The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform

Fiona Powrie - One of the best experts on this subject based on the ideXlab platform.

  • dysregulated hematopoietic stem and progenitor cell activity promotes Interleukin 23 driven chronic intestinal inflammation
    Immunity, 2012
    Co-Authors: Thibault Griseri, Fiona Powrie, Chris Schiering, Brent S Mckenzie
    Abstract:

    In Interleukin-23 (IL-23)-dependent colitis, there is excessive accumulation of short-lived neutrophils and inflammatory monocytes in the intestine. It is unknown whether this reflects changes in mature cell populations or whether the IL-23-driven colitogenic T cell program regulates upstream hematopoietic stem and progenitor cells (HSPC). Here we have shown dysregulation of hematopoiesis in colitis mediated by inflammatory cytokines. First, there was an interferon-gamma-dependent accumulation of proliferating hematopoietic stem cells in the bone marrow and spleen. Second, there was a strong skew toward granulocyte-monocyte progenitor (GMP) production at the expense of erythroid and lymphoid progenitors. Extramedullary hematopoiesis was also evident, and granulocyte macrophage-colony stimulating factor (GM-CSF) blockade reduced the accumulation of splenic and colonic GMPs, resulting in amelioration of colitis. Importantly, transfer of GMPs exacerbated colitis. These data identify HSPCs as a major target of the IL-23-driven inflammatory axis suggesting therapeutic strategies for the treatment of inflammatory bowel disease.

  • Interleukin 23 drives intestinal inflammation through direct activity on t cells
    Immunity, 2010
    Co-Authors: Philip P Ahern, Sofia Buonocore, Fiona Powrie, Kevin J Maloy, Chris Schiering, Mandy J Mcgeachy, Daniel J Cua
    Abstract:

    Mutations in the IL23R gene are linked to inflammatory bowel disease susceptibility. Experimental models have shown that Interleukin-23 (IL-23) orchestrates innate and T cell-dependent colitis; however, the cell populations it acts on to induce intestinal immune pathology are unknown. Here, using Il23r−/− T cells, we demonstrated that T cell reactivity to IL-23 was critical for development of intestinal pathology, but not for systemic inflammation. Through direct signaling into T cells, IL-23 drove intestinal T cell proliferation, promoted intestinal Th17 cell accumulation, and enhanced the emergence of an IL-17A+IFN-γ+ population of T cells. Furthermore, IL-23R signaling in intestinal T cells suppressed the differentiation of Foxp3+ cells and T cell IL-10 production. Although Il23r−/− T cells displayed unimpaired Th1 cell differentiation, these cells showed impaired proliferation and failed to accumulate in the intestine. Together, these results highlight the multiple functions of IL-23 signaling in T cells that contribute to its colitogenic activity.

  • innate lymphoid cells drive Interleukin 23 dependent innate intestinal pathology
    Nature, 2010
    Co-Authors: Sofia Buonocore, Philip P Ahern, Fiona Powrie, Kevin J Maloy, Holm H Uhlig, Ivaylo I Ivanov, Dan R Littman
    Abstract:

    The key role of Interleukin (IL)-23 in the pathogenesis of autoimmune and chronic inflammatory disorders is supported by the identification of IL-23 receptor (IL-23R) susceptibility alleles associated with inflammatory bowel disease, psoriasis and ankylosing spondylitis. IL-23-driven inflammation has primarily been linked to the actions of T-helper type 17 (TH17) cells. Somewhat overlooked, IL-23 also has inflammatory effects on innate immune cells and can drive T-cell-independent colitis. However, the downstream cellular and molecular pathways involved in this innate intestinal inflammatory response are poorly characterized. Here we show that bacteria-driven innate colitis is associated with an increased production of IL-17 and interferon-gamma in the colon. Stimulation of colonic leukocytes with IL-23 induced the production of IL-17 and interferon-gamma exclusively by innate lymphoid cells expressing Thy1, stem cell antigen 1 (SCA-1), retinoic-acid-related orphan receptor (ROR)-gammat and IL-23R, and these cells markedly accumulated in the inflamed colon. IL-23-responsive innate intestinal cells are also a feature of T-cell-dependent models of colitis. The transcription factor ROR-gammat, which controls IL-23R expression, has a functional role, because Rag-/-Rorc-/- mice failed to develop innate colitis. Last, depletion of Thy1+ innate lymphoid cells completely abrogated acute and chronic innate colitis. These results identify a previously unrecognized IL-23-responsive innate lymphoid population that mediates intestinal immune pathology and may therefore represent a target in inflammatory bowel disease.

  • the Interleukin 23 axis in intestinal inflammation
    Immunological Reviews, 2008
    Co-Authors: Philip P Ahern, Ana Izcue, Kevin J Maloy, Fiona Powrie
    Abstract:

    Immune responses in the intestine are tightly regulated to ensure host protective immunity in the absence of immune pathology. Interleukin-23 (IL-23) has recently been shown to be a key player in influencing the balance between tolerance and immunity in the intestine. Production of IL-23 is enriched within the intestine and has been shown to orchestrate T-cell-dependent and T-cell-independent pathways of intestinal inflammation through effects on T-helper 1 (Th1) and Th17-associated cytokines. Furthermore, IL-23 restrains regulatory T-cell responses in the gut, favoring inflammation. Polymorphisms in the IL-23 receptor have been associated with susceptibility to inflammatory bowel diseases (IBDs) in humans, pinpointing the IL-23 axis as a key, conserved pathway in intestinal homeostasis. In addition to its role in dysregulated inflammatory responses, there is also evidence that IL-23 and the Th17 axis mediate beneficial roles in host protective immunity and barrier function in the intestine. Here we discuss the dual roles of IL-23 in intestinal immunity and how IL-23 and downstream effector pathways may make novel targets for the treatment of IBD.

  • Interleukin 23 restrains regulatory t cell activity to drive t cell dependent colitis
    Immunity, 2008
    Co-Authors: Ana Izcue, Sofia Buonocore, Carolina V Arancibiacarcamo, Philip P Ahern, Knut Jørgen Måløy, Yoichiro Iwakura, Fiona Powrie
    Abstract:

    Interleukin-23 (IL-23) is an inflammatory cytokine that plays a key role in the pathogenesis of several autoimmune and inflammatory diseases. It orchestrates innate and T cell-mediated inflammatory pathways and can promote T helper 17 (Th17) cell responses. Utilizing a T cell transfer model, we showed that IL-23-dependent colitis did not require IL-17 secretion by T cells. Furthermore, IL-23-independent intestinal inflammation could develop if immunosuppressive pathways were reduced. The frequency of naive T cell-derived Foxp3+ cells in the colon increased in the absence of IL-23, indicating a role for IL-23 in controlling regulatory T cell induction. Foxp3-deficient T cells induced colitis when transferred into recipients lacking IL-23p19, showing that IL-23 was not essential for intestinal inflammation in the absence of Foxp3. Taken together, our data indicate that overriding immunosuppressive pathways is an important function of IL-23 in the intestine and could influence not only Th17 cell activity but also other types of immune responses.

Ulrich H Von Andrian - One of the best experts on this subject based on the ideXlab platform.

  • nociceptive sensory neurons drive Interleukin 23 mediated psoriasiform skin inflammation
    Nature, 2014
    Co-Authors: Lorena Riolblanco, Jose Ordovasmontanes, Mario Perro, Elena Naval, Aude Thiriot, David Alvarez, Silke Paust, John Wood, Ulrich H Von Andrian
    Abstract:

    In mice, it is possible to induce a psoriasis-like condition by applying imiquimod; here, the production of Interleukin-23 that is stimulated by such skin inflammation is shown to depend on the interaction of nociceptors expressing the Nav1.8 and TRPV1 channels with skin-resident dendritic cells. Repeated topical application of the antiviral immune modifier imiquimod (IMQ) to murine skin provokes Interleukin-23-mediated inflammatory lesions that resemble human psoriasis. Ulrich von Andrian and colleagues show that the production of skin inflammation in this disease model depends on the interaction of a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 with skin-resident dendritic cells. Taken together with other recent work, this finding suggests a scenario in which noxious pain fibres integrate environmental signals to modulate local immune responses to a variety of infectious and pro-inflammatory stimuli. The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and Interleukin (IL)-17-producing γδ T (γδT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation1,2,3,4. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear5,6. We exposed the skin of mice to imiquimod, which induces IL-23-dependent psoriasis-like inflammation7,8. Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors9,10,11, DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response12. These findings indicate that TRPV1+Nav1.8+ nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.

  • nociceptive sensory neurons drive Interleukin 23 mediated psoriasiform skin inflammation
    Nature, 2014
    Co-Authors: Lorena Riolblanco, Jose Ordovasmontanes, Mario Perro, Elena Naval, Aude Thiriot, David Alvarez, Silke Paust, John N Wood, Ulrich H Von Andrian
    Abstract:

    The skin has a dual function as a barrier and a sensory interface between the body and the environment. To protect against invading pathogens, the skin harbours specialized immune cells, including dermal dendritic cells (DDCs) and Interleukin (IL)-17-producing γδ T (γδT17) cells, the aberrant activation of which by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by a meshwork of peripheral nerves consisting of relatively sparse autonomic and abundant sensory fibres. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear. We exposed the skin of mice to imiquimod, which induces IL-23-dependent psoriasis-like inflammation. Here we show that a subset of sensory neurons expressing the ion channels TRPV1 and Nav1.8 is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of DDCs, the principal source of IL-23, is in close contact with these nociceptors. Upon selective pharmacological or genetic ablation of nociceptors, DDCs failed to produce IL-23 in imiquimod-exposed skin. Consequently, the local production of IL-23-dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were markedly reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with DDCs and restored the inflammatory response. These findings indicate that TRPV1(+)Nav1.8(+) nociceptors, by interacting with DDCs, regulate the IL-23/IL-17 pathway and control cutaneous immune responses.

  • noxious pain fibers drive Interleukin 23 mediated psoriasiform skin inflammation ccr6p 275
    Journal of Immunology, 2014
    Co-Authors: Lorena Riol, Ulrich H Von Andrian, Jose Ordovasmontanes
    Abstract:

    To protect against invading pathogens, the skin harbors specialized immune cells, including dermal dendritic cells (dDCs) and T cells, such as IL-17 producing γδT cells (γδT17) whose aberrant activation by IL-23 can provoke psoriasis-like inflammation. The skin is also innervated by peripheral nerves consisting of autonomic and sensory fibers. Interactions between the autonomic nervous system and immune cells in lymphoid organs are known to contribute to systemic immunity, but how peripheral nerves regulate cutaneous immune responses remains unclear. Here, we have exposed the skin of mice to, imiquimod (IMQ), which induces IL-23 dependent psoriasis-like inflammation. We show that a subset of TRPV1+ NaV1.8+ pain fibers is essential to drive this inflammatory response. Imaging of intact skin revealed that a large fraction of dDCs, the principal source of IL-23, is in close contact with pain fibers. Upon selective pharmacological or genetic ablation of nociceptors, dDCs failed to produce IL-23 in IMQ exposed skin. Consequently, the local production of IL-23 dependent inflammatory cytokines by dermal γδT17 cells and the subsequent recruitment of inflammatory cells to the skin were dramatically reduced. Intradermal injection of IL-23 bypassed the requirement for nociceptor communication with dDC and restored the inflammatory response. These findings indicate that nociceptors, by interacting with dDCs, regulate the IL-23/IL-17 pathway and control dermal immune responses.

Bruce Randazzo - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of guselkumab an anti Interleukin 23 monoclonal antibody compared with adalimumab for the continuous treatment of patients with moderate to severe psoriasis results from the phase iii double blinded placebo and active comparator c
    Journal of The American Academy of Dermatology, 2017
    Co-Authors: Andrew Blauvelt, Kim Papp, Christopher E M Griffiths, Bruce Randazzo, Y Wasfi, Yaungkaung Shen, Alexa B Kimball
    Abstract:

    Background Guselkumab, an Interleukin-23 blocker, was superior to adalimumab in treating moderate to severe psoriasis in a phase II trial. Objectives We sought to compare efficacy and safety of guselkumab with adalimumab and placebo in patients with psoriasis treated for 1 year. Methods Patients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 329); placebo→guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20, then every 8 weeks; n = 174); or adalimumab (80 mg week 0, 40 mg week 1, then 40 mg every 2 weeks through week 47; n = 334). Physician-reported outcomes (Investigator Global Assessment, Psoriasis Area and Severity Index [PASI]), patient-reported outcomes (Dermatology Life Quality Index, Psoriasis Symptoms and Signs Diary), and safety were evaluated through week 48. Results Guselkumab was superior (P  Limitations Analyses were limited to 48 weeks. Conclusions Guselkumab demonstrated superior efficacy compared with adalimumab and was well tolerated in patients with psoriasis through 1 year.

  • efficacy and safety of guselkumab an anti Interleukin 23 monoclonal antibody compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment results from the phase iii double blind p
    Journal of The American Academy of Dermatology, 2017
    Co-Authors: Kristian Reich, Bruce Randazzo, Y Wasfi, Yaungkaung Shen, April W Armstrong, Peter Foley, Michael Song, Kenneth B Gordon
    Abstract:

    Background Phase II data suggested that guselkumab, an anti-Interleukin-23 monoclonal antibody, was efficacious in psoriasis. Objective We sought to assess efficacy and safety of guselkumab in moderate to severe psoriasis versus placebo and adalimumab, including interrupted treatment and switching adalimumab nonresponders to guselkumab. Methods Patients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 496); placebo→guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20; n = 248); or adalimumab (80 mg week 0, then 40 mg week 1, and every 2 weeks through week 23; n = 248). At week 28, guselkumab 90% or greater improvement in Psoriasis Area and Severity Index (PASI) score from baseline (PASI 90) responders were rerandomized to guselkumab or placebo with guselkumab after loss of response. Placebo→guselkumab responders and adalimumab responders received placebo, then guselkumab after loss of response. Nonresponders received guselkumab. Results At week 16, more patients receiving guselkumab achieved an Investigator Global Assessment (IGA) score 0/1 (cleared/minimal) (84.1% vs 8.5%) and PASI 90 (70.0% vs 2.4%) versus placebo (coprimary end points). Guselkumab was superior to adalimumab at week 16 (IGA score 0/1, 75% or greater improvement in PASI score from baseline, and PASI 90) and week 24 (IGA score 0/1 and 0, PASI 90, 100% improvement in PASI score from baseline) ( P P Limitations One-year follow-up limits retreatment data. Conclusions Guselkumab is a highly effective, well-tolerated, maintenance therapy, including in adalimumab nonresponders.

  • a phase 2 trial of guselkumab versus adalimumab for plaque psoriasis
    The New England Journal of Medicine, 2015
    Co-Authors: Kenneth B Gordon, Bruce Randazzo, Y Wasfi, Yaungkaung Shen, Kristina Callis Duffin, Robert Bissonnette, J C Prinz, Philippe Szapary, Kristian Reich
    Abstract:

    BackgroundLittle is known about the effect of specific anti–Interleukin-23 therapy, as compared with established anti–tumor necrosis factor therapies, for the treatment of moderate-to-severe plaque psoriasis. MethodsIn a 52-week, phase 2, dose-ranging, randomized, double-blind, placebo-controlled, active-comparator trial, we compared guselkumab (CNTO 1959), an anti–Interleukin-23 monoclonal antibody, with adalimumab in patients with moderate-to-severe plaque psoriasis. A total of 293 patients were randomly assigned to receive guselkumab (5 mg at weeks 0 and 4 and every 12 weeks thereafter, 15 mg every 8 weeks, 50 mg at weeks 0 and 4 and every 12 weeks thereafter, 100 mg every 8 weeks, or 200 mg at weeks 0 and 4 and every 12 weeks thereafter) through week 40, placebo, or adalimumab (standard dosage for psoriasis). At week 16, patients in the placebo group crossed over to receive guselkumab at a dose of 100 mg every 8 weeks. The primary end point was the proportion of patients with a Physician’s Global Asse...

Nicolas Servant - One of the best experts on this subject based on the ideXlab platform.

  • a critical function for transforming growth factor beta Interleukin 23 and proinflammatory cytokines in driving and modulating human t h 17 responses
    Nature Immunology, 2008
    Co-Authors: Elisabetta Volpe, Nicolas Servant, Raphael Zollinger, Sofia I Bogiatzi, Philippe Hupe, Emmanuel Barillot
    Abstract:

    Interleukin 17 (IL-17)-producing T helper 17 cells (T(H)-17 cells) have been described as a T helper cell subset distinct from T helper type 1 (T(H)1) and T(H)2 cells, with specific functions in antimicrobial defense and autoimmunity. The factors driving human T(H)-17 differentiation remain controversial. Using a systematic approach combining experimental and computational methods, we show here that transforming growth factor-beta, Interleukin 23 (IL-23) and proinflammatory cytokines (IL-1beta and IL-6) were all essential for human T(H)-17 differentiation. However, individual T(H)-17 cell-derived cytokines, such as IL-17, IL-21, IL-22 and IL-6, as well as the global T(H)-17 cytokine profile, were differentially modulated by T(H)-17-promoting cytokines. Transforming growth factor-beta was critical, and its absence induced a shift from a T(H)-17 profile to a T(H)1-like profile. Our results shed new light on the regulation of human T(H)-17 differentiation and provide a framework for the global analysis of T helper responses.

Kenneth B Gordon - One of the best experts on this subject based on the ideXlab platform.

  • efficacy and safety of guselkumab an anti Interleukin 23 monoclonal antibody compared with adalimumab for the treatment of patients with moderate to severe psoriasis with randomized withdrawal and retreatment results from the phase iii double blind p
    Journal of The American Academy of Dermatology, 2017
    Co-Authors: Kristian Reich, Bruce Randazzo, Y Wasfi, Yaungkaung Shen, April W Armstrong, Peter Foley, Michael Song, Kenneth B Gordon
    Abstract:

    Background Phase II data suggested that guselkumab, an anti-Interleukin-23 monoclonal antibody, was efficacious in psoriasis. Objective We sought to assess efficacy and safety of guselkumab in moderate to severe psoriasis versus placebo and adalimumab, including interrupted treatment and switching adalimumab nonresponders to guselkumab. Methods Patients were randomized to guselkumab 100 mg (weeks 0 and 4, then every 8 weeks; n = 496); placebo→guselkumab (weeks 0, 4, and 12 then guselkumab at weeks 16 and 20; n = 248); or adalimumab (80 mg week 0, then 40 mg week 1, and every 2 weeks through week 23; n = 248). At week 28, guselkumab 90% or greater improvement in Psoriasis Area and Severity Index (PASI) score from baseline (PASI 90) responders were rerandomized to guselkumab or placebo with guselkumab after loss of response. Placebo→guselkumab responders and adalimumab responders received placebo, then guselkumab after loss of response. Nonresponders received guselkumab. Results At week 16, more patients receiving guselkumab achieved an Investigator Global Assessment (IGA) score 0/1 (cleared/minimal) (84.1% vs 8.5%) and PASI 90 (70.0% vs 2.4%) versus placebo (coprimary end points). Guselkumab was superior to adalimumab at week 16 (IGA score 0/1, 75% or greater improvement in PASI score from baseline, and PASI 90) and week 24 (IGA score 0/1 and 0, PASI 90, 100% improvement in PASI score from baseline) ( P P Limitations One-year follow-up limits retreatment data. Conclusions Guselkumab is a highly effective, well-tolerated, maintenance therapy, including in adalimumab nonresponders.

  • a phase 2 trial of guselkumab versus adalimumab for plaque psoriasis
    The New England Journal of Medicine, 2015
    Co-Authors: Kenneth B Gordon, Bruce Randazzo, Y Wasfi, Yaungkaung Shen, Kristina Callis Duffin, Robert Bissonnette, J C Prinz, Philippe Szapary, Kristian Reich
    Abstract:

    BackgroundLittle is known about the effect of specific anti–Interleukin-23 therapy, as compared with established anti–tumor necrosis factor therapies, for the treatment of moderate-to-severe plaque psoriasis. MethodsIn a 52-week, phase 2, dose-ranging, randomized, double-blind, placebo-controlled, active-comparator trial, we compared guselkumab (CNTO 1959), an anti–Interleukin-23 monoclonal antibody, with adalimumab in patients with moderate-to-severe plaque psoriasis. A total of 293 patients were randomly assigned to receive guselkumab (5 mg at weeks 0 and 4 and every 12 weeks thereafter, 15 mg every 8 weeks, 50 mg at weeks 0 and 4 and every 12 weeks thereafter, 100 mg every 8 weeks, or 200 mg at weeks 0 and 4 and every 12 weeks thereafter) through week 40, placebo, or adalimumab (standard dosage for psoriasis). At week 16, patients in the placebo group crossed over to receive guselkumab at a dose of 100 mg every 8 weeks. The primary end point was the proportion of patients with a Physician’s Global Asse...