IL-17 and Th17 cells in human inflammatory diseases

Microbes and Infection 11 (2009) 625e630 www.elsevier.com/locate/micinf

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IL-17 and Th17 cells in human inflammatory diseases Pierre Miossec* Department of Immunology and Rheumatology, Hoˆpital Edouard Herriot and Immunogenomics and inflammation research unit EA 4130, University of Lyon; Lyon, France Available online 14 April 2009

Abstract IL-17 was discovered in 1995/96 as a T cell derived cytokine with effects on inflammation and neutrophil activation. In 2006, the precise cell source of IL-17 was identified in the mouse, and these cells were named Th17 cells. They play a role in various human diseases associated with inflammation and destruction such as rheumatoid arthritis, psoriasis, Crohn’s disease, multiple sclerosis, where IL-17 can be seen as a therapeutic target. Ó 2009 Elsevier Masson SAS. All rights reserved. Keywords: IL-17; Cytokines; Inflammation; Destruction; TNFa; IL-1

IL-17 has gained much publicity very recently, when in 2005e2006, the cell source of IL-17 named Th17 cells was identified in the mouse. The protein IL-17 itself had been discovered 10 years before as a T cell derived cytokine. These new findings on Th17 cells confirmed and extended the results obtained previously following the identification of IL-17. Demonstration of the role of IL-17 in many chronic inflammatory conditions further supported the concept of IL17 targeting for treatment. We will review these new findings in light of the previous knowledge [1]. This paper will focus on the possible contribution of IL-17, a central player in immune regulation, and the related Th17 cells to chronic inflammatory diseases, in some of which IL-17 could be a therapeutic target.

1. Identification of IL-17 IL-17 was described in 1995/96 as a proinflammatory cytokine produced by T cells. The key experiment was the demonstration that the addition of IL-17 to mesenchymal cells/ fibroblasts was able to increase IL-6 and other proinflammatory

* Tel.: þ334 72 11 74 87; fax: þ334 72 11 74 29. E-mail address: [email protected] 1286-4579/$ - see front matter Ó 2009 Elsevier Masson SAS. All rights reserved. doi:10.1016/j.micinf.2009.04.003

cytokine production, showing immediately its link to inflammation [2,3]. At the same time, IL-17 was shown to induce neutrophil induction and maturation, an indication of its role in the acute mechanisms in host defense. This result indicated very early the link between IL-17 and neutrophil biology. IL-17 was discovered under the name of CTLA-8, a gene product without clear function. Its link with rheumatoid arthritis (RA) was immediately established. Synoviocytes obtained from the synovium membrane of RA patients were used in these first experiments. The results suggested a potential contribution of IL-17 to RA pathogenesis. This was later extended to other chronic inflammatory diseases. 2. The IL-17 family and its receptors IL-17 now referred to as IL-17A, is the founding member of the IL-17 family, which includes IL-17AeF. IL-17F shows a 50% sequence homology with IL-17A and has similar effects as IL-17A but to a lower extend [4]. However when combined with TNF, a synergistic effect is observed, almost as potent as with IL-17A. IL-17A and F are produced as dimers including a significant proportion of A/F heterodimers. Th17 cells have been first described in the mouse by the production of IL-17A, and they also produced a list of other proinflammatory cytokines including IL-17F, IL-22, TNF, IL6. IL-22 is a member of the IL-10 family, that synergizes with

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IL-17A or IL-17F to regulate genes associated with skin innate immunity [5]. In particular IL-22 was shown to mediate dermal inflammation [6]. In addition, Th17 cells are involved in cell interactions through the expression of RANKL. Such RANKe RANKL interaction is the final bridge whereby osteoblasts activate osteoclasts leading to bone destruction. Similar interactions are found between fibroblasts and dendritic cells. A first receptor for IL-17 named IL-17R was described in 1995e1996 when IL-17 was discovered. Its rather low affinity for IL-17 suggested the presence of additional chains [7,8]. Sequence screening showed proteins with a partial homology with IL-17R [9]. The first member of the IL-17R family is the original IL-R receptor renamed as IL-17RA. The second is IL17RC. The physical association of the two receptors has been shown although it is still unclear whether these are two chains of a single receptor or two different receptors. It was previously proposed that IL-17A could be the receptor for IL-17A and IL-17RC the receptor for IL-17F. It appears now that IL17RA and RC interact together for an optimal response, in particular when IL-17 is combined with TNF. Indeed the inhibition of the two receptors is needed to reduce the response to the combination of IL-17 with TNF [4].

3. Th17, the cellular source of IL-17 The most recent step was the identification in 2006 of the cell source of IL-17 [10,11]. IFNg was defined as a maker of Th1 cells and IL-4 of Th2 cells. The source of IL-17 was found to be different and these cells were named Th17. In the mouse, this new subset was identified by the demonstration of the inhibitory effect of IFNg on IL-17 production in mouse models of autoimmune diseases [12e14]. The next step was the discovery of IL-23, a monocyte product, shown to be a key cytokine in the induction of brain inflammation in experimental models of encephalomyelitis [15]. These results have been obtained in the mouse and as such should be considered with caution when applied to the human situation. This will be discussed in detail in another chapter. Even in the mouse, more recent results indicated the frequent co-expression of IFNg and IL-17. Contribution of one of the two cytokines could lead to different pathogenic pathways, leading to the same clinical presentation as observed in mouse models of autoimmunity [16,17]. Results with RA T cells clones indicated that IL-17 was often produced in association with IFNg but not with IL-4 [18]. However in situ immunostaining of the RA synovium showed two isolated populations of T cells producing either IFNg or IL-17. Double positive cells were rarely seen. It thus remains to be demonstrated whether these secreting patterns are still dynamic or fixed. Of interest in this context was the demonstration that cytokine secreting T cells have a particular morphology with a plasma cell appearance, a pattern that can be induced in vitro and is associated with the loss of TCR and CD3 but not of CD4 [19]. As for B cells, the plasma cell morphology of the IFNg and IL-17 producing cells strongly suggests that this is a fixed pattern related to a final stage of differentiation.

4. IL-17 and human inflammatory diseases Following the discovery of IL-17 and of its key properties, a number of both human and mouse, spontaneous as well induced diseases, were shown to be associated with IL-17 overexpression and production. Although the list of diseases will certainly increase, RA emerged as the best studied situation and we will first focus on this disease. It should be kept in mind that most of these results could also apply to the long list of chronic inflammatory diseases. Diseases such as RA, multiple sclerosis (MS), Crohn’s disease have in common the local chronic inflammatory reaction with production of inflammatory cytokines, leading to matrix destruction and defective repair [20]. 5. Rheumatoid arthritis RA is characterized by the chronic inflammation of the synovium membrane of joints. Resulting cell interactions induce proinflammatory cytokine production which in turn activates the release of proteases leading to bone and cartilage destruction. Concordant results using mouse and human models of RA showed that IL-17 is involved in the proinflammatory patterns associated with joint inflammation [21]. In the mouse, a single injection of IL-17 alone into a normal knee is sufficient to induce cartilage damage [22]. The continuous administration of IL-17 by gene over-expression into a normal knee induces massive damage with extensive inflammatory cell migration, bone erosions, and cartilage degradation [23]. The results indicate that the local release of IL-17 alone could reproduce the key features of human RA. Conversely, inhibition with specific inhibitors including blocking antibodies and soluble receptor, provided protection from inflammation and destruction [24]. Addition of IL-4 through gene therapy acting more broadly on other cytokines could inhibit IL-17 production and action and protect from bone destruction by reducing the key interactions between RANK and RANK ligand [24]. The link between IL-17 and human RA was reinforced when it was shown that pieces of RA synovium could produce bioactive IL-17. This activity was measured with a bioassay where supernatants of RA synovium pieces induced a massive production of IL-6 by RA synoviocytes [25]. Using the first available monoclonal antibody blocking human IL-17, such production was reduced by two-thirds. This robust production of IL-6 using supernatants containing IL-17 was in contrast with the limited effect of recombinant IL-17 alone. The same findings were obtained with human bone explants obtained during wrist surgery. Here again high levels of functional IL17 were detected, indicating the role of T cells from bone marrow in juxta-articular bone destruction [25,26]. As expected this effect was associated with RANK ligand expression by these T cells, interacting with RANK expressing cells, not only osteoclasts but also mature dendritic cells [26,27]. In addition to synovium inflammation, IL-17 induces inflammation associated bone resorption [26] and contributes to similar conditions such as joint prosthesis loosening and periodontal disease [28,29]. In a clinical study of a series of

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RA patients, expression of IL-17 in RA synovium biopsies was associated with an increase in both activity and severity of the disease, confirmed on biopsies showing increased joint damage and higher IL-17 expression [30]. The role of IL-17 in chronicity was confirmed, by showing that in the mouse collagen arthritis model, the IL-17 effect was dependent on the presence of TNF at the early phase, whereas at a later stage the disease was mostly IL-17 driven, and now TNF independent [31]. 6. Psoriasis Psoriasis is an inflammatory skin disease with skin infiltration by immune cells which have migrated from blood. Some patients have joint manifestations combining inflammation and destruction during psoriatic arthritis. Among the infiltrated cells, activated T cells represent a large proportion. Using various approaches, skin biopsies from patients with psoriasis show a high expression of IL-17 as well of IL-23 and IL-22 [32]. At this stage the respective contribution of these three cytokines is still unclear. Of the three, mouse results have demonstrated the specificity of IL-22 for skin defense. This could suggest that inhibition of IL-22 would be more appropriate as being more skin specific. However, the first positive results from a clinical trial with an anti-IL-17 antibody were obtained in patients with psoriasis. These results demonstrated the implication of IL-17, but do not exclude an indirect effect. Indeed interactions with less specific inflammatory cytokines such as TNF are also involved. In skin biopsies from psoriasis patients treated with a TNFa inhibitor, a reduced expression of IL-23, IL-22 and IL-17 was observed [32]. 7. Crohn’s disease

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immune cells from blood results from their migration through the brain blood barrier. Such migration is differently regulated when compared to that seen in inflamed organs outside the central nervous system. Chronic inflammation of the brain leads to the destruction of myelin sheaths leading to reduction in influx transmission and function loss. When considering human MS, IL-17 was on the top list of genes found to be over expressed in brain biopsies from MS patients through extensive gene array studies. Mouse models of MS have been instrumental in the definition of the contribution of cytokines to the differentiation of Th17 cells. The key studies were performed in mice with experimental autoimmune encephalomyelitis (EAE). The first step was the discovery of IL-23. Before, it was considered that IL-12 and IFNg were the key cytokines involved in EAE, then classified as a Th1 disease. IL-12, which induces IFNg, is composed of two chains: p35 and p40 [35]. IL-23 was later described as a new cytokine, composed of two chains, the p40 chain shared with IL-12, and of a unique chain p19, not found in IL-12 [36]. Mice lacking the p35 chain, and thus lacking IL12, developed EAE. Surprisingly mice lacking the p19 chain, and thus lacking IL-23, were resistant [15]. In contrast to what was previously thought, IL-12 and IFNg were not crucial for inducing EAE, but IL-23 was necessary [37,38]. In EAE, Th17 cells can disrupt the blood barrier leading to central nervous system inflammation [39,40]. Recently the association between IL-17/Th17 and EAE/MS has been revisited. Experiments in the mouse indicated that in fact the two Th1 and Th17 pathways could contribute to disease but it was impossible to differentiate clinically the two forms [17]. Studies of brain lesions showed accumulation of neutrophils when the Th17 pathway is activated and accumulation of monocytes when the Th1 pathway is activated. These results are of interest when trying to link disease to particular cytokine/pathway contribution. This may explain disease heterogeneity as indicated by clinical response to a particular cytokine/cellular inhibitor.

Crohn’s disease is an inflammatory bowel disease which affects specific locations of the digestive tract. These locations are different in ulcerative colitis. In both diseases, local inflammation in the mucosa leads to destruction of the lamina, with complications such as perforations, and internal or external fistulas. Inflammatory joint manifestations different from those seen in RA can be associated as part of the spondylarthropathies. As in RA and psoriasis, the contribution of TNF has been demonstrated by the positive effect of TNF inhibition in a significant proportion of patients with inflammatory bowel disease. Clinical studies have used biopsies obtained from endoscopy. The key cytokines IL-23 and IL-17 and also IL-12 were found over expressed in lesions of Crohn’s disease [33]. However Crohn’s disease and ulcerative colitis may differ in some aspects of pathogenesis. Some studies have found differences in cytokine expression with IL-17 being more associated with ulcerative colitis and IFNg with Crohn’s disease [34].

The hyper IgE syndrome is a primary immunodeficiency associated with very high levels of IgE, skin and lung manifestations, bone disorders and infections. IgE is the prototypic immunoglobulins produced under the action of the Th2 cytokines, IL-4 and IL-13. Recently, various mutations in the Stat3 gene have been identified in those patients resulting in Stat3 loss of function [41]. Stat3 is a key transcription factor associated with the Th17 pathway. Indeed defects in Th17 cells have been observed in these hyper IgE patients [42]. These findings result from the balance between the Th17 and Th2 pathways, where the Th17 pathway inhibits the Th2 pathway and IgE production.

8. Multiple sclerosis

10. IL-17 targeting for treatment

Multiple sclerosis is an inflammatory disease which affects the central nervous system. Accumulation of inflammatory

Cytokine targeting has shown efficacy with various inhibitors including monoclonal antibodies against TNF or against

9. Hyper IgE syndrome

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the cell receptor of IL-6, a TNF soluble receptor and an IL-1 receptor antagonist. Some of the tools based on similar concepts are now available to target the IL-17 pathway. 11. IL-17 specific inhibitors The two major options are the targeting of the ligand or the receptor [43]. Tools ready for human applications include monoclonal antibodies against IL-17 and against IL-17R. Preclinical studies have demonstrated their efficacy in mouse and human models of inflammatory diseases [44], where the combination of IL-17 and TNFa inhibitors is often more potent [45]. Additional targets have been identified from recent research on IL-17 and IL-17R families. Regarding the ligand, the possible choice is now between IL-17A or IL-17F or both, and for the receptor, IL-17RA or IL-17RC or both. In addition, as for the other proinflammatory cytokines, active research is looking for small molecules able to control the intracellular signaling pathways, particularly RORgammat, the transcription factor characteristic of the Th17 pathway [46]. 12. Use of non-IL-17 anti-cytokine inhibitors Such inhibitors can act on pathways upstream of IL-17 and/ or on other cytokines in addition to IL-17. Since IL-23 is implicated in IL-17 production, the inhibition of IL-23 is a way to control the Th17 pathway by acting upstream. Treatment with a monoclonal antibody against p40, which is common to IL-12 and IL-23, has shown efficacy in psoriasis and Crohn’s disease, but not clearly in RA and MS [47,48]. In active Crohn’s disease, a local reduction of IL-12 and IL-23 was seen after treatment [49]. Specific inhibitors of IL-23 remain to be tested and compared with the p40 inhibitors. Similarly specific inhibitors of IL-21 and IL-22 will have to be compared with IL-17 inhibitors. Some cytokines have broad anti-IL-17 properties. IL-4 inhibits the production and functions of IL-17 as well as TNF, IL-1, IL-6 [24,50]. IL-25/IL-17E is a member of the IL-17 family [51], with anti-inflammatory properties on Th17 cells [52]. 13. Acting on regulatory pathways New treatments could use the effects of Th17 cells on the function of regulatory T cells [53]. IL-17, TNF-a, IL-6 and IL-1, not only promote inflammation but also inhibit regulatory T cell functions. The use of IL-17 inhibitors could be a way to control first inflammation but also to restore regulatory T cell functions. In RA patients TNFa inhibitors may control the disease not only by inhibiting TNFa, but also by correcting part of the defective regulatory T cell functions [54]. Other options include targeting the IL-6 receptor with a monoclonal antibody or the IL-1 receptor with an IL-1 receptor antagonist, known to have clear effects on systemic inflammation [55,56].

14. Limitations of IL-17 targeting Targeting cytokines may interfere with immune defense. Inhibition of TNF was associated with an increased risk of tuberculosis reactivation. For IL-17, the link with neutrophil biology was apparent from the first results. Thus inhibition of IL-17 may affect the acute defense mechanisms involving neutrophils. Indeed in the mouse, inhibition of IL-17 has been associated with increased mortality from bacterial lung infections [57]. IL-17 appears to be critical for neutrophil activation and migration [58]. IL-17 is a strong inducer of IL8, a key chemokine for neutrophils. Conversely, IL-17 appears to have inhibitory effect on the production of chemokines for mononuclear cells. In addition, inhibition of the IL-23 pathway has been associated with defects in the cell mediated immunity including increased severity of mycobacterial infections in the mouse. 15. Position of IL-17 targeting as a treatment The position of IL-17 inhibition in the treatment of inflammatory conditions remains to be defined. As of today positive results have been obtained with a monoclonal against IL-17A in patients with psoriasis. Trials have started or are ready to start in RA, Crohn’s disease. Limitations for targeting IL-17 could be the rather low effect of IL-17 at least when used alone, the reduced numbers of IL-17 secreting cells in tissues, and the overlap with the effects of TNF. The combined inhibition of TNF and IL-17 possibly used sequentially, may allow the targeting of two different cell types, monocytes and T cells. Anti-TNF nonresponders may have an IL-17 driven disease. In addition secondary loss of response to TNF inhibition may result from the induction of other pathways, possibly involving IL-17, and replacing the initial TNF contribution, as observed in the mouse [31]. 16. Conclusion The story of IL-17 and of the Th17 subset is a new revival of the contribution of some T cells to chronic inflammation and extra-cellular matrix destruction. A growing list of diseases has been associated with IL-17 but the final demonstration of its contribution to disease pathogenesis is still missing. Tools are now getting ready to test these concepts in the clinic. References [1] P. Miossec, Interleukin-17 in rheumatoid arthritis: if T cells were to contribute to inflammation and destruction through synergy, Arthritis Rheum 48 (2003) 594e601. [2] F. Fossiez, O. Djossou, P. Chomarat, L. Flores-Romo, S. Ait-Yahia, C. Maat, J.J. Pin, P. Garrone, E. Garcia, S. Saeland, D. Blanchard, C. Gaillard, B. Das Mahapatra, E. Rouvier, P. Golstein, J. Banchereau, S. Lebecque, T cell interleukin-17 induces stromal cells to produce proinflammatory and hematopoietic cytokines, J Exp Med 183 (1996) 2593e2603.

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