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. CONCLUSION: 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.

Small interfering RNA molecules as potential anti-human rhinovirus agents: in vitro potency, specificity, and mechanism.

RNA silencing or interference (RNAi) is a sequence-specific, post-transcriptional process of mRNA degradation. The degradation of target gene mRNA can be induced by short dsRNA molecules (21-25-nt) corresponding to the sequence of the target gene to be silenced. Short dsRNA molecules have been shown to be very effective in inducing RNA silencing in several human cell lines. In this study, we have shown that short dsRNA molecules corresponding to the human rhinovirus-16 (HRV-16) genome induce effective inhibition of the viral replication in cell culture. This inhibition is sequence-specific and dose-dependent. A single or double nucleotide sequence change in an effective dsRNA molecule can significantly reduce the ability of the molecule to induce RNA silencing. Reducing the length of siRNA molecules to 19-nt or shorter abolishes their activity. Therefore, the results of this study demonstrate certain siRNA molecules are inhibitory for the replication of HRV-16 when transfected into human cells; further studies are warranted to explore the potential clinical value of these siRNA molecules as anti-human rhinovirus agents.

An adenine-to-guanine nucleotide change in the IRES SL-IV domain of picornavirus/hepatitis C chimeric viruses leads to a nonviable phenotype.

The inability for the internal ribosomal entry site (IRES) of hepatitis C virus (HCV) to be readily studied in the context of viral replication has been circumvented by constructing chimeras such as with poliovirus (PV), in which translation of the genome polyprotein is under control of the HCV IRES. During our attempts to configure the PV/HCV chimera for our drug discovery efforts, we discovered that an adenine- (A) to-guanine (G) change at nt 350 in domain IV of the HCV IRES resulted in a nonviable phenotype. Similarly, a mengovirus (MV)/HCV chimera using the same configuration with a G at nt 350 (G-350) was found to be nonviable. In contrast, a bovine viral diarrhea virus (BVDV)/HCV chimera remained viable with G-350 in the HCV IRES insert. Second-site, resuscitating mutations were identified from the G-350 PV/HCV and MV/HCV viruses after blind passaging. For both viruses, the resuscitating mutations involved destabilization of domain IV in the HCV IRES. The nonviability of G-350 in the picornavirus/HCV chimeric background might be linked to translation efficiency as indicated by analyses with dual reporter and PV/HCV replicon constructs.