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Multifaceted Role of Th17 Cells in Psoriatic Disease
Published in Siba P. Raychaudhuri, Smriti K. Raychaudhuri, Debasis Bagchi, Psoriasis and Psoriatic Arthritis, 2017
In 2005, the discovery of CD3+/CD4+ Th17 cells changed the paradigm for understanding autoinflammatory disease processes [7,8]. Th17 cells are a distinct form of CD4+ T cells that by either induction or activation can produce a completely distinct cytokine repertoire. These cells respond to the interleukin 1 receptor 1 (IL-1R1) and interleukin 23 receptor (IL-23R) signaling pathways. It has been postulated that transforming growth factor β (TGFβ), IL-1, IL-6, and IL-23 induce retinoic acid orphan receptors (RORγt and RORα), which result in the upregulation of IL-23R and eventual differentiation of naïve CD4+ T cells into Th17 cells. This has been eloquently summarized in a model for the development of Th17 cells, consisting of three overlapping steps: differentiation, amplification, and stabilization [9]. In particular, TGFβ and IL-6 induce differentiation, IL-21 expressed by developing Th17 cells mediates amplification, and IL-23 expands and stabilizes previously differentiated Th17 cells (also summarized in Table 6.1) [9].
The history of psoriasis
Published in M. Alan Menter, Caitriona Ryan, Psoriasis, 2017
M. Alan Menter, Bobbak Mansouri
With advances in our understanding of the molecular pathways of psoriasis, newer, more targeted biologic therapies have been developed. The discovery of the critical role of interleukin-23 (IL-23)/Th17 axis in the immunopathogenesis of psoriasis has been the most fundamental advance to date in psoriasis research and has led to the development of many selective biologic agents that target this pathway. Ustekinumab, an antibody to the common p40 subunit of IL-12 and IL-23, has shown considerable efficacy in the treatment of psoriasis and psoriatic arthritis, and it was licensed for use in psoriasis in 2008 in Europe and Canada and in 2009 in the United States.26,27 Finally, the first of the anti-IL-7 molecules, secukinumab and ixekizumab, have been approved for psoriasis in 2015 and 2016, respectively.28,29 The third of these molecules, broadalumb, was approved by the FDA in July. Multiple, new targeted treatments are currently in clinical development for the treatment of psoriasis, including IL-23 inhibitors, and bispecific anti-TNF-α/IL-17A fusion proteins.
Ustekinumab
Published in John Y. M. Koo, Ethan C. Levin, Argentina Leon, Jashin J. Wu, Alice B. Gottlieb, Moderate to Severe Psoriasis, 2014
The etiology of psoriasis is unknown, although it is generally believed to be a complex T-cell-mediated inflammatory disease with a genetic basis [1,2]. Psoriasis shares immunologic and genetic features with other T-cell-mediated autoimmune inflammatory conditions, such as Crohn’s disease, rheumatoid arthritis, and multiple sclerosis; CD4+ T-helper cells, called T-helper (Th) 17 cells, are important in the pathogenesis of many of these diseases [3], including psoriasis [2,4–6]. Interleukin-23 (IL-23) stimulates survival and proliferation of Th17 cells and thus serves as a key master cytokine regulator for these diseases. In psoriasis, IL-23 is overproduced by activated dermal dendritic cells, and this cytokine stimulates Th17 cells within the dermis to make IL-17A and IL-22. In turn, IL-17A and IL-22 drive keratinocyte activation and hyperproliferation in psoriasis. This chapter will focus on the role of the IL-23/Th17 inflammatory pathway in psoriasis pathogenesis and on the specific targeting of IL-12/IL-23 by ustekinumab.
Cytokine alterations in psoriasis: an updated review
Published in Expert Review of Clinical Immunology, 2021
Homa Seyedmirzaei, Nima Rezaei
The interplay between innate and adaptive systems is vital to the disease’s pathogenesis in terms of the immune system’s role. Psoriasis plaques are a result of abnormal keratinocyte differentiation in an inflamed environment [6]. T-cells, plasmacytoid and myeloid dendritic cells, neutrophils, and Langerhans cells are reported to be differently distributed in these plaques [7]. Different chemokines and cytokines mediate the interplay between these cells and keratinocytes. For example, the interleukin 23 (IL-23) and Tumor Necrosis Factor-alpha (TNF-α) are the main cytokine pathways explaining the inflammation in psoriasis. Different cells such as dendritic cells and macrophages secrete these cytokines, which can activate T-helper 17 and other macrophages, respectively [8]. New cytokines appear, and therefore, keratinocytes start to have abnormal changes. These cells could also be a significant source of pro-inflammatory cytokines themselves and stimulate the immune cells present in the skin [9].
How can we improve peptide drug discovery? Learning from the past
Published in Expert Opinion on Drug Discovery, 2021
Regarding peptide delivery, we stress that oral activity is not the same as oral bioavailability, and that there are cases where oral delivery is desired, but systemic oral bioavailability is not. The most obvious case here is for gut disorders where the receptor sites are in or near the lumen of the digestive tract. Linaclotide, a 14 amino peptide used in the treatment of IBS is a good example here. The stabilization of this peptide by its three disulfide bonds is sufficient to protect it from digestive proteases. These types of disorders, where oral delivery is desired, but systemic exposure is not, are being explored by multiple pharmaceutical companies, including Protagonist in the development of a gut-restricted, interleukin-23 receptor antagonist peptide, currently in a Phase 2 clinical trial for Crohn’s disease. These applications aside, it is still the case that oral delivery remains a major challenge for peptide-based drug design, and approaches ranging from cyclization, N-methylation, stapling, and scaffold grafting are being pursued.
Perspectives on the pharmacological management of psoriasis in pediatric and adolescent patients
Published in Expert Review of Clinical Pharmacology, 2021
Emmanuel Mahé, Maud Amy De La Bretêque, Céline Phan
The near future looks promising for the treatment of children and adolescents with psoriasis, particularly if new therapeutics can be evaluated rapidly in young patient populations. In the field of topical therapies, the arrival of combined therapies and new nonsteroidal drugs – such as benvitimob, a first-in-class aryl hydrocarbon receptor (AhR)-modulating agent (TAMA). Among oral treatments, validation of the use of apremilast in young patients is expected in 2021, and new classes of drugs, such as Janus kinase inhibitors, are set to arrive on the market. Among the biologics, the evaluation of anti–interleukin-23 is ongoing. The better knowledge of genetic of psoriasis also leads to new approaches. For instance, generalized pustular psoriasis is a rare, life-threatening type of psoriasis that may develops in childhood. In some of these patient’s loss-of-function mutations have been found in IL36RN, which encodes an interleukin-36–receptor antagonist. Recently a monoclonal antibody against the interleukin-36 receptor (BI 655,130) has been developed with promising results [76].