MDI1228, a Topical Pan-JAK Inhibitor, Disrupts Dermal Fibroblast-T cell Chemokine Crosstalk to Resolve Autoimmune Skin Diseases

Dermal fibroblasts (dFBs) have emerged as active immunomodulators, but whether they can be therapeutically targeted remains unexplored. Here we developed MDI1228, a novel topical pan JAK inhibitor with nanomolar potency against JAK1/2/3/TYK2 (IC50 0.11-0.85 nM) and high selectivity.

Topical MDI1228 ameliorated both DNFB induced ACD and MC903 induced AD in mice, reducing T cell infiltration and cytokine production. Mechanistically, MDI1228 not only directly inhibits T cell activation and cytokine production but also disrupts fibroblast-T cell crosstalk by reducing dFB-derived chemokine expression. Single cell transcriptomics identified dFBs as the primary source of CXCL9/10 in ACD and CCL2 in AD.