Current Drug Targets - Volume 14, Issue 12, 2013

The heterodimeric cytokines IL-12 and IL-23 play a key role in T helper cell and innate lymphocyte cell differentiation and expansion. They are composed of a shared p40 chain, which pairs with a p35 or p19 chain to form IL-12 and IL-23, respectively. Preclinical model systems have predicted an important role of the p40 chain in intestinal inflammation. Moreover, genome-wide association studies have revealed that variants of the gene encoding the IL-23 receptor, as well as the locus harboring the gene encoding the p40 chain, confer genetic risk for developing Crohn’s disease (CD) and ulcerative colitis (UC). Two monoclonal antibodies neutralizing the p40 chain (ustekinumab and briakinumab) and hence blocking both IL-12 and IL-23 activity, have been developed, which demonstrated clinical benefit in early phase trials, and hinted towards efficacy in a subpopulation of patients with CD who had failed prior anti-TNF antibody treatment. A dedicated phase 3 clinical trial of ustekinumab in patients suffering from moderate-to-severe CD who had previously failed anti-TNF antibody treatment indeed demonstrated a significant benefit over placebo for clinical response, but not remission, in this particularly difficult to treat patient population. Here we review the immunological and genetic background to anti-IL-12/IL-23-directed therapeutic strategies, and the lessons that can be learned from results of these and related clinical trials that tackle associated biological pathways.

The advent of anti-Tumor Necrosis Factor (TNF) therapy has changed the way of treating inflammatory bowel disease (IBD). However, primary and secondary failure are relatively frequent with all anti-TNF agents, which are available only as parenteral agents. Tofacitinib is an oral janus kinase (JAK) inhibitor that inhibits JAK family kinase members, in particular JAK1 and JAK3, achieving a broad limitation of inflammation by interfering with several cytokine receptors. It first proved its efficacy as an immunosuppressive regimen after renal transplantation, and was recently approved by the FDA for rheumatoid arthritis. First data in IBD are promising, especially in ulcerative colitis. Ongoing clinical trials in both UC and Crohn’s disease (CD) are needed to further explore its efficacy in CD and to better assess its safety profile.

Interleukin 18 (IL-18) is an IL-1 super family cytokine that is involved in infection, inflammation and autoimmune diseases. Mounting evidence suggests that IL-18 exert a dual role in inflammation and homeostasis. IL-18 can act as a promoter of T cell immunities, such as type 1 and 17 helper T cell responses, and thus enhances T cell-mediated inflammation, whereas IL-18 increases the barrier function and regeneration of epithelial cells and protects the host from inflammatory stimuli. Although the functional role of IL-18 in regulation of inflammation remains controversial, accumulating evidence indicates the contribution of IL-18 to the pathogenesis of inflammatory bowel diseases (IBD). For example, levels of serum and/or mucosal IL-18 and IL-18 binding protein are elevated in the patients with IBD. Furthermore, polymorphisms in IL-18 and IL-18-related molecules, such as the IL-18 receptor and/or an IL-18 activator NLRP3, genes are found in the patients with IBD. Thus, these preclinical data imply that IL-18 can be a novel therapeutic target for the treatment of IBD. In this review, we focus on IL-18 biology and physiological roles in animal models and human IBD, to provide an outline for development of IL-18 blockade strategies.

Crohn’s disease (CD) and ulcerative colitis (UC), two chronic and relapsing inflammatory bowel diseases (IBD), are supposed to develop in genetically-predisposed individuals as a result of an excessive immune mucosal response directed against normal components of the gut microbiota. There is also evidence that defects in counter-regulatory mechanisms play a major role in the pathogenesis of IBD. One such a defect involves TGF-β1, a cytokine produced by multiple cells types and able to inhibit pathogenic responses in the gut. In both CD and UC, TGF-β 1 is highly produced but unable to signal through the TGF-β receptor-associated Smad pathway and suppress production of inflammatory molecules. Abrogation of TGF-β1 activity has been related to Smad7, an intracellular protein that binds to TGF-β receptor and inhibits TGF-β1-driven Smad-dependent signalling. Indeed, silencing of Smad7 with a specific antisense oligonucleotide restores TGF-β1/Smad signalling, thereby down-regulating inflammatory cytokine production and ameliorating experimental colitis in mice. Altogether these observations led to the development of an oral pharmaceutical compound containing the specific Smad7 antisense oligonucleotide (herein termed GED0301), which seems to be safe and well tolerated in CD patients. In this article we summarize the data supporting the pathogenic role of Smad7 in IBD and discuss the recent results of the use of GED0301 in CD.

Significant advances have been achieved in the understanding of the pathogenesis of inflammatory bowel disease (IBD). A number of susceptibility genes have been detected by large genome wide screening-approaches. New therapeutic concepts emerge from these insights. The most important progress in recent years certainly is the introduction of biologics in the therapy of IBD. TNF blockers have been shown to be very effective for the control of complicated disease courses. Currently, in addition to the three already established anti-TNF antibodies, new anti-TNF molecules, for example Golimumab, are in clinical trials and also reveal promising results. However, not all of the patients respond to anti-TNF treatment and many patients lose their response. Therefore, additional therapeutic approaches are urgently needed. Attractive therapy targets are cytokines as well as their receptors and signaling pathways. At the moment a large number of biologicals and inhibitors are tested in clinical trials and some of them provide very promising results for the treatment of IBD patients. In particular, inhibition of IL-12p40 by specific antibodies as well as of the janus kinase (JAK)3 by a small molecule promise to be very effective approaches. Though antibodies targeting for example IL-6, IL-6R, IL-13 or CCR9 are only in the early steps of clinical development, they have already demonstrated to be a possible treatment option which needs to be confirmed in further trials. Taken together a large number of new therapeutic anti-cytokine approaches are currently tested in clinical trials in IBD patients. In this review, the new therapeutic approaches for cytokine inhibition in IBD patients are discussed.

Tumor necrosis factor (TNF) is a central pro-inflammatory cytokine that regulates the expression of numerous signaling pathways implicated in the progression of the immunological reaction. Unraveling the importance of TNF on the pathogenesis of inflammatory bowel disease (IBD) promoted anti-TNF antibodies as novel therapeutic agents. Initially, the main hypothesis behind the clinical application of anti-TNF antagonists in the clinic was that they exert their effects solely through neutralization of TNF. Anti-TNF antibodies induce and maintain clinical remission in patients with minimal side-effects. However, the cellular and molecular mechanisms of actions of the anti-TNF antibodies remain unknown. Various mechanisms of action have been proposed such as activation of transmembrane TNF mediated reverse signaling, induction of apoptosis, pro-inflammatory cytokine down-regulation, complement dependent cytotoxicity, antibodydependent cell-mediated cytotoxicity, and finally activation of regulatory immune cells via interactions with the Fc receptors. The observed discrepancies in the clinical efficacies as well as the differences in the structure of the various TNF antagonists nourish the investigation for additional modes of function.

Inflammatory bowel diseases (IBD) are characterized by a persistent recruitment of large quantities of leucocytes from the blood to the gut mucosa. Adhesion molecules, such as integrins and their ligands, are the main players in this complex process. Leucocyte traffic control using a specific integrin inhibitors, such as natalizumab, has been plagued by severe systemic effects. The α4β7 – integrin and its ligand, the MadCAM-1, have been of special interest, since they are found exclusively on the gut-homing lymphocyte subpopulations and in the intestinal mucosa respectively. It follows that inhibition of such molecules should offer gut-specific immunosuppression, without the systemic effects of aspecific integrin- antagonists. We review the role of vedolizumab, a humanized antibody against the α4β7 – integrin, in both ulcerative colitis (UC) and Crohn's disease (CD). Results from clinical trials show that vedolizumab is effective in the induction and maintenance of remission in active CD and UC and has a very good safety profile. These data allow to confidently prospect that vedolizumab will be an important therapeutic option in the future of IBD treatment.

Much work has been done to understand the molecular mechanisms underlying the inflammatory bowel diseases (IBD). IL-13 has emerged as an important cytokine effective in ulcerative colitis (UC) and fistulizing Crohn's disease (CD). IL-13 is a T helper 2-type cytokine with pleiotropic effects, involved in parasite expulsion, asthma pathophysiology, natural history of cancer and other human pathologies. Great interest has therefore been developed in inhibiting its function as a therapeutic intervention in these diseases. The multifunctional properties of IL-13, with particular emphasis on its role in both CD and UC, as well as current developing pharmacologic agents inhibiting the IL-13 signaling pathway have been reviewed. Anti-IL-13 agents seem to be promising therapeutic strategies for the future management of IBD and other human diseases.

The inflammatory response in patients with inflammatory bowel disease is a complex self-amplifying process with multiple cellular and molecular pathways controlling activation and shut-off of the process. Available therapeutic interventions with drugs that have a very selective action, such as anti-tumor necrosis factor antibodies, or broader effects such as corticosteroids still leave a significant proportion of patients with Crohn’s disease and ulcerative colitis insufficiently treated. Cellular therapies are emerging as promising new approaches to treat inflammatory bowel diseases and in particular Crohn's disease. Experimental and clinical data are the origin of the increasing utilization of cell therapies for severe immune-mediated diseases including inflammatory bowel disease. The types of cell therapies for these diseases can be divided into two different areas: hematopoietic stem cell therapies, and selected/conditioned immune cell therapy, the latter including mesenchymal stem cells and T-regulatory cells-based therapies.

Inflammatory bowel diseases (IBD) are considered barrier diseases. After misleading initial results, the pathogenic importance of a disturbed mucosa is now widely accepted, largely because a certain percentage of first-degree relatives of patients with IBD do have permeability alterations, as assessed by oral markers. In the presence of a normal appearing gut mucosa, functional alterations of the highly dynamic inter-enterocyte tight junctions have to be considered to be responsible for the observed alterations. Indeed, various alterations of the transmembrane and intracytoplasmic proteins have been reported in IBD. An important therapeutic goal is to maintain disease remission by preservation of the correct organization of these complexes. Of the potential therapeutic approaches, the various anti-TNF agents are the best-studied agents, but other treatments may tighten the gut through as yet unknown mechanisms.

Azathioprine is an efficient maintenance treatment of IBD, able to maintain a complete clinical and anatomical remission in about one third of patients. However there are concerns regarding its long term tolerance, particularly myelosuppression and malignancy. Azathioprine is not required in about one third of Crohn's Disease patients and more than half of Ulcerative Colitis patients who will experience a mild disease course. In patients with more severe disease, although anti-TNF agents are more powerful and act more rapidly, there is a subset of patients with moderate-to-severe IBD without important anatomical damage who may achieve a prolonged steroid-free clinical and anatomical remission on azathioprine monotherapy. It is thus advised to initiate azathioprine monotherapy in these intermediate cases, and to continue azathioprine if anatomical remission is achieved.

Therapeutic approaches in inflammatory bowel disease have changed significantly in the past decade. Early aggressive immunosuppression has become the mainstay of therapy for patients at risk for complicated disease. Azathioprine is the most widely used immunosuppressant; however, a subgroup of patients is intolerant or refractory. Since the late 1990s, methotrexate (MTX) has become more widely used as an immunomodulator in patients with chronic inflammatory diseases such as rheumatoid arthritis and psoriasis. Yet according to recent clinical data, methotrexate remained the second most commonly used immunosuppressive in inflammatory bowel diseases. Two landmark trials and subsequent studies provided evidence for the use of methotrexate in Crohn’s disease, both for induction and maintenance of remission. The evidence is less solid in ulcerative colitis, for which results of further randomized controlled trials are pending (e.g. Meteor, Merit). A potential new indication of MTX could be combination therapy with biologicals. While this is state of the art therapy in rheumatoid arthritis, data in inflammatory bowel diseases are less clear. Some studies suggest that combination with immunosuppressants could prevent the development of anti-drug antibodies, while others suggested anti- TNF induced autoimmune disorders as a potential indication. In contrast, improved efficacy was not reported by one study (COMMIT). Limitations include frequent side effects, route of administration, pregnancy and concerns about long-term safety. This review summarizes current knowledge on the efficacy and side effects of methotrexate, and tries to reevaluate the drug in the current IBD armamentarium.

Dysregulated recruitment of leukocytes into the intestine is a characteristic feature of IBD. Several families of molecules regulate the influx of these cells into sites of inflammation within the gastrointestinal tract. Pharmacological blockade of interactions between molecules that mediate the formation of stable bonds (integrins) and their endothelial ligands has already shown clinical efficacy. Antibodies that target participant molecules have been approved by the US Federal Drug Administration for use in Crohn’s, multiple sclerosis (MS) (i.e. natalizumab) and psoriasis (i.e. efalizumab). A more recent additional family of drugs, which might also interfere with lymphocyte traffic (i.e. sphingosine-1- phosphate receptor agonists: fingolimod) is in clinical use for MS and just recently entered the clinical trial stage for ulcerative colitis. In the present review we discuss basic aspects of clinically relevant molecules and compile the clinical studies that support the targeting of specific steps of the leukocyte adhesion cascade for therapeutic purposes in IBD.

Peroxisome proliferator–activated receptor gamma (PPARγ) is a nuclear receptor, originally described in adipose tissue, that controls the expression of a large number of regulatory genes in lipid metabolism and insulin sensitization. Well known by endocrinologists, thiazolidinediones (TZDs) are classical PPARγsynthetic agonists which were currently used as insulin-sensitizing agents in the treatment of type 2 diabetes. While the clinical benefits of TZDs in treating metabolic disorders have been clearly demonstrated, new studies performed in animal models of colitis and in patients with ulcerative colitis have also revealed the key roles of PPARγ activation in the regulation of inflammation and immune response, notably in the colon through epithelial cells. During inflammation, PPAR acts directly to negatively regulate gene expression of proinflammatory genes in a ligand-dependent manner by antagonizing the activities of other transcription factors such as members of the NF-κB and AP-1 families. A major mechanism that underlies the ability of PPARs to interfere with the activities of these transcription factors has been termed transrepression. PPARγ acts by inhibiting signaldependent transcription factors that mediate inflammatory programs of gene activation. However, due to safety issues concerning particularly the greater risk of myocardial infarction, use of TZDs has been severely limited for the treatment of type 2 diabetes and/or inflammatory diseases, justifying the development of a new family of PPARγ agonists with major transrepressive effects and without toxicity. By the demonstration that the anti-inflammatory effects of 5- aminosalicylic acid (5-ASA) in patients with ulcerative colitis were mediated by PPARγ activation, several molecules having 5-ASA similarities have been developed and screened leading to the selection of a aminophenyl-alpha-methoxypropionic acids named GED-0507-34-Levo (GED). This compound activating PPARγ has 100-to 150-fold higher anti-inflammatory activity than 5-ASA. This new PPAR modulator is giving promising results both in vitro and in vivo, without toxicity and is currently evaluated in a phase 2 clinical trial. The aim of this review is to present and discuss the evidence suggesting that PPARγ targeting is of therapeutic interest in the treatment of UC.

Inflammatory bowel diseases (IBD) are chronic, relapsing, and destructive inflammatory disorders of the gastrointestinal tract. Both Crohn’s disease (CD) and ulcerative colitis (UC) seem to arise from an impaired dialog between the environment and gut microbiota in genetically susceptible hosts, leading to an inappropriate immune activation and resulting in the over-production of pro-inflammatory cytokines. IL-6 is a key modulator of inflammatory response. It is a phylogenetically important cytokine with relevance in IBD, as well as in other chronic inflammatory diseases and cancer. Influencing the production of this cytokine can change the balance of effector CD4+ T cell subsets and induce B cell antibody production. Moreover, given IL-6 is mostly produced from innate immune cells such as macrophages, neutrophils and mast cells, it is a strategic bridge between the innate and the adaptive system. Interestingly, IL-6 induced signaling can be primarily seen in a relatively small number of IL-6 responsive cells whereas in a chronic phase of inflammation it is able to activate almost all cells of the body through a process known as trans-signaling. In this review, we discuss the role of IL-6 in chronic inflammation, with particular emphasis on its role in CD and UC, and we explore the potential to develop anti-IL-6 agents for IBD treatment.