IL-17A is essential for cell activation and inflammatory gene circuits in subjects with psoriasis.
BACKGROUND
In subjects with psoriasis, inflammation and epidermal hyperplasia are thought to be controlled by T cell-derived cytokines. Evidence suggests that the T(H)17 cell cytokine IL-17A (IL-17) might play a role in disease pathogenesis.


OBJECTIVE
We sought to understand the effect that neutralization of IL-17 has on the clinical features of psoriasis and to understand the role that IL-17 has in inflammatory pathways underlying psoriasis in human subjects.


METHODS
We examined skin lesions obtained from 40 subjects participating in a phase I, randomized, double-blind, placebo-controlled trial of the anti-IL-17 mAb ixekizumab (previously LY2439821) in which subjects received 5, 15, 50, or 150 mg of subcutaneous ixekizumab or placebo at weeks 0, 2, and 4.


RESULTS
There were significant dose-dependent reductions from baseline in keratinocyte proliferation, hyperplasia, epidermal thickness, infiltration into the dermis and epidermis by T cells and dendritic cells, and keratinocyte expression of innate defense peptides at 2 weeks. By week 6, the skin appeared normal. Quantitative RT-PCR and microarrays revealed an ablation of the disease-defining mRNA expression profile by 2 weeks after the first dose of study drug. The effect of IL-17 blockade on expression of genes synergistically regulated by IL-17 and TNF-α was of higher magnitude at 2 weeks than in prior studies with TNF-α antagonism.


CONCLUSIONS
Our data suggest that IL-17 is a key "driver" cytokine that activates pathogenic inflammation in subjects with psoriasis. Neutralizing IL-17 with ixekizumab might be a successful therapeutic strategy in psoriasis.
The Rockefeller University, New York, NY 10065, USA. James.Krueger@rockefeller.edu
James G
JG
Krueger
Scott
S
Fretzin
Mayte
M
Suárez-Fariñas
Patrick A
PA
Haslett
Krista M
KM
Phipps
Gregory S
GS
Cameron
Juliet
J
McColm
Artemis
A
Katcherian
Inna
I
Cueto
Traci
T
White
Subhashis
S
Banerjee
Robert W
RW
Hoffman
D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000276:immunology / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020381:Interleukin-17 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D008213:Lymphocyte Activation; D008969:Molecular Sequence Data; D020411:Oligonucleotide Array Sequence Analysis; D011565:Psoriasis / Q000276:immunology / Q000503:physiopathology* / Q000628:therapy*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012867:Skin / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D058504:Th17 Cells / Q000276:immunology*; D016896:Treatment Outcome; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000276:immunology / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha; C549079:ixekizumab