The Vitamin D Analogue Calcipotriol Reduces the Frequency of CD8+IL‐17+ T Cells in Psoriasis Lesions

The vitamin D analogue calcipotriol is an immunomodulatory drug widely used to treat psoriasis; however, how calcipotriol affects the immune cells in psoriasis lesions is not fully understood. The aim of this atudy was to investigate the effect of calcipotriol on the frequency of CD4+ and CD8+ T cells and innate lymphoid cells (ILC) and their production of IL‐17A, IFN‐γ and IL‐22 in psoriasis lesions in patients with chronic plaque psoriasis. Eighteen patients with psoriasis were included, and two similar psoriasis lesions were chosen for each patient. One lesion was treated with calcipotriol (50 μg/g) and the other with vehicle twice a day for 14 days. The clinical effect was measured by degree of erythema, scaling and induration in each lesion (SUM score). Skin biopsies were collected for histological and immunohistochemical analyses. Skin‐derived cells were isolated and analysed by flow cytometry. After 14 days of treatment with calcipotriol, a significant clinical and histological effect was seen; however, we found no differences in the frequency of CD4+ and CD8+ T cells or ILC between calcipotriol‐ and vehicle‐treated skin. The main finding was a significant decrease in CD8+IL‐17+ T cells in skin‐derived cells from calcipotriol‐treated skin, which was further supported by the absence of CD8+IL‐17+ T cells in immunohistochemical staining of calcipotriol‐treated skin. No changes in the frequency of IL‐22+ or IFN‐γ+ cells were observed. Our findings show that the vitamin D analogue calcipotriol reduces the frequency of CD8+IL‐17+ T cells in psoriasis lesions concomitant with clinical improvement.

[1]  A. T. Te Velde,et al.  Composition of innate lymphoid cell subsets in the human skin: enrichment of NCR(+) ILC3 in lesional skin and blood of psoriasis patients. , 2014, The Journal of investigative dermatology.

[2]  Y. Tokura,et al.  Calcipotriol increases hCAP18 mRNA expression but inhibits extracellular LL37 peptide production in IL-17/IL-22-stimulated normal human epidermal keratinocytes. , 2014, Acta dermato-venereologica.

[3]  C. Geisler,et al.  Increased number and frequency of group 3 innate lymphoid cells in nonlesional psoriatic skin , 2014, The British journal of dermatology.

[4]  S. Gan,et al.  A critical evaluation of clinical research study designs. , 2014, The Journal of investigative dermatology.

[5]  F. Villanova,et al.  Characterization of innate lymphoid cells (ILC) in human skin and blood demonstrates increase of NKp44+ ILC3 in psoriasis , 2013, The Journal of investigative dermatology.

[6]  R. Hegazy,et al.  Assessment of interleukin-17 and vitamin D serum levels in psoriatic patients. , 2013, Journal of the American Academy of Dermatology.

[7]  H. Fujita.  The role of IL-22 and Th22 cells in human skin diseases. , 2013, Journal of dermatological science.

[8]  D. Elashoff,et al.  Propionibacterium acnes induces an interleukin-17 response in acne vulgaris that is regulated by vitamin A and vitamin D , 2013, The Journal of investigative dermatology.

[9]  K. Kabashima,et al.  Calcipotriol modulates IL-22 receptor expression and keratinocyte proliferation in IL-22-induced epidermal hyperplasia. , 2013, Journal of dermatological science.

[10]  C. Geisler,et al.  The Vitamin D Receptor and T Cell Function , 2013, Front. Immunol..

[11]  C. Geisler,et al.  CD4+ T cells producing interleukin (IL)‐17, IL‐22 and interferon‐γ are major effector T cells in nickel allergy , 2013, Contact dermatitis.

[12]  Rosa Parisi,et al.  Global epidemiology of psoriasis: a systematic review of incidence and prevalence. , 2013, The Journal of investigative dermatology.

[13]  Eric Vivier,et al.  Innate lymphoid cells — a proposal for uniform nomenclature , 2013, Nature Reviews Immunology.

[14]  T. Ruzicka,et al.  Vitamin D analog calcipotriol suppresses the Th17 cytokine-induced proinflammatory S100 "alarmins" psoriasin (S100A7) and koebnerisin (S100A15) in psoriasis. , 2012, The Journal of investigative dermatology.

[15]  Subhashis Banerjee,et al.  Anti-interleukin-17 monoclonal antibody ixekizumab in chronic plaque psoriasis. , 2012, The New England journal of medicine.

[16]  J. Ortonne,et al.  Brodalumab, an anti-interleukin-17-receptor antibody for psoriasis. , 2012, The New England journal of medicine.

[17]  D. Bruce,et al.  Converging pathways lead to overproduction of IL-17 in the absence of vitamin D signaling. , 2011, International immunology.

[18]  Sneha S. Joshi,et al.  1,25-Dihydroxyvitamin D3 Ameliorates Th17 Autoimmunity via Transcriptional Modulation of Interleukin-17A , 2011, Molecular and Cellular Biology.

[19]  V. Hornung,et al.  Cytosolic DNA Triggers Inflammasome Activation in Keratinocytes in Psoriatic Lesions , 2011, Science Translational Medicine.

[20]  Y. Iwakura,et al.  1α,25-Dihydroxyvitamin D3 and all-trans retinoic acid synergistically inhibit the differentiation and expansion of Th17 cells. , 2010, Immunology letters.

[21]  P. Teeling,et al.  Overrepresentation of IL-17A and IL-22 Producing CD8 T Cells in Lesional Skin Suggests Their Involvement in the Pathogenesis of Psoriasis , 2010, PloS one.

[22]  P. Kvist,et al.  Comparison of the effects of vitamin D products in a psoriasis plaque test and a murine psoriasis xenograft model , 2009, Journal of Translational Medicine.

[23]  S. Durham,et al.  Th22 cells represent a distinct human T cell subset involved in epidermal immunity and remodeling. , 2009, The Journal of clinical investigation.

[24]  Frank O. Nestle,et al.  Mechanisms of Disease: Psoriasis. , 2009 .

[25]  H. Volk,et al.  IL-22 and IL-20 are key mediators of the epidermal alterations in psoriasis while IL-17 and IFN-γ are not , 2009, Journal of Molecular Medicine.

[26]  T. Ruzicka,et al.  IL-17A Enhances Vitamin D3-Induced Expression of Cathelicidin Antimicrobial Peptide in Human Keratinocytes1 , 2008, The Journal of Immunology.

[27]  James T. Elder,et al.  Induction of IL-17+ T Cell Trafficking and Development by IFN-γ: Mechanism and Pathological Relevance in Psoriasis1 , 2008, The Journal of Immunology.

[28]  Elizabeth J Horn,et al.  National Psoriasis Foundation clinical consensus on psoriasis comorbidities and recommendations for screening. , 2008, Journal of the American Academy of Dermatology.

[29]  I. Mellman,et al.  Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide , 2007, Nature.

[30]  P. van Erp,et al.  The effect of the combination of calcipotriol and betamethasone dipropionate versus both monotherapies on epidermal proliferation, keratinization and T‐cell subsets in chronic plaque psoriasis , 2004, Experimental dermatology.

[31]  G. Girolomoni,et al.  Human CD25+ Regulatory T Cells Maintain Immune Tolerance to Nickel in Healthy, Nonallergic Individuals 1 , 2003, The Journal of Immunology.

[32]  J. Welsh,et al.  A crucial role for the vitamin D receptor in experimental inflammatory bowel diseases. , 2003, Molecular endocrinology.

[33]  A. Ishida-Yamamoto,et al.  Similarly potent action of 1,25-dihydroxyvitamin D3 and its analogues, tacalcitol, calcipotriol, and maxacalcitol on normal human keratinocyte proliferation and differentiation. , 2003, Journal of dermatological science.

[34]  C. Albanesi,et al.  IL-17 Is Produced by Nickel-Specific T Lymphocytes and Regulates ICAM-1 Expression and Chemokine Production in Human Keratinocytes: Synergistic or Antagonist Effects with IFN-γ and TNF-α , 1999, The Journal of Immunology.

[35]  S. K. Szabo,et al.  Identification and quantitation of interferon-gamma producing T cells in psoriatic lesions: localization to both CD4+ and CD8+ subsets. , 1998, The Journal of investigative dermatology.

[36]  P. Kerkhof,et al.  Epidermal differentiation characteristics of the psoriatic plaque during treatment with calcipotriol , 1996, Archives of Dermatological Research.

[37]  M. Yamamura,et al.  The cytokine network in lesional and lesion-free psoriatic skin is characterized by a T-helper type 1 cell-mediated response. , 1993, The Journal of investigative dermatology.

[38]  J. Lemire.  Immunomodulatory role of 1,25‐dihydroxyvitamin D3 , 1992, Journal of cellular biochemistry.

[39]  P. Kerkhof,et al.  Simultaneous assessment of inflammation and epidermal proliferation in psoriatic plaques during long‐term treatment with the vitamin D3 analogue MC903: modulations and interrelations , 1991 .

[40]  P. Elias,et al.  1,25-Dihydroxyvitamin D production and receptor binding in human keratinocytes varies with differentiation. , 1988, The Journal of biological chemistry.

[41]  R. Anderson,et al.  Photosynthesis of previtamin D3 in human skin and the physiologic consequences. , 1980, Science.

[42]  Mark Lebwohl,et al.  Psoriasis , 1906, The Lancet.

[43]  M. Haussler,et al.  Molecular Mechanisms of Vitamin D Action , 2012, Calcified Tissue International.

[44]  池田 詩子.  1α,25-dihydroxyvitamin D3 and all-trans retinoic acid synergistically inhibit the differentiation and expansion of Th17 cells , 2011 .

[45]  J. Reichrath,et al.  Biologic effects of topical calcipotriol (MC 903) treatment in psoriatic skin. , 1997, Journal of the American Academy of Dermatology.

[46]  P. V. D. van de Kerkhof,et al.  Simultaneous assessment of inflammation and epidermal proliferation in psoriatic plaques during long-term treatment with the vitamin D3 analogue MC903: modulations and interrelations. , 1991, The British journal of dermatology.