Identification of cellular pathways of "type 1," Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis

Asifa S. Haider, Michelle A. Lowes, Mayte Suárez-Fariñas, Lisa C. Zaba, Irma Cardinale, Artemis Khatcherian, Inna Novitskaya, Knut M. Wittkowski, James G. Krueger

Research output: Contribution to journalArticle

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Abstract

Therapeutic modulation of psoriasis with targeted immunosuppressive agents defines inflammatory genes associated with disease activity and may be extrapolated to a wide range of autoimmune diseases. Cyclosporine A (CSA) is considered a "gold standard" therapy for moderate-to-severe psoriasis. We conducted a clinical trial with CSA and analyzed the treatment outcome in blood and skin of 11 responding patients. In the skin, as expected, CSA modulated genes from activated T cells and the "type 1" pathway (p40, IFN-γ, and STAT-1-regulated genes). However, CSA also modulated genes from the newly described Th17 pathway (IL-17, IL-22, and downstream genes S100A12, DEFB-2, IL-1β, SEPRINB3, LCN2, and CCL20). CSA also affected dendritic cells, reducing TNF and inducible NO synthase (products of inflammatory TNF- and inducible NO synthase-producing dendritic cells), CD83, and IL-23p19. We detected 220 early response genes (day 14 posttreatment) that were down-regulated by CSA. We classified >95% into proinflammatory or skin resident cells. More myeloid-derived than activated T cell genes were modulated by CSA (54 myeloid genes compared with 11 lymphocyte genes), supporting the hypothesis that myeloid derived genes contribute to pathogenic inflammation in psoriasis. In circulating mononuclear leukocytes, in stark contrast, no inflammatory gene activity was detected. Thus, we have constructed a genomic signature of successful treatment of psoriasis which may serve as a reference to guide development of other new therapies. In addition, these data also identify new gene targets for therapeutic modulation and may be applied to wide range of autoimmune diseases.

Original languageEnglish (US)
Pages (from-to)1913-1920
Number of pages8
JournalJournal of Immunology
Volume180
Issue number3
StatePublished - Feb 1 2008
Externally publishedYes

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Th17 Cells
Nitric Oxide Synthase Type II
Psoriasis
Dendritic Cells
Cyclosporine
Inflammation
T-Lymphocytes
Genes
Nitric Oxide Synthase
Skin
Autoimmune Diseases
Pharmacogenomic Testing
Interleukin-23 Subunit p19
Therapeutics
Mononuclear Leukocytes
Interleukin-17
Immunosuppressive Agents
Interleukin-1

ASJC Scopus subject areas

  • Immunology

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Identification of cellular pathways of "type 1," Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis. / Haider, Asifa S.; Lowes, Michelle A.; Suárez-Fariñas, Mayte; Zaba, Lisa C.; Cardinale, Irma; Khatcherian, Artemis; Novitskaya, Inna; Wittkowski, Knut M.; Krueger, James G.

In: Journal of Immunology, Vol. 180, No. 3, 01.02.2008, p. 1913-1920.

Research output: Contribution to journalArticle

Haider, AS, Lowes, MA, Suárez-Fariñas, M, Zaba, LC, Cardinale, I, Khatcherian, A, Novitskaya, I, Wittkowski, KM & Krueger, JG 2008, 'Identification of cellular pathways of "type 1," Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis', Journal of Immunology, vol. 180, no. 3, pp. 1913-1920.
Haider, Asifa S. ; Lowes, Michelle A. ; Suárez-Fariñas, Mayte ; Zaba, Lisa C. ; Cardinale, Irma ; Khatcherian, Artemis ; Novitskaya, Inna ; Wittkowski, Knut M. ; Krueger, James G. / Identification of cellular pathways of "type 1," Th17 T cells, and TNF- and inducible nitric oxide synthase-producing dendritic cells in autoimmune inflammation through pharmacogenomic study of cyclosporine A in psoriasis. In: Journal of Immunology. 2008 ; Vol. 180, No. 3. pp. 1913-1920.
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AU - Zaba, Lisa C.

AU - Cardinale, Irma

AU - Khatcherian, Artemis

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