医学免疫学课件：Th17 cells and psoriasis

1、Th17 cells and psoriasis OutlineI. Effector cytokines and differentiation process of Th17 cells Pathogenesis of psoriasis related to Th17 cells A. Th17 cells and autoimmune diseases B. Introduction of psoriasis C. The inflammatory triangle in psoriasisTherapies against psoriasis targeting th17 cells

2、 A. Assessment criterion of therapeutic effectiveness in psoriasis B. Current FDA approved therapies for psoriasis C. Secukinumab (AIN-457) D. Further development of psoriasis treatment Figure1. Subsets of Th cellsFrom：Induction and effector functions of TH17 cellsNature, 2008(453):1Th17 cellsIL-22I

3、L-17A,FIL-21Effector cytokines of Th 17 cellsEffector cytokines of Th 17 cells: IL-17proinflammatorycytokines, chemokines and metalloproteinasessimilar function often expressed coordinately in Th17IL-17AIL-17FRecruitment of neutrophil cellsNK cellsTh17 cellsActivated T cellsIL-22Effector cytokines o

4、f Th 17 cells: IL-22the expression of -defensins in epithelial cellspromote epidermal hyperplasiaIL-21CD4+ T cells (stimulated by IL-6)Th 17 cellsT follicular helper cellsNK cellsproliferation and differentiation of CD8+ T cellsB-cell differentiation and antibody class switching differentiation/ampl

5、ification of TH17 cellsEffector cytokines of Th 17 cells: IL-21Figure2. The differentiation of TH17 cellsFrom：Induction and effector functions of TH17 cellsNature, 2008(453):1OutlineI. Effector cytokines and differentiation process of Th17 cells Pathogenesis of psoriasis related to Th17 cells A. Th1

6、7 cells and autoimmune diseases B. Introduction of psoriasis C. The inflammatory triangle in psoriasisTherapies against psoriasis targeting th17 cells A. Assessment criterion of therapeutic effectiveness in psoriasis B. Current FDA approved therapies for psoriasis C. Secukinumab (AIN-457) D. Further

7、 development of psoriasis treatment A. Th17 cells and autoimmune diseases Th17 in innate immunity:G+ bacteriaG- bacteriaFungiTh17 cellsOther subsets of T helper cellsSites of infectionFunction of cytokines:IL-17 ：promote cartilage and bone destruction disrupt tight junctions of the bloodbrain barrie

8、r Increased IL-17Observed inRheumatoid arthritisMultiple sclerosisInflammatory bowel diseasepsoriasisIL-22IL-23acanthosisdermal inflammationdisrupt tight junction of BBBB. PsoriasisPsoriasis: an immune-mediated, genetic disease manifesting in the skin or joints or both.Comorbid diseases: psoriatic a

9、rthritis, cardiovascular disorders, Crohns disease, lymphomaFrom：Psoriasis. The Lancet. 2015, 386: 98394Figure3. Histopathological features of psoriasis dilated and contorted dermal blood vesselsmixed inflammatory infiltratewith neutrophilsmany T cells in the dermis (detection of CD3)dilated and con

10、torted dermal blood vesselsC. Plausible mechanism:Th 17 disease:Cross-talk between innate and adaptive immunityinterleukin-23/T helper cell 17 (Th17) axisA triangle between TNF, type I IFNs and IL-17Figure 4. The interplay between TNF and type I IFNs in psoriasistype I IFNs enhance their own product

11、ion and that of TNF, TNF silences type I IFN productionpDCbacterial insults Virus insultsStimulationFrom: An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17Cytokine & Growth Factor Reviews. 2015(26): 2533From: An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17Cytokine &

12、 Growth Factor Reviews. 2015(26): 2533Figure5. Normal skin and skin of patients on anti-TNF treatmentFigure 6. The interplay between TNF-IL17neutrophilCXCL1, CXCL2, CXCL5, IL-8lymphocytes neutrophils Langerhans cellsneutrophilsFrom: An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17Cy

13、tokine & Growth Factor Reviews. 2015(26): 2533Figure 7. The interplay between Type I IFN-IL-17Skin injurypDC -defensins S100 family proteinskerotinocyteFrom: An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17Cytokine & Growth Factor Reviews. 2015(26): 2533epidermal regeneration and wo

14、und healingFigure 9. Triangle of TNF, IL-17, and IFN From: An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17Cytokine & Growth Factor Reviews. 2015(26): 2533OutlineI. Effector cytokines and differentiation process of Th17 cells Pathogenesis of psoriasis related to Th17 cells A. Th17 c

15、ells and autoimmune diseases B. Introduction of psoriasis C. The inflammatory triangle in psoriasisTherapies against psoriasis targeting th17 cells A. Assessment criterion of therapeutic effectiveness in psoriasis B. Current FDA approved therapies for psoriasis C. Secukinumab (AIN-457) D. Further de

16、velopment of psoriasis treatment A. Assessment of therapeutic effectiveness in psoriasis: 1. Psoriasis Area and Severity Index (PASI) the degree of erythema, induration, scalingthe percent of body surface area (BSA) involvedMeaningful response to a given therapy: A reduction in the PASI score of at

17、least 75%PASI-75: the proportion of patients achieving 75% reduction by a certain time point2. The modified investigators global assessment (Modified IGA)Meaningful response to a given therapy: a score of 0 (clear) or 1 (almost clear)5-point instrument0: normal skin4: severe psoriasistopical agents

18、(steroidal and non-steroidal)ultravioletphototherapysystemic therapy immunosuppressive agents such as methotrexate and cyclosporineB. Current FDA approved therapies for psoriasisBiologic agents TNF-alpha inhibitors ：Etanercept, Infliximab, AdalimumabPhosphodiesterase 4 inhibitor：ApremilastIL-12/IL-2

19、3p40 inhibitor: Briakinumab IL-6 pathway inhibitor: OlokizumabFigure10. Drugs targeting Th17 pathways and their use in human diseasesFrom：The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases Arch. Immunol. Ther. Exp. 2015 (63):435449Recently FDA-approved: IL-17A inhibitor：Secukinumab (AIN-4

20、57)Immunogenicity:very few cases of anti-secukinumab antibody formationanti-secukinumab antibodies not related to reduced efficacySecukinumab (AIN-457)Pharmacokinetics:Bioavailability with subcutaneous administration : 55 to 77%Volume of distribution in interstitial fluid of skin : 27 to 40% of that

21、 in serum (after a single subcutaneous dose of 300 mg)Half-life: 22 to 31 daysParameters increase in higher body weightsA phase III clinical trailFIXTURE：Full Year Investigative Examination of Secukinumab vs. Etanercept Using Two Dosing Regimens to Determine Efficacy in PsoriasisStudy design:double-

22、blind, both placebo- and active-controlled 52-week 1306 patients25%-secukinumab at a dose of 300 mg25%-secukinumab at a dose of 150 mg25%- etanercept at a dose of 50mg25%-placebo at a dose of 50 mgSecukinumab: once weekly for 5 weeks, then every 4 weeksPlacebo or etanercept: twice weekly for 12 week

23、s, then once weeklyFrom: Secukinumab in Plaque Psoriasis Results of Two Phase 3 TrialsN Engl J Med 2014(371):326-38.Figure 11. Speed of Response in FIXTURE studyFigure 12. Efficacy over 52 weeksFrom: Secukinumab in Plaque Psoriasis Results of Two Phase 3 TrialsN Engl J Med 2014(371):326-38.Conclusio

24、nthe superior efficacy of secukinumab over the TNF inhibitor etaneceptclinical response occurred more rapidly with secukinumabinterleukin-17A as an important therapeutic target in psoriasisHigh efficacy of secukinumabsuperiority over other biologics (etanercept, ustekinumab)300 mg subcutaneous dose:

25、 PASI-75 80% PASI-90 55%150 mg subcutaneous dose: PASI-75 70% PASI-90 40% Existing therapiesPASI-75methotrexate and cyclosporine40-70%TNF-inhibitorinfliximab50-80%adalimumabetanerceptacitretin30-50%apremilast30%Table 1. Pre-existing therapies with a wide range of clinical efficacyD. Further developm

26、ent of psoriasis treatmentfind new targeted pathways with high efficacydevelop etiological and personalized therapy stratify people with psoriasis into populations(based on etiology) target specific dysfunctional pathway in patients Problem: no response to a specific biologic agentResolution:Figure

27、9. Triangle of TNF, IL-17, and IFN From: An inflammatory triangle in psoriasis: TNF, type I IFNs and IL-17Cytokine & Growth Factor Reviews. 2015(26): 2533Reference:Bettelli, E., Korn, T. & Oukka, M. ,et al. Induction and effector functions of TH17 cells. Nature. 2008, 453(7198): 1051-1057Yang, J., S

28、undrud, M. S. & Skepner, J., Targeting Th17 cells in autoimmune diseases. Trends in Pharmacological Sciences. 2014, 35(10): 493-500Yamagata, T., Skepner, J.& Yang, J., Targeting Th17 Effector Cytokines for the Treatment of Autoimmune Diseases. Archivum Immunologiae et Therapiae Experimentalis, 2015,

29、 63(6): 405-414Tabarkiewicz, J., Pogoda, K., Karczmarczyk, et al. The Role of IL-17 and Th17 Lymphocytes in Autoimmune Diseases. Archivum Immunologiae et Therapiae Experimentalis, 2015, 63(6): 435-449Langley, R. G., Elewski, B. E., Lebwohl, M.,et al. Secukinumab in Plaque Psoriasis Results of Two Phase 3 Trials. New England Journal of Medicine, 2014, 371(4): 326-338Jaleel, T., Elmets, C., Weinkle, A., et al. Secukinumab (AIN-4