well be that the bioactive form of this cytokine is an IL-17A/F heterodimer, as potentially suggested by a recent case of IL-17 deficiency caused by a mis-folded IL-17F variant (53
In vitro studies in which human keratinocytes are treated with T cell derived cytokines have defined a relatively narrow range of products induced only by IL-17, but a much larger set of genes is induced by the combination of IL-17 with TNF (36
). Thus, both TNF and IL-17 are likely co-inducers of a broad set of genes that are highly up-regulated in the psoriasis transcriptome, but the in vivo contribution of each cytokine to this response should be considered. The set of genes suppressed at week 2 in this study is much larger and of greater magnitude than TNF/IL-17 genes suppressed with 2 weeks of treatment with a TNF antagonist, etanercept (28
) suggesting that IL-17 may be the dominant cytokine inducing synergistic and additive genes for the combined TNF/IL-17 response.
Our results also begin to cement the idea that different inflammatory skin diseases such as atopic dermatitis and psoriasis may be reaction patterns to different underlying cytokines produced by distinct T-cell subsets (25
). The data in this manuscript argue strongly for psoriasis as an IL-17/Th17 disease, whereas there is very little expression of the IL-17 axis in atopic dermatitis (10
). In contrast to psoriasis, expression of Th2 and Th22 cytokines are very high in atopic dermatitis and these might thus be the key drivers of this distinct skin disease (6
), but still one that has many parallel features to psoriasis (55
). Eventually, there will need to be cytokine antagonism studies in atopic dermatitis and other inflammatory skin diseases to establish the pathogenic role of specific cytokines or combinations. We hope this study might serve as a model of how to do early proof-of-concept clinical studies with incorporation of in-depth biomarker research at an early stage of hypothesis testing. In fact, the data from this study has informed the design of a phase 2 study of ixekizumab, which was just recently published. This study showed significant clinical efficacy at 12 weeks with this antibody in patients with chronic moderate-to-severe psoriasis, as noted earlier (27
). Furthermore, the extent and duration of the collapse of the inflammatory milieu observed in this study provides a mechanistic explanation for the high degree of clinical efficacy and durability of the clinical response observed in the phase 2 study(27
In summary, neutralization of IL-17 with the monoclonal antibody, ixekizumab, decreased expression of genes associated with numerous circuits of inflammation resulting in a rapid reversal of the psoriatic phenotype. The clinical and genetic effects were dose dependent. Neutralization of IL -17 modulates genes upstream and downstream of known IL-17 effects and has a stronger effect on the expression of genes that are known to be coregulated by IL-17 and TNF than does TNF inhibition alone. Combined, our data suggest that IL-17 and/or Th17 T cells have essential functions in the pathogenesis of psoriasis.