MDI1228, a topical pan-JAK inhibitor, disrupts dermal fibroblast-T cell chemokine crosstalk to resolve allergic contact and atopic dermatitis.

INTRODUCTION

Allergic contact dermatitis (ACD) and atopic dermatitis (AD) are driven by distinct T cell programs, and safe long-term topical therapies remain limited. Dermal fibroblasts (dFBs) have emerged as active immunomodulators, but whether they can be therapeutically targeted remains unexplored.

METHODS

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. MDI1228 was evaluated in DNFB‑induced ACD and MC903‑induced AD mouse models, as well as in primary mouse and human cell‑based assays.

RESULTS

Topical MDI1228 ameliorated both ACD and AD in mice, reducing T cell infiltration and cytokine production. Mechanistically, MDI1228 not only directly inhibited T cell activation and cytokine production but also disrupted 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. Conditioned medium and neutralization experiments demonstrated that CXCL9/10‑CXCR3 and CCL2‑CCR2 signaling axes contribute to T cell polarization in a context‑dependent manner. Compared with glucocorticoids, prolonged topical application of MDI1228 showed minimal systemic toxicity and preserved tissue homeostasis.

DISCUSSION: These findings identify dFBs as a central therapeutic node and demonstrate that MDI1228, by directly targeting T cells and disrupting dFB‑derived chemokine axes via JAK inhibition, offers a potent and safe topical treatment for both ACD and AD.