IL-17 and limits of success

Abstract

Interleukin-17 (IL-17) is a potent proinflammatory cytokine that protects host against fungal and extracellular bacterial infections. On the other hand, excessive or dysregulated production of IL-17 underlines susceptibility to autoimmune disease. Consequently, blocking IL-17 has become an effective strategy for modulating several autoimmune diseases, including multiple sclerosis (MS), psoriasis, and rheumatoid arthritis (RA). Notably, however, IL-17 blockade remains ineffective or even pathogenic against important autoimmune diseases such as inflammatory bowel disease (IBD). Furthermore, efficacy of IL-17 blockade against other autoimmune diseases, including type 1 diabetes (T1D) is currently unknown and waiting results of ongoing clinical trials. Coming years will determine whether efficacy of IL-17 blockade is limited to certain autoimmune diseases or it can be extending to other autoimmune diseases. These efforts include new clinical trials aimed at testing second-generation agents with the goal of increasing efficiency, spectrum and ameliorating side effects of IL-17 blockade. Here we briefly review the roles of IL-17 in pathogenesis of selected autoimmune diseases and provide updates on ongoing and recently completed trials of IL-17 based immunotherapies.

IL-17 plays an important role in the clearance of extracellular bacteria (e.g. Staphylococcus aureus, Clostridium rodentium, Klebsiella pneumonia) and fungal infections. However, members of the IL-17 family also also central players in driving autoimmunity. Dysregulated production of IL-17 can result in excessive pro-inflammatory cytokine production and chronic inflammation, leading to tissue damage and autoimmunity. Here we describe in brief details the roles of IL-17 in pathogenesis of selected autoimmune diseases and current or recently concluded clinical trials (Table 1) assessing the efficacy of IL-17-neutralizing antibodies (biologics) as immunotherapies.

Table 1:

IL-17 and IL-17R Inhibitor Drugs^*

Drug Name (Experiment Name)	Drug Type	Target	Disease	Study Status
Ustekinumab	Human monoclonal antibody	IL-17, IL-12, IL-23, IFN-Ɣ	Psoriasis	Approved
			Crohn’s Disease	Approved
			Type 1 Diabetes	Phase I/II
secukinumab	Human IgG1κ monoclonal antibody	IL-17A	Psoriasis	Approved
			Psoriatic Arthritis	Approved
			Ankylosing Spondylitis	Approved
			Rheumatoid Arthritis	Terminated
			Multiple Sclerosis	Terminated
			Crohn’s Disease	Terminated
ixekizumab	Humanized IgG4 monoclonal antibody	IL-17A	Psoriasis	Approved
			Plaque Psoriasis	Approved
			Psoriatic Arthritis	Phase III
			Rheumatoid Arthritis	Phase II
brodalumab	Human monoclonal antibody	IL-17 Receptor	Psoriasis	Approved
			Moderate/Severe Crohn’s Disease	Terminated
			Inflammatory Bowel Disease	Terminated
			Psoriatic arthritis	Phase III
			Rheumatoid Arthritis	Terminated
ABT-122	Human recombinant IgG1 (Dual variable domain immunoglobulin; DVD-Ig)	IL-17 TNF-α	Psoriasis	Phase II
			Rheumatoid Arthritis
			Psoriatic Arthritis
CJM112	Human IgG1 monoclonal antibody	IL-17A	Multiple Sclerosis	Phase II
risankizumab	Humanized monoclonal antibody	Binds to p19 subunit of IL-23A disrupting receptor activation and IL-23/17 axis	Psoriasis	Phase II
			Psoriatic Arthritis
			Crohn’s Disease
briakinumab	Human IgG1λ monoclonal antibody	P40 subunit of IL-23 and IL-12	Moderate/Severe chronic Plaque Psoriasis	Terminated
			Crohn’s disease	Phase II
bimekizumab	Humanized IgG1 monoclonal antibody	IL-17A IL-17F	Psoriasis	Phase III
			Psoriatic arthritis
			Rheumatoid Arthritis
			Inflammatory Bowel Disease
BCD-085	Humanized monoclonal antibody	IL-17	Severe Psoriasis	Phase III
afasevikumab	Human monoclonal antibody (IgG1-κ)	IL-17A IL-17F	Multiple Sclerosis	Discontinued
perakizumab	Humanized monoclonal antibody (IgG1-κ)	IL-17A	Psoriatic arthritis	Phase I
RG7624	Human monoclonal antibody	IL-17A and/or IL-17F	Psoriasis	Phase I
SCH-900117	Human monoclonal antibody	IL-17A	Rheumatoid arthritis	Phase I
PF-06342674	Human monoclonal antibody	IL-17 receptor antagonist	Type 1 Diabetes	Phase I
			Multiple Sclerosis
ABBV-257	Human monoclonal antibody; Dual-variable domain immunoglobulins 1	IL-17 TNF-α inhibitor	Rheumatoid Arthritis	Phase I
CNTO 6785	Human monoclonal antibody	IL-17A	Rheumatoid Arthritis	Phase II

^*Lists IL-17 and IL-17 Receptor Inhibitor Drugs along with their targets, conditions approved for, and/or clinical trial status.

Role of IL-17 in autoimmunity

The IL-17 family represents a distinct and complex cytokine signaling system that is highly conserved across vertebrate evolution [1–3]. To date, the IL-17 family has been shown to consist of six structurally-related ligands (IL-17A, B, C, D, E, and F) and five receptors (IL-17RA, RB/IL-25R, RC, RD/SEF and RE). IL-17A, often referred to only as IL-17, is the most intensively studied and characterized. IL-17 was initially thought to be produced exclusively by CD4 α T cells, but subsequently a variety of adaptive and innate immune cells have been found to produce IL-17 [4]. These include a subset of γδ T cells (γδ17), natural killer T cells (NKT17), and group 3 innate lymphoid cells (ILC3). Macrophages, dendritic cells and neutrophils have also been reported to secrete IL-17 in response to infection or in the context of tissue inflammation [5].

A common feature of both adaptive and innate lymphocytes that secrete IL-17 is the expression of the transcription factor, retinoic acid receptor-related orphan receptor-γt (RORγt) [6]. Cytokines and transcription factors that regulate Th17 cell differentiation are distinct from those regulating differentiation of Th1 and Th2 cells [7]. Although the majority of the Th17 pathway components are similar, it is now well-established that the conditions that promote and regulate the Th17 differentiation are different in mice and humans [8, 9]. The IL-23 along with IL-1β cytokines, however, play critical roles in Th17 development in both mice and humans [10–13]. Additionally, TGF-β (transforming growth factor β) plays an important role in promoting differentiation of Th17 cells in mice, but its role in human Th17 development remains controversial [9, 14]. On the other hand, IL-6 is often used to induce in vitro differentiation of mouse Th17 cells and STAT3-mediated activation of the RORγt transcription factor and to alleviate Foxp3-mediated inhibition of the Th17 program [15, 16]. However, IL-6 does not seem to be absolutely required for generation of human Th17 [17]. Similarly, IL-21 activates STAT3 and can act in an autocrine manner to promote murine Th17 differentiation [18, 19], but it remains controversial whether there is an absolute requirement for IL-21 for differentiation of mouse Th17 cells[20, 21]. In humans, IL-21 to act in synergy with TGF-β to promote generation of Th17 cells[22], but it noteworthy that IL-21 in combination with TGF-β and IL-6 had been described to promote a mixed Th17/Tfh (follicular helper T cell) phenotype[23].

Role of IL-17 in pathogenesis of Type 1 Diabetes (T1D)

The non-obese diabetic (NOD) mouse has been instrumental in studying the pathogenesis of [24]T1D [25, 26]. NOD mice develop normally, but start to develop insulitis after the age of 4 to 5 weeks due to islet infiltration by autoreactive T cells, B cells, and macrophages. The insulitis remains benign for a variable period of time that precedes the attack and destruction of insulin-producing β-cells by autoreactive T cells leading to insulin deficiency and hyperglycemia [24, 27–29]. The role of IL-17 in the pathogenesis of autoimmune diabetes is not yet fully understood. For example, IL-17 knockout NOD mice display delayed onset of diabetes and reduced severity of insulitis[30]. Moreover, NOD mice lacking both IL-17 and IFN-γ receptors showed enhanced protection from overt hyperglycemia (not insulitis) when compared to IL-17 single-knockout NOD mice[31, 32]. The authors of the latter study concluded that the IL-17 and IFN-γ pathways synergize to initiate beta cell destruction. Another study showed that adoptive transfer of highly purified islet antigen specific Th17 polarized BDC2.5 transgenic T cells leads to the induction of T1D in NOD/SCID (Severe Combined Immunodeficiency) mice [33]. However, in-vivo instability of these cells and their conversion to the Th1-like cells in NOD/SCID mice precludes a definitive conclusion that the Th17 cells are directly involved in the pathogenesis of autoimmune diabetes in NOD mice[34, 35].

In humans, there is clinical data supporting a pathogenic role for Th17 cells in the development of T1D. Patients with T1D present with elevated plasma levels of IL-17 increased circulating IL17-producing T cells and islet antigen-specific Th17 cells [36]. Pancreatic lymph nodes (PLN) from T1D patients have an increased frequency of Th17 cells and analysis of islets obtained from recently deceased T1D patients expressed high levels of transcription factor RORγt and IL-17A[37]. In combination with IL-1β and IFN-γ, IL-17 mediates increased β-cell apoptosis in human pancreatic islet cells in vitro [38]. Thus, clinical data suggests that IL-17-producing cells may be pathogenic in the early stages of the disease and therapeutic strategies targeting Th17 cells could be a viable option for the treatment of T1D. Clinical data also provides a strong rationale to test agents that can suppress multiple pro-inflammatory axes simultaneously in the early phases of T1D. Currently, a phase I/II trial (Table 1) led by Jan P. Dutz’s group in collaboration with the JDRF Canadian Clinical Trials Network (CCTN) is evaluating the efficacy of ustekinumab in new-onset T1D subjects[39]. Ustekinumab is a monoclonal antibody that targets the human p40 subunit thereby inducing blockade of both IL-17 and IFN-γ signaling pathways. Ustekinumab is currently approved for the treatment of psoriasis and if proved to be efficacious in T1D, could be utilized in the clinical setting for diabetes patients (Table 1). There are ongoing clinical trials for PF-06342674 to evaluate the immunogenicity, tolerability, safety, and pharmacokinetics in adult’s patients with Type 1 Diabetes [https://clinicaltrials.gov/ct2/show/NCT02038764 and Table 1].

Role of IL-17 in Multiple Sclerosis (MS)

Multiple sclerosis (MS) is a chronic immune-mediated demyelinating disease of the central nervous system (CNS) characterized by focal lymphocytic infiltration, leading to the damage of myelin and axons [40]. Several recent findings from studies using animal models and MS patients indicate that Th17 cells, instead of Th1/Th2 cells, are critical players in the disease development [41, 42]. Most of the animal studies are undertaken using the well-characterized experimental autoimmune encephalomyelitis (EAE) model. Landmark studies in 2003 show that the IL-23-induced Th17 production plays a central role in the pathogenesis of EAE [43]. Additional evidence for the role of Th17 cells in driving EAE was shown in mice with targeted deletion of STAT3 in the CD4⁺ T cell compartment (CD4-STAT3KO), which became resistant to the development of EAE due to their inability to generate Th17 cells[44]. Additionally, adoptive transfer of antigen-specific Th17 cells, but not Th1 cells isolated from established EAE donors induced severe EAE in recipient mice [45]. It is noteworthy that γδT cells provide an early source of innate IL-17 and create an amplification loop for IL-17 secretion by Th17 cells[46].

Consistent with the results in mice, studies in humans have established a significant role for IL-17 in the pathogenesis of MS. Th17 cells are detected at high frequencies in the cerebrospinal fluid (CSF) and peripheral blood of patients, especially during an acute neurological episode as compared to patients with non-inflammatory neurological diseases[47]. IL-17 production is increased in the perivascular lymphocytes, astrocytes and oligodendrocytes located in the active areas of MS lesions in the CNS indicating that IL-17 is involved in the early phase of MS[48]. An increased proportion of IL-17A mRNA was observed in the brain of MS patients in both acute and chronically progressing lesions, but not in normal non-inflamed specimens[49–51]. The levels of GM-CSF, which is essential for Th17 responses, have also been shown to be elevated in the CSF and blood of MS patients [42].

The first evidence that blocking IL-17 may be efficacious in ameliorating lesion activity in MS came from the treatment of patients with secukinumab. Interestingly, secukinumab was found to be safe with no serious adverse events and no anti-secukinumab antibodies were detected in treated patients [52, 53]. Another phase II study that was launched to examine the efficacy and safety of secukinumab in patients with relapsing-remitting MS was initiated (NCT01874340). Unfortunately, this clinical trial had been terminated prematurely because another anti-IL-17 fully human monoclonal antibody, CJM112, was shown to have better potential for treating MS patients[54]. Currently, a phase II proof-of-concept study (MABINGO) is being initiated to evaluate the efficacy of CJM112 relative to fingolimod in controlling brain MRI disease activity in MS patients transitioning from natalizumab treatment[55], (See table 1).

Role of IL-17 in pathogenesis of Psoriasis

Psoriasis is a chronic skin disease resulting from the dysregulated interactions between keratinocytes and infiltrating immune cells, and is characterized by dermal hyperplasia[56]. A causal link between IL-17 and psoriasis was first documented in mice. Deletion of genes encoding either IL-23 or IL-17 significantly decreased the progression of psoriasis in mice [57]. Mice injected with IL-17-blocking or -neutralizing monoclonal antibodies decreased downstream signaling of 1L-17 and Th17 cells and significantly reduced epidermal hyperplasia[58]. The major role of IL-17 in psoriasis in humans was first identified in the genome-wide association studies that linked IL-23 and Act1 polymorphisms to psoriasis, which regulates IL-17 production and IL-17-mediated signaling, respectively[59]. Although Th17 cells has been considered the primary source of IL-17, IL-17-producing γδT cells (γδ17) have been identified as a lead source of IL-17 involved in the activation of keratinocytes in psoriasis[58]. Patients with severe psoriasis have high frequencies of γδ17 T cells in psoriatic skin lesions[60]. The clearest evidence for a role of IL-23/Th17 in psoriasis was elucidated by studies documenting higher serum and lesion levels of IL-17 in psoriasis patients when compared to controls. One of these studies described a correlation between IL-17 levels and disease severity. Generalized pustular psoriasis patients with more severe disease were observed to have the highest serum levels of IL-17. RNA levels of IL-17A, IL-17C and IL-17F are elevated within psoriatic lesions and vary with disease severity.

Recent clinical studies that block IL-17A demonstrate its importance in psoriasis pathogenesis[61]. Currently, secukinumab has been approved for plaque psoriasis treatment and there are ongoing Phase III trials of isekizumab and brodalumab [62], (Table 1).With these successes, quests for new agents to target IL-17 in psoriasis are still ongoing. However, a recent phase Ib/IIa trial of fynomab (COVA322), which targets both IL-17 and TNF-α was discontinued due to safety concerns [25]. Despite this, the quest for an ideal biologic to treat psoriasis continues.

Role of IL-17 in pathogenesis of Rheumatoid Arthritis (RA)

RA is a chronic systemic autoimmune disease that is characterized by inflammatory damage to multiple joints with bone and cartilage destruction, pannus formation and hyperplastic synovium in the affected joints [18, 63, 64]. There is a positive correlation between IL-17, disease activity, and Th17 cells, which expand and produce more IL-17 in blood of patients with active disease [65].In addition, γδ T cells are also a major source of IL-17. Hu etal group’s [31] has indicated that increases in IL-17-producing γδ T cells correlated with disease development and induction of inflammatory responses. IL-17 mRNA and protein expression were higher in the joints of RA patients as compared to healthy individuals [66, 67]. Moreover, serum and synovial levels of IL-17 correlated with disease activity[68]. IL-17 also plays a vital role particularly in the early stage of the disease by stimulating the fibroblast-like synoviocytes (FLS) to produce vascular endothelial growth factor (VEGF)[69], which leads to an increase in vascularity in mouse joints and promotes the growth of blood vessels [70]. IL-17 also provokes the secretion of other proinflammatory cytokines including, IL-8, IL-6, and Prostaglandin E2 [71]. In mice, increased expression of IL-17 by viral infections enhanced collagen-induced arthritis and accelerated joint destruction as well as synovial inflammation [70]. Furthermore, Th17 promotes osteoclastic bone erosion during collagen arthritis by provoking the expression of the receptor activator of nuclear factor-kB ligand (RANKL). IL-17 significantly increases the RANKL/osteoprotegerin (OPG) ratio [72]. Moreover, intra-articular injection of IL-17 in the joints of healthy mice led to inflammation and depletion of cartilage proteoglycans causing tissue degradation [73, 74]. Similarly, long-term intraarticular injection of IL-17 using gene transfer reproduced symptoms of rheumatoid arthritis.

Interestingly, antibody blockade of IL-17 (ixekizumab and secukinumab) or its receptor IL-17RA (brodalumab) protected against the development and manifestations of arthritis in patients with RA [75], (Table 1). In patients with RA, secukinumab induced an ACR20 (American College of Rheumatology standard scale to measure the amount of improvement in RA in designated joints after treatment) response rate of 46% when compared to the 20% using placebo treatment in their Phase III clinical trial [76], also see Table 1. Use of another IL-17 drug (ixekizumab) showed that inhibition of IL-17A could minimize the clinical parameters in as early as one week after the start of treatment. The Phase II trial with ixekizumab showed a 75% reduction in skin lesions in RA patients at week 12 as compared to placebo group with an 8% reduction [76, 77].

Previously, TNFα has been shown to be a key cytokine in the collagen-induced arthritis model. Although TNF contributes to the pathogenesis of the early stages of the disease, it is not involved in the later stages of the disease. Contrarily, IL-17 seems to play a role in more than just the early stages of other chronic disease[78]. Since TNFα and IL-17 have shared functions, the rationale for testing IL-17 inhibitors in the clinical setting is often based on the concept that patients who do not respond to TNF inhibitors may have an IL-17-driven disease. This finding is another indication that IL-17 contributes to the chronicity of the disease.

Other IL-17A-targeting drugs include SCH-900117, CNTO6785 and bimekizumab, which are in Phase I to Phase III of their clinical trials (Table 1). Another randomized, placebo-controlled, phase II, dose-ranging study has been carried out to evaluate the immunogenicity, pharmacokinetics, safety and efficacy of CNTO6785, which is the human monoclonal antibody to interleukin 17A in rheumatoid arthritis patients with insufficient response to methotrexate (MTX) therapy (Table 1). Their study showed that although CNTO6785 was well-tolerated, it was not clinically efficacious in RA patients with insufficient response to MTX. However, it did suggest that due to the favorable safety profile, CNTO6785 could be a potential treatment candidate for other autoimmune diseases [79], also see Table 1.

Role of IL-17 in the pathogenesis of Systemic Lupus Erythematosus (SLE)

SLE is a chronic and heterogeneous autoimmune disease that is characterized by the presence of autoantibodies against various autoantigens leading to damage in tissues such as the skin, joints, and kidneys. Several factors, including environmental influences, molecular mediators, various immune cells, and genetic susceptibility loci lead to the development and progression of lupus [80]. Recent studies have demonstrated that IL-17 and Th17 cells play a pivotal role in SLE progression in both mouse models and patients [81]. Other preclinical studies showed that lupus-prone mice (MRL/lpr) had an expansion of Th17 cells and increased expression of IL-17A mRNA, which correlated to increased disease activity [82]. In addition, lymphocytes from lymph nodes, splenocytes, including double negative (DN) T cells of MRL/lpr mice produced significantly higher levels of IL-17 than lymphocytes from the control MRL/MPJ mice [83]. In addition, B6/lpr mice had significantly more Th17 cells than the control mice. Similarly, autoimmune BXD2 mice had an increased level of IL-17 than wild-type mice.

There are several potential targets for therapy in SLE. Interactions among CD4⁺ T cells can be disrupted by blocking IL-17 signaling. This can be seen in IL-17 receptor-deficient mice, which had decreased B cell development in germinal centers and reduced humoral responses [84]. Plasmacytoid dendritic cells and monocytes play an important role in the production of other cytokines (i.e. IL-23) that stimulate the production of IL-17 [85]. Increased levels of IL-6 and IL-23 have been reported in both the tissue and serum of patients with SLE along with increased levels of IL-17-producing cells [86]. Additionally, αβ TCR⁺CD⁻CD8⁻ double negative (DN) T cells, which is a small T cell subset in mice and healthy individuals[87] produce IFN-γ, IL-1β, and a significant fraction of IL-17 along with the increased numbers of γδ T cells in the peripheral blood of SLE patients. However, despite knowledge of factors contributing to the pathogenesis of SLE and numerous endeavors to develop efficacious treatment for patients with SLE, there is still a paucity of approved medications. The only approved treatment over that last 60 years for SLE patient is belimumab, which is a human monoclonal antibody that inhibits B-cell activating factor (BAFF). Although, IL-17 has not yet been therapeutically targeted in human SLE, ustekinumab treatment could yield potential improvements in cutaneous lupus [80]. There are still ongoing clinical trials with composite endpoints for SLE that may progress in capturing clinically meaningful therapeutic responses [88].

Role of IL-17 in the pathogenesis of Hashimoto’s thyroiditis (HT)

HT is one of the most prevalent autoimmune thyroid diseases (AITD). It is characterized by autoantibody production, lymphocyte infiltration, and fibrosis of the thyroid gland that lead to tissue inflammation and cell destruction [89, 90]. Activation of CD4⁺ T cells, especially Th17 cells, plays a critical role in the pathogenesis of HT. These cells are characterized by the surface expression of CCR6, IL-23R, IL-12R-beta2, CD49, and CD161. In addition to IL-17A and IL-17F, Th17 cells produce IL-21, IL-9, IL-22, and TNFα. IL-17 also induces the expression of other proinflammatory cytokines (IL-6, IL-8, GM-CSF, G-CSF), metalloproteinases, and chemokines. Patients with HT have increased numbers of CD4⁺ T cells in the interstitium [91, 92] and increased serum concentrations of IL-6 and IL-23, which promote Th17 differentiation [91, 93]. Similarly, high levels of Th17 cells in untreated children with HT suggests their participation in development of HT [94]. Moreover, Li et al [95] noted a vigorous relation between the concentration of IL-17 and stromal fibrosis of the thyroid, suggesting that elevated IL-17 promotes local inflammation and causes atrophy of thyrocytes and fibrosis. Additionally, there is an increased level of IL-17 mRNAs in PBMCs of HT patients [96]. Recent studies have shown a significant positive correlation between percentage of Th17 cells and level of Thyrotropin stimulating antibodies (TSAbs) [94, 97] as well as a positive correlation between the proportions of CD4⁺ IL17⁺/CD4⁺ CD25⁺ CD127⁻ FoxP3⁺ T cells and levels of TSAbs in newly diagnosed GD (Graves’ disease) patients. There was also a positive correlation between the thyroperoxidase (TPO) and thyroglobulin (TG) antibodies and CD4⁺ CD161⁺ CD196⁺/CD4⁺ CD25⁺ CD127⁻ T cells in untreated Hashimoto’s thyroiditis patients, which supports a role of Th17 in the progression of autoimmune thyroid diseases [97]. Besides Th17 cells, IL-17-producing γδ T cells have also been identified as a significant source of IL-17 in the thyroid tissue of patients with HT that may account for 55 % of CD3⁺ T cells in inflamed glands [98]. As discussed above, IL-17 and Th17 could play a vital role in the pathogenesis of HT and could be a potential target for prevention and treatment.

Role of IL-17 in pathogenesis of Inflammatory Bowel Disease (IBD)

IBD is a chronic relapsing inflammatory disorder that leads to chronic gastrointestinal inflammation and includes ulcerative colitis (UC) and Crohn’s disease (CD) [99]. It has been shown that IBD patients with inflamed gastrointestinal mucosa show immense Th17 cell infiltration and monocytes/macrophages that produce Th17-related cytokines. In both UC and CD tissues, there are high levels of IL-17-producing cells and upregulation of RNA transcripts for IL-17A and IL-17F in inflamed guts when compared with healthy controls. Other studies have indicated a positive correlation between the severity of disease and levels of IL-17-secreting PBMCs in UC patients [99–101]. Other groups have shown that IL-23- and IL-17-producing intestinal lymphocytes were remarkably increased in UC and CD. IFN-γ production was also enhanced by γδ T cell activation providing a source of IL-17 production in PBMCs of IBD patients [102, 103].

Indeed, understanding the important role of lL-17 in the pathogenesis of IBD could pave the way to the development of therapeutic targets in the IL-17 pathway. Since the role of IL-17 has been established in the pathogenesis of IBD, recent drug development strategies are focused on using IL-17-neutralizing mAbs. IL17R knockout mice have shown substantial protection against trinitrobenzenesulfonic acid- (TNBS-)-induced colitis when compared with the wild-type mice[104]. Furthermore, colonic inflammation due to acute TNBS colitis has been attenuated in mice overexpressing an IL-17R IgG1 fusion protein after induction of TNBS [104]. Blockade of IL-17 in animal models of IBD as well as in humans, however, has led to controversial results. As a consequence, current clinical trials are focused on combined IL-17A and IL-17F inhibition. (See Table 1). Vidofludimus (SC12267, 4SC-101) is a recent oral immunomodulator that inhibits dihydroorotate dehydrogenase (DHODH) and targets IL-17A and IL-17F and IFN-δ by impairing the NFκB and JAK/STAT pathways [105]. Since it has been used for clinical trials, the efficacy, safety, and tolerability of vidofludimus in IBD patients have been proved in phase 2 double-blind, randomized, multicenter placebo-controlled trials and dose-finding studies. The safety and efficacy evaluation of vidofludimus calcium have been analyzed in moderate-to-severe ulcerative colitis patients for induction and maintenance therapy (ClinicalTrials.gov identifier (NCT number): NCT03341962). Secukinumab, a human anti-IL-17A antibody, has failed to have any significant efficacy in CD patients [106, 107]. In Crohn’s patients, brodalumab and secukinumab have been administrated for clinical trials and unexpectedly, increased disease activity and subsequently failed the trial [108]. Thus, there is a lot to be learned about IL-17 in IBD and deciphering of why IL-17 blockade is yet to provide remedy for IBD patients.

Role of IL-17 in Celiac disease (CD)

CD is a prototypic CD4 T cell-dependent disease that leads to an intolerance of dietary gluten [109]. Several factors contribute to the pathogenesis of CD. HLA-DQ2 is a strong genetic determinant that is expressed in more than 90% of CD patients, whereas HLA-DQ8 molecules are expressed by the rest of celiac patients [110]. The production of cytokines following the activation of T cells plays a critical role in the development of CD [111]. A number of cytokines have been implicated in the pathogenesis of CD. Increased levels of IL-6 and IL-17 have been reported in patients with CD [112, 113]. Another study on patients with IBD and CD, found increased levels of IL-17, IL-21 and IFN-γ in their cohort [112]. It is apparent from these and other studies that IL-17 is a potential contributor to CD development whose pathogenic role is a focus in several ongoing investigations. Ex vivo experiments have shown that intracellular IL-17A is produced from CD4 T cell as well as CD8 T cells in biopsy samples in response to peptic-tryptic digest of gliadin [113]. Indeed, they have demonstrated that in the small bowel context of CD, gliadin-reactive CD4+ T cells are the main source of IL-17A [114, 115]. While Th17 primarily produces IL17, specific Treg cell populations, which are increased in lymphocytic colitis have also been found to be producing IL-17 in the mucosa of CD, UC and IBD patients. In addition, another study showed that mRNA levels of IL-17A, IFNγ, and Foxp3 in untreated CD patients were significantly higher than their levels patients treated for CD [116]. These results support a role of IL-17 in the pathogenesis of CD and potential use it in monitoring of clinical progression.

Recent studies are also focusing on the correlation between polymorphisms in IL-17 gene and CD. Indeed, IL-17A (197A/G) gene polymorphism had an impact on the development of acute myeloid leukemia, gastric carcinogenesis, and UC [117, 118]. However, similar studies in CD patients did not show a statistically significant association between the IL-17 (−197A/G) polymorphism and CD[119]. Another study looking at genetic variations (single nucleotide polymorphisms) of the IL4, IL5, IL9, IL13, IL17B and NR3C1 (GR) susceptibility loci of chromosome 5q (CELIAC2) found no significant allele or haplotype frequency differences between CD and control group [120]. Outside of those types of studies, there are currently no approved clinical trials investigating immunomodulatory therapeutics for CD perhaps likely because CD can be well-managed by dietary modification.

Concluding remarks

IL-17 is a significant contributor to the development and/or acute and chronic phases of several autoimmune diseases. Nonetheless, immunotherapies inhibiting this cytokine and its activity have been found to be efficacious in controlling and modulating severity of a limited numbers of autoimmune conditions. On other hand, it was outright pathogenic or ineffective in cases of other drugs. Understanding the mechanistic reasons behind these discrepancies will be very useful in expansion utilization of IL-17 in clinic. Additional efforts are currently focused on producing second generation therapies that are safer and more tolerable. Furthermore, efforts are also directed towards determining whether IL-17 blockade can be efficacious in treating other autoimmune diseases. The next few years will determine whether IL-17 based immunotherapy has reached its limits or whether its magic can be expanded and find opportunity in treating other conditions. We bet on the latter.

Highlights.

• IL-17 is becoming an important therapeutic target for autoimmune diseases, but yet to reach its full potentials as it inefficacious or outright pathogenic in cases of certain autoimmune diseases.

• Here we review the roles of IL-17 in selected autoimmune diseases and provide updates on ongoing or recently completed clinical trials aiming to extend therapeutic application of IL-17 blockade to other immunotherapies.