Background/Purpose: In autoimmune diseases, activation of Th1 and Th17 pathways has been associated with disease maintenance and progression.  Engagement of endosomal Toll-like receptors (TLRs) 7, 8 and 9 through interaction with immune complexes containing nucleic acids induces production of proinflammatory cytokines leading to the activation of Th1 and Th17 responses.  Blocking the engagement of these receptors through an antagonist may inhibit this pathway, thus providing a novel approach to the treatment of autoimmune diseases.

Methods: In C57BL/6 mice, psoriasis-like skin lesions were induced by intradermal injection of IL-23.  Skin lesions were examined histopathologically and gene expression was monitored.  IL-23 injection stimulated upregulation in the skin of genes of multiple cytokines (including IL-12, IL-21, IL-23 and IL-17) keratinocyte peptides (including LL-37) and inflammasome protein NLRP3.  Treatment of mice with IMO-8400 was carried out by subcutaneous administration. 

Results: IMO-8400 was well tolerated at the dose level used in this study.  IMO-8400 treatment showed reduction in epidermal hyperplasia and infiltration of leukocytes.  In addition, mice treated with IMO-8400 showed suppression of multiple cytokines including IL-12, IL-21, IL-23 and IL-17 compared to untreated mice.  Expression of inflammasome protein NLRP3 and of keratinocyte genes Defensin B4, S100a4 and LL-37 was also suppressed in IMO-8400 treated mice compared to untreated mice.   

Conclusion: Treatment with IMO-8400 exerts a therapeutic effect on the IL-23 mediated induction of psoriatic lesions by blocking Th1 and Th17 pathways and NLRP3. IMO-8400 is in development for the treatment of lupus and other autoimmune diseases.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/a-selective-inhibitor-of-endosomal-toll-like-receptors-imo-8400-suppresses-activation-of-multiple-cytokines-th17-response-and-inflammasome-activation/