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.
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-gamma, 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-1beta, 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.
Haider
Asifa S
AS
Laboratory for Investigative Dermatology, Rockefeller University, New York, NY, 10021, USA.
Lowes
Michelle A
MA
Suárez-Fariñas
Mayte
M
Zaba
Lisa C
LC
Cardinale
Irma
I
Khatcherian
Artemis
A
Novitskaya
Inna
I
Wittkowski
Knut M
KM
Krueger
James G
JG
D015703:Antigens, CD / Q000032:analysis; D001327:Autoimmune Diseases / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D017252:CD3 Complex / Q000032:analysis; D016572:Cyclosporine / Q000008:administration & dosage*; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D007136:Immunoglobulins / Q000032:analysis; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D020381:Interleukin-17 / Q000235:genetics; D053645:Interleukin-2 Receptor alpha Subunit / Q000032:analysis; D008562:Membrane Glycoproteins / Q000032:analysis; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D010597:Pharmacogenetics; D011565:Psoriasis / Q000188:drug therapy / Q000235:genetics* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D012867:Skin / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics; D000097802:CD83 Antigen
D015703:Antigens, CD; D017252:CD3 Complex; D016572:Cyclosporine; D007136:Immunoglobulins; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D053645:Interleukin-2 Receptor alpha Subunit; D008562:Membrane Glycoproteins; D052247:Nitric Oxide Synthase Type II; D014409:Tumor Necrosis Factor-alpha; D000097802:CD83 Antigen; C496319:NOS2 protein, human