The application of molecular techniques to gastroenterology continues to yield important advances in the development of drugs to treat gastrointestinal disorders. Important new drugs have emerged through the collaborative and complementary efforts of basic scientists, clinicians, and clinical researchers in academia and the pharmaceutical industry. The challenge has been exciting, with a few surprises along the way. Consider peptic ulcer disease as an example.
The discovery of H receptors and the availability of potent and 2 selective H-receptor antagonists signaled the beginning of a new era 2 in the treatment of gastric hypersecretory states and peptic ulcers. Introduction of proton pump inhibitors offered another therapeutic option. Though H-receptor antagonists and proton pump inhibitors 2 are important and useful drugs, the discovery of the link between H. Our intent in Drug Development: Molecular Targets for GI Diseases is to bring together hands-on experts to review promising areas of gastrointestinal pharmacology.
The delicate regulatory mechanisms between proinflammatory and anti-inflammatory cytokines in the mucosa of patients with IBD are yet to be refined. Nevertheless, several approaches to cytokine-based therapy have already been initiated with differing results regarding efficacy and safety.
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In models of experimental colitis, IL rather than IL has been suggested to be the main determinant of chronic intestinal inflammation. Leukocyte infiltration into the intestine is important in IBD initiation and perpetuation. In addition, chemokines and chemokine receptors coordinate trafficking of leukocytes.
Th1, Th2, and Th The final phenotype of effector T cells depends on the antigens and the cytokine milieu present at the time of activation, but details of these phenomena still remain largely unkown.
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IL testing is a good example showing a difference between the paths from bench to bedside and that, in some instances, theory that IL could be beneficial to IBD patients contradicts the results of clinical practice showing quite disappointing results with IL use in IBD. TRegs represent a T-cell subset with great immunological importance as molecular targets for IBD therapy.
IL activates different signaling pathways to exert its anti-inflammatory action, and it has been suggested that IL could represent an important potential therapeutic target in IBD. Dekavil is an immunocytokine consisting of a targeting antibody fused to the anti-inflammatory cytokine IL Dekavil has entered Phase II clinical trials in combination with methotrexate for the therapy of Rheumatoid Arthritis and investigations in IBD indications are being considered.
Each of the cytokines above has been discussed as a single entity and as an isolated therapeutic opportunity in the panel of strategies for IBD. Another perspective could be that of targeting multiple cytokines simultaneously to control disease activity. This concept parallels the concept that, in the inflamed mucosa, a variety of cytokines interact together. One example of this multifocused strategy is tofacitinib, a small-molecule Janus-activated kinase JAK inhibitor. JAKs are a family of cytoplasmic enzymes that are important to downstream signaling of many cytokines after interacting with the transmembrane receptor.
The identification of new mechanisms in IBD pathophysiology has pointed to more specific molecular targets for therapy, including those interfering with inhibition of leukocyte trafficking to the gut. Several other compounds that interfere with gut homing have been evaluated, including antibodies against MAdCAM-1, which was shown to be effective in moderate-severe UC. Initiation and perpetuation of chronic inflammation rely on immunity mechanisms and oxidative stress balance. Oxidative stress has a crucial role in intestinal inflammation.
When inflammation is initiated, activated leukocytes produce a wide spectrum of proinflammatory cytokines and also trigger oxidative reactions, which affect the redox equilibrium within the gut mucosa. This oxidative stress—induced imbalance maintains inflammation by initiating redox-sensitive signaling pathways and proinflammatory transcription molecules. For example, IBD could possibly be treated by inducing local production of anti-inflammatory molecules, as well as by developing biologic therapies that target selective molecules affecting redox balance and molecular signaling e.
The ultimate goal of histologic healing in IBD is still far from becoming a reality, and the closest therapeutic scenario related to clinical practice is biological healing, which is directly related to mucosal healing. Important steps in mucosal healing include cell proliferation, migration, expansion, and differentiation leading to mucosal healing and intestinal epithelial normalization.
These cells promote the healing and regeneration process through a very well balanced function which is regulated by special molecular mediators and tissue repair feedback signaling. Although it is difficult to discern which factors are of importance in determining these events and which are bystanders in these mucosal healing phenomena, it would be important to delineate factors that could be critical in the process of mucosal healing.
This approach of revealing the optimal strategies for mucosal healing could also point toward new therapeutic molecules for IBD.
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However, it is clear that the therapeutic needs in IBD are still unmet, and the efficacy of these new therapies is limited in some groups of patients. Several novel strategies have been developed to address these needs of IBD patients for more effective and safer therapies.
These strategies include reinforcing epithelial barrier function, proinflammatory cytokine inhibition, blocking of inflammatory cell trafficking, and enhancing TReg function Table 2. Advances in molecular genetics have shown that several IBD-related genes involved in immune pathways could represent useful therapeutic targets. An example of the dynamic interaction of adaptive immunity is in the role of Th17 cells in IBD. Patients with CD have been shown to have increased Th17 cells; hence, anti-IL antibody secukinumab was tried as a therapeutic strategy.
Unexpectedly, secukinumab resulted in the worsening of CD and more adverse events in treated patients, which was attributed to the complex biology of Th17 cells.
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A drawback of current clinical trials is inadequate or lack of immunophenotyping of patients. However, recent advances in high-throughput technologies provide an opportunity to monitor the dynamics and the complexity of the immune system, which may to lead to a more personalized treatment approach in IBD. It is important to mention that different drugs could produce similar therapeutic effects regarding modification of inflammatory pathways.
Many studies 40 — 44 have challenged new perspectives on the discovery of molecular targets for definitive IBD therapy. We have learned that experimental data do not always correspond to disease in clinical settings and that many improvements and refinements of our molecular approach to IBD have yet to be done.
New studies assessing the complex immune signatures in response to different therapies are needed. This poses the question of whether further and profound progress can be made with targeting cytokines in IBD. A possible answer is to target several cytokines at the same time, through a combination of different targeted antibodies, through interfering with overlapping intracellular signaling pathways, or through enhancement of anti-inflammatory cytokines.
However, it does not seem wise to randomly test possible combinations. Instead, it is mandatory that we increase and repeatedly test our knowledge about the pathogenesis of IBD using model systems. Even in the same patient, the underlying immunopathologic processes may change over time, regardless of the initial triggering events.
Finally, the expanding role of new delivery systems that allow more targeted drug delivery is also expected to benefit IBD therapeutics. These new delivery systems that allow more targeted drug delivery include for example nanomedicine which represents a major challenging field with its main aims: Although the real applications of these systems still need major work, nevertheless new challenges are open, and perspectives based on integrated multidisciplinary approaches would enable both a deeper basic knowledge and the expected advances in biomedical field.
The great challenge of balancing the control of mucosal inflammation and avoidance of harmful events remains to be successfully addressed. Despite the increased knowledge gained from animal and human studies, many aspects of mucosal immunity in patients with IBD remain unclear.
Recently, significant progress has been made in high-throughput technologies such as genomic sequencing, which provide multiparametric data that can be used to not only define the various immune cell states but also assess how they interact with each other in various conditions. More detailed knowledge of the complexity of the immune system in IBD will improve the classification of IBD, the development of more representative animal models, and the design of new biologic therapies for a more personalized treatment approach.
No potential conflict of interest relevant to this article was reported.
National Center for Biotechnology Information , U. Journal List Gut Liver v. Published online May Katsanos 1 and Konstantinos A. This article has been cited by other articles in PMC. Abstract Therapy for inflammatory bowel disease IBD has changed, with several new agents being evaluated. Crohn disease, Inflammatory bowel disease, Molecular targets, Therapy targets, Colitis, ulcerative.
Mucosal healing, tissue destruction Dendritic cells, adipocytesM Fibroblasts, myofibroblasts. Open in a separate window. Epithelial barrier The epithelial cells comprise enterocytes, goblet cells, neuro-endocrine cells, Paneth cells, and microfold cells or M cells. Apoptosis regulation The control of cell death in the intestinal epithelium is delicately balanced.
Antigen-presenting cells 1 Macrophages During pathogen invasion and inflammation, intestinal macrophages recruited from blood monocytes rapidly convert to a proinflammatory phenotype. Atypical lymphocytes The atypical lymphocytes and natural killer T cells are also a part of the innate immune response system.
Paneth cells, defensins, and the autophagy pathway Paneth cells are epithelial cells found at the base of the small intestinal crypts which can sense luminal microbiota and antigens and secrete antimicrobial peptides to contribute to innate immunity. Cytokines In patients with IBD, a large variety of cytokines are derived from different cells of the mucosal immune system, including intestinal epithelial cells, macrophages, natural killer cells, mucosal effector T cells T helper [Th] 1, 2, and 17 , and regulatory T cells TRegs.
Multiple cytokine inhibition Each of the cytokines above has been discussed as a single entity and as an isolated therapeutic opportunity in the panel of strategies for IBD. Critical overview Novel strategies for more effective and safer therapies. Able to predict individual disease courses and therapeutic responses through the assessment of molecular biomarkers.
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