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. 2025 Jan 24;192(2):293-305.
doi: 10.1093/bjd/ljae375.

CCR8/CCL1 and CXCR3/CXCL10 axis-mediated memory T-cell activation in patients with recalcitrant drug-induced hypersensitivity

Tsu-Man Chiu  1   2   3 , Chun-Bing Chen  4   5   6   7   8   9 , Chun-Wei Lu  4   6   7   8 , Rosaline Chung-Yee Hui  4   7 , Min-Hui Chi  4   7 , Ya-Ching Chang  4   7 , Jennifer Wu  4   7   8 , Kuan-Yu Chen  4   7 , Yang Yu-Wei Lin  4 , Pei-Chi Lo  4 , Tsai-Ching Hsu  2 , Chuang-Wei Wang  4   5   6 , Wen-Hung Chung  4   5   6   7   8   9   10   11   12
Affiliations

CCR8/CCL1 and CXCR3/CXCL10 axis-mediated memory T-cell activation in patients with recalcitrant drug-induced hypersensitivity

Tsu-Man Chiu et al. Br J Dermatol. .

Abstract

Background: As a drug-induced hypersensitivity syndrome, drug reaction with eosinophilia and systemic symptoms (DRESS) is potentially fatal. Most patients with DRESS recover within a few weeks; however, some patients may suffer from a prolonged disease course and develop autoimmune sequelae.

Objectives: To investigate the immune mechanism and therapeutic targets of patients with recalcitrant DRESS with a prolonged disease course.

Methods: Thirty-two patients with recalcitrant DRESS with a prolonged treatment course (≥ 8 weeks; 'prolonged DRESS'), 28 patients with DRESS with a short treatment course (< 2 weeks; 'short-duration DRESS') and 26 healthy donors (HDs) were enrolled.

Results: Bulk transcriptome results showed that the mRNA expression levels of CCR8 and CXCR3 were significantly increased in blood samples from patients in the acute stage of prolonged DRESS [Padj = 1.50 × 10-9 (CCR8) and Padj = 2.60 × 10-4 (CXCR3), patients with prolonged DRESS compared with the HD group]. Serum and skin lesion concentrations of CCL1 and CXCL10 (ligands of CCR8 and CXCR3, respectively) were significantly increased in patients with prolonged DRESS compared with patients with short-duration DRESS. The results from high-parameter flow cytometry and autoantibody screening also identified significant increases in CD8+ GNLY+ CXCR3+ effector memory T cells, CD8+ central memory T cells, CD4+ CCR8+ T helper 2 cells and IgG anti-HES-6 autoantibodies in patients with prolonged DRESS. Furthermore, in vitro blocking assays revealed that Janus kinase inhibitors (JAKi; mainly tofacitinib and upadacitinib) significantly decreased the release of CCL1 and CXCL10. Some patients with prolonged DRESS were successfully treated with JAKi.

Conclusions: JAKi (tofacitinib and upadacitinib) were associated with decreased concentrations of CCL1 and CXCL10, suggesting that they may attenuate CCR8/CCL1 and CXCR3/CXCL10 axis-mediated memory T-cell activation, which contributes to disease pathogenesis in patients with recalcitrant DRESS and a long-term treatment course.

Plain language summary

Drug-induced hypersensitivity syndrome is a severe reaction to medication. Most people get better in a few weeks, but some may take longer to recover. This study looked at how the immune system works in people with this syndrome who needed treatment for longer. Higher levels of proteins that can trigger skin inflammation were found in these patients. Treatment with drugs called ‘JAK inhibitors’ blocked the release of proteins called CCL1 and CXCL10. We found that some people with drug-induced hypersensitivity who needed longer treatment were successfully treated with these drugs. JAK inhibitors may help lower the activation of certain immune responses. This could help control drug-induced hypersensitivity in people who need long-term treatment.

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Conflict of interest statement

Conflicts of interest: The authors declare no conflicts of interest.

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