Ponesimod, a selective S1P1 receptor modulator: a potential treatment for multiple sclerosis and other immune-mediated diseases

The first oral treatment for relapsing multiple sclerosis, the nonselective sphingosine-1-phosphate receptor (S1PR) modulator fingolimod, led to identification of a pivotal role of sphingosine-1-phosphate and one of its five known receptors, S1P(1)R, in regulation of lymphocyte trafficking in multiple sclerosis. Modulation of S1P3R, initially thought to cause some of fingolimod's side effects, prompted the search for novel compounds with high selectivity for S1P1R. Ponesimod is an orally active, selective S1P(1)R modulator that causes dose-dependent sequestration of lymphocytes in lymphoid organs. In contrast to the long half-life/slow elimination of fingolimod, ponesimod is eliminated within 1 week of discontinuation and its pharmacological effects are rapidly reversible. Clinical data in multiple sclerosis have shown a dose-dependent therapeutic effect of ponesimod and defined 20mg as a daily dose with desired efficacy, and acceptable safety and tolerability. Phase II clinical data have also shown therapeutic efficacy of ponesimod in psoriasis. These findings have increased our understanding of psoriasis pathogenesis and suggest clinical utility of S1P(1)R modulation for treatment of various immune-mediated disorders. A gradual dose titration regimen was found to minimize the cardiac effects associated with initiation of ponesimod treatment. Selectivity for S1P(1)R, rapid onset and reversibility of pharmacological effects, and an optimized titration regimen differentiate ponesimod from fingolimod, and may lead to better safety and tolerability. Ponesimod is currently in phase III clinical development to assess efficacy and safety in relapsing multiple sclerosis. A phase II study is also ongoing to investigate the potential utility of ponesimod in chronic graft versus host disease

The Aesthetic Self. The Importance of Aesthetic Taste in Music and Art for Our Perceived Identity

To what extent do aesthetic taste and our interest in the arts constitute who we are? In this paper, we present a series of empirical findings that suggest an Aesthetic Self Effect supporting the claim that our aesthetic engagements are a central component of our identity. Counterfactual changes in aesthetic preferences, for example, moving from liking classical music to liking pop, are perceived as altering us as a person. The Aesthetic Self Effect is as strong as the impact of moral changes, such as altering political partisanship or religious orientation, and significantly stronger than for other categories of taste, such as food preferences (Study 1). Using a multidimensional scaling technique to map perceived aesthetic similarities among musical genres, we determined that aesthetic distances between genres correlate highly with the perceived difference in identity (Study 2). Further studies generalize the Aesthetic Self Effect beyond the musical domain: general changes in visual art preferences, for example from more traditional to abstract art, also elicited a strong Self Effect (Study 3). Exploring the breadth of this effect we also found an Anaesthetic Self Effect. That is, hypothetical changes from aesthetic indifference to caring about music, art, or beauty are judged to have a significant impact on identity. This effect on identity is stronger for aesthetic fields compared to leisure activities, such as hiking or playing video games (Study 4). Across our studies, the Anaesthetic Self Effect turns out to be stronger than the Aesthetic Self Effect. Taken together, we found evidence for a link between aesthetics and identity: we are aesthetic selves. When our tastes in music and the arts or our aesthetic interests change we take these to be transformative changes.Peer Reviewe

Analysis of the Paired TCR α- and β-chains of Single Human T Cells

Analysis of the paired i.e. matching TCR α- and β-chain rearrangements of single human T cells is required for a precise investigation of clonal diversity, tissue distribution and specificity of protective and pathologic T-cell mediated immune responses. Here we describe a multiplex RT-PCR based technology, which for the first time allows for an unbiased analysis of the complete sequences of both α- and β-chains of TCR from single T cells. We validated our technology by the analysis of the pathologic T-cell infiltrates from tissue lesions of two T-cell mediated autoimmune diseases, psoriasis vulgaris (PV) and multiple sclerosis (MS). In both disorders we could detect various T cell clones as defined by multiple T cells with identical α- and β-chain rearrangements distributed across the tissue lesions. In PV, single cell TCR analysis of lesional T cells identified clonal CD8+ T cell expansions that predominated in the epidermis of psoriatic plaques. An MS brain lesion contained two dominant CD8+ T-cell clones that extended over the white and grey matter and meninges. In both diseases several clonally expanded T cells carried dual TCRs composed of one Vβ and two different Vα-chain rearrangements. These results show that our technology is an efficient instrument to analyse αβ-T cell responses with single cell resolution in man. It should facilitate essential new insights into the mechanisms of protective and pathologic immunity in many human T-cell mediated conditions and allow for resurrecting functional TCRs from any αβ-T cell of choice that can be used for investigating their specificity

The role of IL-23 and the IL-23/TH17 immune axis in the pathogenesis and treatment of psoriasis

Psoriasis is a chronic, immune-mediated disease affecting more than 100 million people worldwide and up to 2.2% of the population. The aetiology of psoriasis is thought to originate from an interplay of genetic, environmental, infectious and lifestyle factors. The manner in which genetic and environmental factors interact to contribute to the molecular disease mechanisms has remained elusive. However, the interleukin 23 (-23)/T-helper 17 (17) immune axis has been identified as a major immune pathway in psoriasis disease pathogenesis. Central to this pathway is the cytokine -23, a heterodimer composed of a p40 subunit also found in -12 and a p19 subunit exclusive to -23. -23 is important for maintaining 17 responses, and levels of -23 are elevated in psoriatic skin compared with non-lesional skin. A number of agents that specifically inhibit -23p19 are currently in development for the treatment of moderate-to-severe plaque psoriasis, with recent clinical trials demonstrating efficacy with a good safety and tolerability profile. These data support the role of this cytokine in the pathogenesis of psoriasis. A better understanding of the -23/17 immune axis is vital and will promote the development of additional targets for psoriasis and other inflammatory diseases that share similar genetic aetiology and pathogenetic pathways

Immunogenicity of Biotherapy Used in Psoriasis:The Science Behind the Scenes

A potential limitation in the use of biologic drugs used to treat psoriasis is the development of anti-drug antibodies (ADAs). Many factors contribute to this unwanted immune response, from the product itself, to its mode of administration, the underlying disease, and patient characteristics. ADAs may decrease the efficacy of biologic drugs by neutralizing them or modifying their clearance and may account for hypersensitivity reactions. This article reviews the scientific basis of immunogenicity and the mechanisms by which it affects clinical outcomes. It also considers testing for immunogenicity and how biologic therapy of psoriasis may be tailored on the basis of immunogenicity

Biologic therapies for psoriasis. A systematic review

Alefacept, efalizumab, etanercept, and infliximab are currently approved for the treatment of adults with moderate to severe plaque psoriasis, and phase 3 trials for adalimumab are ongoing. The high level of evidence from large randomized, double-blind, placebo-controlled clinical studies for each of these biologics allows high-grade recommendations and helps define uncertainties, one of which is longterm safety. For tumor necrosis factor-a blocking agents, safety profiles are available from clinical experience in other indications. In general, biologics are safe and effective in the treatment of psoriasis, with potential to address unmet medical needs. Their distinct profiles allow dermatologists to match the biologic agent to individual characteristics of patients who are candidates for systemic therapy or phototherapy. In this evidence-based review of the literature, we assess the effects on psoriasis of induction therapy with 5 biologics and provide preliminary treatment guidelines

Selection of conserved TCR VDJ rearrangements in chronic psoriatic plaques indicates a common antigen in psoriasis vulgaris

Psoriasis vulgaris is a common HLA-associated inflammatory skin disease. Although its etiology is still unknown, it is thought to involve T cell-mediated inflammatory mechanisms. In examining the lesional psoriatic TCR beta chain (TCRB) usage in a pair of identical twins concordant for psoriasis, we observed repetitive TCR VDJ rearrangements which indicated antigen-specific oligoclonal T cell expansion. Several of these TCRB rearrangements were identical or highly homologous in the amino acid composition of the complementarity determining region 3 (CDR3), suggesting that T cells with these TCR might be important for disease manifestation. This conclusion was strengthened by TCR analysis of other psoriasis patients. Several repetitive lesional TCRB rearrangements were found that were similar to the conserved CDR3 seen in the twins. Since TCR antigen specificity is largely determined by the beta chain CDR3, selection of T cells with conserved TCRB CDR3 motifs could indicate the presence of a common antigen as a major target of the lesional psoriatic immune response

The role of IL-23 and the IL-23/TH17 immune axis in the pathogenesis and treatment of psoriasis

Psoriasis is a chronic, immune-mediated disease affecting more than 100 million people worldwide and up to 2.2% of the population. The aetiology of psoriasis is thought to originate from an interplay of genetic, environmental, infectious and lifestyle factors. The manner in which genetic and environmental factors interact to contribute to the molecular disease mechanisms has remained elusive. However, the interleukin 23 (-23)/T-helper 17 (17) immune axis has been identified as a major immune pathway in psoriasis disease pathogenesis. Central to this pathway is the cytokine -23, a heterodimer composed of a p40 subunit also found in -12 and a p19 subunit exclusive to -23. -23 is important for maintaining 17 responses, and levels of -23 are elevated in psoriatic skin compared with non-lesional skin. A number of agents that specifically inhibit -23p19 are currently in development for the treatment of moderate-to-severe plaque psoriasis, with recent clinical trials demonstrating efficacy with a good safety and tolerability profile. These data support the role of this cytokine in the pathogenesis of psoriasis. A better understanding of the -23/17 immune axis is vital and will promote the development of additional targets for psoriasis and other inflammatory diseases that share similar genetic aetiology and pathogenetic pathways