IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis James G. Krueger, MD, Scott Fretzin, MD, Mayte Suárez-Fariñas,

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Presentation transcript:

IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis James G. Krueger, MD, Scott Fretzin, MD, Mayte Suárez-Fariñas, PhD, Patrick A. Haslett, MB, BS, Krista M. Phipps, Gregory S. Cameron, PhD, Juliet McColm, MD, Artemis Katcherian, Inna Cueto, Traci White, Subhashis Banerjee, MD, Robert W. Hoffman, DO Journal of Allergy and Clinical Immunology Volume 130, Issue 1, Pages 145-154.e9 (July 2012) DOI: 10.1016/j.jaci.2012.04.024 Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 IL-17 neutralization results in decreased keratinocyte proliferation and differentiation, leukocyte infiltration, and keratinocyte release of inflammatory cytokines. A representative example of serial skin biopsy specimens from a subject treated with 150 mg of ixekizumab is presented. Histologic analysis included hematoxylin and eosin (H&E) staining. Immunohistochemical analysis included staining for keratin 16 (K16), Ki67, CD3, CD11c, LL37/cathelicidin, S100A7, S100A8, β-defensin 2 (BD2), and DC-LAMP. Scale bar = 50 μm. Journal of Allergy and Clinical Immunology 2012 130, 145-154.e9DOI: (10.1016/j.jaci.2012.04.024) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 IL-17 neutralization results in decreased expression of cytokines from multiple T-cell subsets. At baseline and weeks 2 and 6, mRNA expression for keratin 16 (K16) and lipocalin (LCN), an IL-17 target gene, were analyzed, as were mRNA expression levels for the T-cell cytokines IFN-γ, IL-17A/F, and IL-22 and the dendritic cell cytokine IL-23. *P < .05 versus baseline. Data are shown as means ± SEMs. Journal of Allergy and Clinical Immunology 2012 130, 145-154.e9DOI: (10.1016/j.jaci.2012.04.024) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Identification of genes modulated greater than 6-fold by IL-17 neutralization. A, DEGs that had a greater than 6-fold change compared with baseline values in the 150-mg group were identified and clustered. mRNA expression of these genes is presented for the placebo group for comparison. B, Gene expression data for untreated lesional skin biopsy specimens (LS) and nonlesional skin biopsy specimens (NS) from a previous experiment.28 The genes are ordered according to the clustering results in Fig 3, A. Asterisks represent those genes that are synergistically regulated by TNF-α and IL-17. Plus signs indicate those that are additively coregulated by TNF-α and IL-17. Journal of Allergy and Clinical Immunology 2012 130, 145-154.e9DOI: (10.1016/j.jaci.2012.04.024) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Comparison of treatment effect at week 2 for ixekizumab, etanercept, and placebo. A and B, Mean (95% CI) for fold change from baseline for each treatment for RT-PCR (Fig 4, A) and histologic variables (Fig 4, B). C, Venn diagram summarizing the number of genes among those in the psoriasis transcriptome with improvement of at least 75%. D, Estimated density distribution of the treatment effect multiplied by the sign of the lesional (LS) versus nonlesional (NL) direction to show only the magnitude of the change toward resolution. The insert graph shows the density distribution of the difference in effect between ixekizumab and etanercept for all genes and the genes in the psoriasis transcriptome. For all genes, one can see a 0-centered distribution (equal effects), but for the psoriasis genes, there is a shift to the right, indicating larger changes with ixekizumab treatment among psoriasis genes. E, Proportion of psoriasis genes improved by more than 75% in each gene set. F, Average improvement in each gene set. Journal of Allergy and Clinical Immunology 2012 130, 145-154.e9DOI: (10.1016/j.jaci.2012.04.024) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Analysis for batch effect between the clinical studies of LY2439821 and etanercept. A and B, Principal component analysis showing the first 2 components of expression values before (Fig E1, A) and after (Fig E1, B) adjustment for a batch effect. C and D, Principal component analysis of the treatment effect for each subject (after treatment vs baseline lesion) on the original data (Fig E1, C) and after adjustment (Fig E1, D). E, Density distribution function for the treatment effect at week 2 for both treatments before and after adjustment. F, Density distribution function for the differences in treatment effect at week 2 before and after adjustment. Journal of Allergy and Clinical Immunology 2012 130, 145-154.e9DOI: (10.1016/j.jaci.2012.04.024) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 Representative example from a subject treated with placebo: keratinocyte proliferation and differentiation, leukocyte infiltration, and keratinocyte release of inflammatory cytokines. A representative example from a subject treated with placebo is presented. Histologic analysis included hematoxylin and eosin (H&E) staining. Immunohistochemical analysis included staining for keratin 16 (K16), Ki76, CD3, CD11c, LL37/cathelicidin, S100A7, S100A8, β-defensin 2 (BD2), and DC-LAMP. Scale bar = 50 μm. Journal of Allergy and Clinical Immunology 2012 130, 145-154.e9DOI: (10.1016/j.jaci.2012.04.024) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 IL-17 neutralization results in decreased hyperplasia and leukocyte infiltration. Histologic analysis included hematoxylin and eosin staining. Immunohistochemical analysis included staining for keratin 16 (K16), Ki76, CD3, CD11c, LL37/cathelicidin, S100A7, S100A8, β-defensin 2 (BD2), and DC-LAMP. Cell counts are shown per square millimeter. *P < .05 versus baseline value. Data are shown as means ± SEMs. Journal of Allergy and Clinical Immunology 2012 130, 145-154.e9DOI: (10.1016/j.jaci.2012.04.024) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E4 IL-17 neutralization effects on some IL-17 target genes and on TNF-α and IL-12. mRNA expression for keratin 16 (K16) and lipocalin (LCN) is shown. IL-17 target gene were analyzed, as were mRNA expression levels for the T-cell cytokines IFN-γ, IL-17A/F, and IL-22 and the dendritic cell cytokine IL-23. *P < .05 versus baseline. Data are shown as means ± SEMs. Journal of Allergy and Clinical Immunology 2012 130, 145-154.e9DOI: (10.1016/j.jaci.2012.04.024) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E5 Correlation between week 2 response to treatment for Ki67 and IL-19. Journal of Allergy and Clinical Immunology 2012 130, 145-154.e9DOI: (10.1016/j.jaci.2012.04.024) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E6 Correlation between μ scores of epidermal response with measures of infiltrating leukocytes, associated cytokines, and defined cytokine response genes in keratinocytes. Each graph is a scatter plot of μ scores versus expression of β-defensin 4 (DEFB4), lipocalin (LCN), IL-8, CXCL1, MX1, CXCL9, CXCL10, IL-17A, IL-17F, IFN-γ, IL-22, the p19 subunit of IL-12, the p40 subunit of IL-12/23, and the p35 subunit of IL-23 and cell counts of CD3+ T cells and CD11c+ dendritic cells in the epidermis and total CD11c+ dendritic cells. Journal of Allergy and Clinical Immunology 2012 130, 145-154.e9DOI: (10.1016/j.jaci.2012.04.024) Copyright © 2012 American Academy of Allergy, Asthma & Immunology Terms and Conditions