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Efficacy of IDOR-1117-2520, a novel, orally available CCR6 antagonist in a preclinical model of skin dermatitis

ABSTRACT: Background and Purpose:  The chemokine receptor CCR6 is important in guiding pathogenic T17 cells that are implicated in numerous autoimmune diseases including psoriasis to sites of inflammation via the chemokine CCL20. On this basis, pharmacological interventions that inhibit CCR6+ immune cell migration provide a novel therapeutic approach for such diseases. However, the translatability from pre-clinical models to human diseases of such an intervention has so far not been assessed in detail. Here, we evaluate the translatability of a preclinical model of Aldara induced skin inflammation to psoriasis with a particular focus on immune cell trafficking and assess the efficacy of the novel, orally available CCR6 antagonist IDOR-1117-2520 in this model. Experimental Approach:  Here, we evaluated the in vivo therapeutic effects of IDOR-1117-2520, a novel, highly selective, potent, and orally available CCR6 small molecule inhibitor, in the Aldara mouse model of skin inflammation. To understand in detail CCR6 inhibition on the inflammatory response, flow cytometry, RNA sequencing, and transcriptome-based cell type deconvolution approaches were used to characterize immune cell migration patterns and to compare the results to publicly available human psoriasis transcriptomics data. Key Results:  IDOR-1117-2520 dose dependently reduced infiltration of CCR6 + immune cells into inflamed skin and was equally efficacious as IL-17 and IL-23 inhibition in reducing inflammation in the skin. Pathway analysis highlighted the strong molecular similarities in immune response between human psoriasis and the Aldara mouse model. Genes associated with the IL-17/IL-23 pathway were prominently expressed in both human psoriasis and in the mouse model. CCR6 inhibition modulated multiple pathways associated with inflammation beyond the proximal IL-17/IL-23 pathway. A chemokine-chemokine receptor interaction map implicated the CCL20-CCR6 as the dominant axis in recruiting pathogenic T17 cells in this model system, as well as in human psoriasis. Conclusion and Implications:  These results suggest that IDOR-1117-2520 could provide a promising novel targeted therapeutic approach to treating psoriasis and, potentially, other autoimmune diseases with an involvement of CCR6/CCL20 axis and the IL-17/IL-23 pathway. The data provide rationale for the further development of IDOR-1117-2520, which is currently being evaluated in a clinical phase 1 trial (ISRCTN28892128).

ORGANISM(S): Mus musculus

PROVIDER: GSE289485 | GEO | 2025/04/01

REPOSITORIES: GEO

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Project description:Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the interleukin-4 receptor alpha chain (IL-4RÎ±-R576) biases induced Treg (iTreg) cells towards a T helper 17 (TH17) cell fate. This skewing reflects the recruitment by IL-4RÎ±-R576 of the adaptor protein growth factor receptor-bound protein 2 (GRB2), which drives IL-17 expression by an extracellular signal-regulated kinase-, IL-6- and STAT3-dependent mechanism. We showed that the IL-4RÎ±-R576 mutation elicits TH17 airway responses in vivo, in a house dust mite (HDM)- or ovalbumin (OVA)-driven model of airway inflammation in the mice carry the IL-4RÎ±-R576 mutation (Il4raR576 mice). Treg cell-specific deletion of genes encoding IL-6RÎ± or the master TH17 cell regulator Retinoid-related Orphan Receptor Î³t (RORÎ³t), but not IL-4 and IL-13, protected mice against exacerbated airway inflammation induced by IL-4RÎ±--576. Analysis of lung tissue Treg cells revealed that the expression of IL-17 and the TH17 cell-associated chemokine receptor CCR6 was largely overlapping and highly enriched in Treg and conventional T (Tconv) cells of allergen-treated Il4raR576 mice. To further characterize the subset of IL-17 producing Foxp3+ Treg in the lung of OVA-treated mice we utilized CCR6 as a marker of Treg cells committed towards the TH17 cell lineage to examine their functional, epigenetic and transcriptional profiles. CCR6+Foxp3EGFP+ Treg cells isolated from OVA-sensitized and challenged Il4raR576 mice, by FACS (Fluorescence Activated Cell Sorting) exhibited decreased methylation of the Foxp3 CNS2 locus comparing to CCR6âFoxp3EGFP+ Treg cells from same animals, indicative of decreased stability. They also exhibited profoundly decreased suppressive function as compared to CCR6â WT and CCR6â Il4raR576 counterparts. Transcriptional profiling of CCR6+Foxp3EGFP+ Treg cells revealed increased relative expression in CCR6+ Il4raR576 Treg cells of genes associated with a TH17 cell signature, including Rorc, Ccr6, Il23r, Il17a, Il17f, Il1r1, Nr1d1, Cstl, and Ahr comparing to CCR6âFoxp3EGFP+ Treg cells from same animals. Three CCR6+Foxp3EGFP+ Il4raR576 replicates and four CCR6âFoxp3EGFP+ Il4raR576 Treg replicates (controls) were sampled

Project description:Mechanisms by which regulatory T (Treg) cells fail to control inflammation in asthma remain poorly understood. We show that a severe asthma-associated polymorphism in the interleukin-4 receptor alpha chain (IL-4Rα-R576) biases induced Treg (iTreg) cells towards a T helper 17 (TH17) cell fate. This skewing reflects the recruitment by IL-4Rα-R576 of the adaptor protein growth factor receptor-bound protein 2 (GRB2), which drives IL-17 expression by an extracellular signal-regulated kinase-, IL-6- and STAT3-dependent mechanism. We showed that the IL-4Rα-R576 mutation elicits TH17 airway responses in vivo, in a house dust mite (HDM)- or ovalbumin (OVA)-driven model of airway inflammation in the mice carry the IL-4Rα-R576 mutation (Il4raR576 mice). Treg cell-specific deletion of genes encoding IL-6Rα or the master TH17 cell regulator Retinoid-related Orphan Receptor γt (RORγt), but not IL-4 and IL-13, protected mice against exacerbated airway inflammation induced by IL-4Rα--576. Analysis of lung tissue Treg cells revealed that the expression of IL-17 and the TH17 cell-associated chemokine receptor CCR6 was largely overlapping and highly enriched in Treg and conventional T (Tconv) cells of allergen-treated Il4raR576 mice. To further characterize the subset of IL-17 producing Foxp3+ Treg in the lung of OVA-treated mice we utilized CCR6 as a marker of Treg cells committed towards the TH17 cell lineage to examine their functional, epigenetic and transcriptional profiles. CCR6+Foxp3EGFP+ Treg cells isolated from OVA-sensitized and challenged Il4raR576 mice, by FACS (Fluorescence Activated Cell Sorting) exhibited decreased methylation of the Foxp3 CNS2 locus comparing to CCR6–Foxp3EGFP+ Treg cells from same animals, indicative of decreased stability. They also exhibited profoundly decreased suppressive function as compared to CCR6– WT and CCR6– Il4raR576 counterparts. Transcriptional profiling of CCR6+Foxp3EGFP+ Treg cells revealed increased relative expression in CCR6+ Il4raR576 Treg cells of genes associated with a TH17 cell signature, including Rorc, Ccr6, Il23r, Il17a, Il17f, Il1r1, Nr1d1, Cstl, and Ahr comparing to CCR6–Foxp3EGFP+ Treg cells from same animals.

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Efficacy of IDOR-1117-2520, a novel, orally available CCR6 antagonist in a preclinical model of skin dermatitis

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