The goal of translational medicine is to transfer discoveries of new molecules and pathways into new treatments. IL-17 was discovered in 1995–1996 at a time when the role of T cells in human inflammatory diseases was still debated 1, 2. This debate has been clarified today as it was shown that acting on co-stimulatory molecules involved in T-cell interactions was beneficial for the treatment of chronic inflammation. Although the production of IL-17 by a particular T-cell subset had already been described in 1999 3, the isolation of the Th17 subset was done in 2005 in the mouse 4–6. Such discovery has been associated with a large number of reports suggesting a new classification of human and mouse diseases according to the contribution of this new pathway. The final demonstration is just starting to be obtained by showing that IL-17 inhibition could be beneficial for the treatment of chronic inflammation.
The discovery of IL-17 and of the Th17 pathway has been a step in the classification of human diseases. Th17 targeting appears rather straightforward in diseases associated with inflammation and matrix destruction, such as rheumatoid arthritis, psoriasis, and Crohn's disease. In other conditions where IL-17 is expressed and Th17 activated, it is unclear whether this is a primary or secondary event, making the use of Th17 inhibitors less obvious.
Key properties of IL-17 and Th17 cells to consider for clinical targeting
IL-17 was discovered by its ability to induce the production of IL-6 by fibroblasts indicating immediately its link to inflammation 2. The induction of IL-8 in the same conditions further supported the role of IL-17 in inflammation through neutrophil migration and activation 2. Another important property discovered also very early is the rather poor effect of IL-17 when used alone whereas the effect of IL-17 in combination with other cytokines is much more potent 7. In particular synergistic interactions are often seen between IL-17 and TNF or IL-1, where IL-17 augments the effect of TNF, in part through a positive enhancing effect on TNF receptor expression 8. Such results suggest that targeting IL-17 could be studied in diseases where TNF inhibitors have been already successful, possibly in the subsets of patients with no or insufficient response to TNF inhibitors.
In addition to its role in inflammation, IL-17 has a key effect on matrix metabolism. This dual effect includes an activation of matrix destruction combined with an inhibitory effect on matrix formation, the net effect being a massive and rapid destruction with a lack of repair 9. When considering immune cell and bone cell interactions, IL-17 increases the expression of RANKL on mesenchymal cells such as osteoblasts and fibroblasts, RANKL interacting then with RANK on osteoclasts and dendritic cells 10. This enhancing effect favors bone destruction and immune cell activation. In addition, a subset of Th17 cells can express RANKL allowing a direct effect of activated bone marrow T cells in bone destruction in the context of inflammation 11, 12.
Inflammation itself increases the formation and function of the Th17 pathway. Pro-inflammatory cytokines largely produced by monocytes are involved, IL-6 more in the mouse and IL-1 more in the human situation 13, 14. Thus, non-specific inflammatory signals, where IL-1 and IL-6 are produced as the first line of defense, further act on Th17 cell development leading to IL-17 production. This amplification results also from the enhancing effect of IL-17 on IL-1, TNF and IL-6 production by monocytes 15. These results indicate that acting on TNF, IL-1, and IL-6 is an indirect way to act on the Th17 pathway. Furthermore, blocking IL-17 at the same time or possibly better sequentially, may be a way to improve the effect of these cytokine inhibitors in the clinic. Pre-clinical results are in line with this concept 16.
Another key property of inflammation involving the Th17 pathway is the down-regulation of the T-cell regulatory pathway 13. In the mouse whereas TGF-β alone favors the T-cell regulatory pathway, in contrast combination of TGF-β with IL-6 favors the Th17 pathway. Accordingly, correction of inflammation acting upstream on IL-6 or directly against IL-17 may be a way to control chronic inflammatory diseases by correcting the T-cell regulatory defects associated with inflammation.
Although Th17 cells are defined by the production of IL-17, they also produce other cytokines such as IL-21, IL-22, TNF, and IL-6. IL-21 is involved in the amplification loop, which induces the Th17 pathway 17. IL-22 appears as a more specialized cytokine involved in skin defense 18. In addition, IL-22 is involved in mucosal immunity and lung defense 19, 20. These two properties indicate the role of IL-22 in the interactions between the immune system and the outside world. Targeting one of these cytokines or the whole Th17 pathway may be a way to differentiate their specific contribution to disease pathogenesis.
Diseases with chronic inflammation and matrix destruction
These are diseases first selected for the use of TNF inhibitors. Three diseases have been selected which share many key clinical and biological features. These are rheumatoid arthritis (RA), psoriasis, and Crohn's disease. The functional characterization of IL-17 was discovered by showing the production of IL-6 by rheumatoid synoviocytes stimulated with IL-17 2. At the same time, a synergistic effect with the combination of TNF was identified. Later mouse and ex vivo human models of RA have extended these results 21. In a mouse model of RA, it was shown that the early contribution of TNF was subsequently lost and replaced by the contribution of IL-17 22. Long-term intra-articular administration of IL-17 via gene transfer can reproduce the key features of RA with massive inflammation, bone erosions, and cartilage damage 11. Psoriasis is a disease easy to follow through skin biopsies. In those biopsies, high expression of IL-17 combined with that of IL-23, IL-22, and IL-6 was observed 18, 23, 24. Similar results were obtained with biopsies of lesions of Crohn's disease 25. Accordingly, these diseases where TNF inhibitors have been already successful, are now considered for the first trials with IL-17 inhibitors. The first positive results were obtained with patients with psoriasis where a single injection of an anti-IL-17 antibody was able to reduce skin lesions. At this stage, they have been presented orally at a recent meeting and as such have to be considered as preliminary. They are in line with the implication of IL-17 in psoriasis, but do not exclude an indirect effect.
Bone destruction as a result of inflammation is the hallmark of RA. Similar aspects are seen in joint prosthesis loosening, periodontal disease, where a high expression of IL-17 has been seen at the site of bone destruction 26. These concepts can probably be extended to bone destruction resulting from bone marrow infiltration by tumor cells as in bone cancer metastasis and bone lesions of myeloma. Even generalized osteoporosis appears linked to pro-inflammatory cytokine activation, which is sensitive to estrogen substitution. In these conditions, IL-17 targeting would be rather easy to justify. The same applies to conditions where TNF inhibitors are active and where the Th17 pathway has been shown to be activated. This includes spondylarthropathies, psoriatic arthritis.
Other chronic inflammatory diseases
The situation is not as simple for this group of diseases 27. MS is another chronic disease leading to brain inflammation and myelin destruction. However the effect of TNF inhibition has been opposite to the protection observed in the diseases listed above. Indeed, such treatment was associated with an increase of lesion activity in MS patients as well as with an induction of central neurological manifestations in patients without MS. It remains unclear whether this is related to the specificity of the blood–brain barrier and/or to limited access of biotechnology products to the brain 28. Because IL-17 and Th17 cells have been clearly associated with mouse models of MS, it is tempting to consider IL-17 inhibition in this context 29. However, safety issues still have to be clarified.
For a long list of diseases, the link between IL-17 and pathogenesis is still unclear. Reports have been published on the over-expression of the Th17 pathway in a variety of diseases including lupus nephritis, asthma, and chronic obstructive pulmonary disease, H. pylori-associated gastritis and gastric cancer, autoimmune myositis 30–32. In this context, arguments for IL-17 targeting are still unsure. Similar results are starting to be obtained in vascular diseases such as giant cell arteritis and Wegener's granulomatosis 33. Often the demonstration is based simply on increased levels in blood or tissue samples. It is unclear if this over-expression indicates a direct pathogenic role for IL-17. Conversely, such activation could simply result from feedback mechanisms.
Acute inflammatory diseases and infections
One of the first described properties of IL-17 was its effect on the differentiation of hematopoietic precursors leading to the production of neutrophils and on the production of chemokines for neutrophils such as IL-8. The link between IL-17 and infectious diseases was shown early in mice lacking IL-17 or the IL-17 receptor. These mice showed increased severity and mortality in models of bacterial peritonitis and lung infection 34, 35. From these results, there was an early indication that blocking IL-17 could increase the incidence and severity of neutrophil-mediated bacterial infections. Accordingly, neutrophil-mediated bacterial infections could represent the major adverse reaction associated with IL-17 inhibition. If this concept is confirmed, then administration or induction of IL-17 rather than its inhibition, could be proposed in these conditions.
More recent results have provided an almost opposite view. Administration of a neutralizing antibody specific for IL-17 was able to prevent abscess formation following bacterial challenge in mice 36. Although this lack of abscess formation could be understood as an inability to control bacterial diffusion, a protective effect was also seen in a mouse model of septic shock induced by cecal ligation and puncture 37. Increased circulating levels of IL-17 were observed and neutralization by anti-IL-17 antibodies improved survival. Such treatment was protective, even when the administration of anti-IL-17A was delayed.
Possible limitations of IL-17 targeting
It is too early to envision the possible success of such an approach. It is obvious that fashion has an effect on targeting the IL-17 pathway 38. Limitations can be seen at different levels. Regarding biology, IL-17 is often poorly active alone but needs combination with other cytokines namely TNF and IL-1 to play a significant effect. When considering disease pathogenesis and looking at diseased tissue biopsies, the frequency of Th17 cells is often low 39. All these properties are in line with the regulatory properties of the Th17 pathway. This could be an argument for the use of a combination of inhibitors shown to be more active in pre-clinical models 40. It could be a combination of TNF and IL-17 inhibitors, acting both on monocyte and T-cell-derived cytokines. Various options could be discussed including the first use of TNF inhibitors to clear most of the inflammatory reaction followed by the use of IL-17 inhibitors in order to induce a more prolonged effect, possibly through a switch from pathogenic Th17 cells to protective regulatory T cells 13. Although IL-17F shares most of its effects with IL-17A, being often less active, it remains to be clarified whether the combined inhibition of the two cytokines would be more effective. Mouse results indicate that some of their inflammatory functions are not identical 41.
Today trials with IL-17 inhibitors are just starting with already signs of efficacy in patients with skin lesions of psoriasis. Although the identification of IL-17 and of the Th17 pathway has given much publicity to the field, it has not yet modified our current approach to treatment. One may ask why it took so much time from the discovery of IL-17 more than 10 years ago to reach clinical targeting. Answers are many but this is a good example of limitations to move from translational research to clinical application 38.
The research in the laboratory of the author has been supported by grants from the Hospices Civils de Lyon and the Région Rhône-Alpes.
Conflict of interest:
The author declares no financial or commercial conflict of interest.