D1.298 - Topical gluconolactone induces immune tolerance in cutaneous lupus erythematosus in human and mice

Dysfunctional regulatory T (Treg) cells are a hallmark of systemic (SLE) and cutaneous lupus erythematosus (CLE), yet therapies targeting Treg stability and function remain scarce.

Phosphoproteomic and metabolomic profiling identified gluconolactone (GDL), a pentose phosphate pathway metabolite, as a key promoter of Treg differentiation. GDL was tested prophylactically and therapeutically in short-term imiquimod-induced skin mouse models, MRL.lpr lupus-prone mice, and human SLE T cells, including topical application in CLE patients.

In vitro, GDL enhanced murine (i)Treg differentiation and suppressive function by upregulating Foxp3 and promoting p-Stat5 while suppressing Th17 differentiation. In IMQ and MRL.lpr models, topical GDL significantly reduced cutaneous inflammation, boosted Treg suppressive function, and inhibited Th17 responses. This was confirmed in ex vivo experiments using PBMCs from SLE patients including significant reduction of IFNg and IL17A mRNA expression in CD4+ T cells. In therapy-refractory CLE patients, topical GDL improved significantly clinical and histological skin features within two weeks.

GDL enhances Treg differentiation and suppresses Th17-driven inflammation in vitro and in vivo, in humans and mice. These findings highlight the therapeutic potential of topical GDL in addressing immune dysregulation in CLE and other autoimmune diseases.