Expression of the Tim3‐galectin‐9 axis is altered in drug‐induced maculopapular exanthema

Abstract

Background Drug‐induced maculopapular exanthemas (MPEs) are mediated by Th1 CD4+ T cells. One of the mechanisms of control of Th1 cells in homeostasis is the interaction between the checkpoint inhibitor Tim3 and its physiological ligand galectin‐9 (Gal9). Disorders affecting this axis may be responsible for various autoimmune and immunological diseases. The aim of this study was to determinate the influence of the Tim3‐Gal9 axis on the development of MPE induced by drugs. Methods Frequencies of different cell subsets and the expression of Tim3 and Gal9 were measured in peripheral blood by flow cytometry and in skin biopsies by immunohistochemistry. Gal9 expression was assessed by RT‐qPCR; its release was measured by multiplex assay. The effects of blocking or enhancing the Tim3‐Gal9 axis on monocyte‐derived dendritic cell (moDC) maturation and T‐cell proliferation were determined by flow cytometry. Results The expression of Tim3 was significantly reduced in peripheral blood Th1 cells and in the skin of MPE patients vs controls. Gal9 expression and release were significantly reduced in patient peripheral blood and moDCs, respectively. The addition of exogenous Gal9 significantly reduced Tim3+ Th1 proliferation, although Treg proliferation increased. Conclusion This study showed the involvement of the Tim3‐Gal9 axis in MPE. The reduced expression of Tim3 in Th1 cells together with the impaired expression of Gal9 in PBMCs and DCs appears to have a role in the development of the disease. The potential of Gal9 to suppress Th1 and enhance Treg proliferation makes it a promising tool for treating these reactions.

Recent developments and highlights in drug hypersensitivity

“…A reduced expression of the checkpoint molecules Tim3 and the galectin 9 in patients with DHRs has been recently demonstrated. It could be responsible for the impaired control of Th1 response and reduction of T regulatory cells (Treg) . Moreover, in cutaneous BL reactions, the involvement of a new Th population, antigen‐specific IL‐22‐secreting T cells (Th22), has been detected …”

“…It could be responsible for the impaired control of Th1 response and reduction of T regulatory cells (Treg). 148 Moreover, in cutaneous BL reactions, the involvement of a new Th population, antigen-specific IL-22-secreting T cells (Th22), has been detected. 149 The involvement of microRNAs (miRNAs) in SJS/TEN has been explored demonstrating that their expression during drug-specific CD4 + T-cell activation and cytokine production depends on the drug involved.…”

Immune dysregulation increases the incidence of delayed‐type drug hypersensitivity reactions

“…Tim‐3 is an immune checkpoint receptor that interacts with its ligand galectin 9 to modulate Th1 CD4 + T‐cell responses. The expression of Tim‐3 has recently been shown to be significantly reduced on peripheral blood CD4 + T cells in the acute phase of drug‐induced maculopapular exanthema, a classical Th1‐mediated iatrogenic disease. Furthermore, galectin 9 expression and release were reduced on dendritic cells.…”

Galectin-9: A Suppressor of Atherosclerosis?

“…It may be because the effects of gal-9 vary depending upon the route of administration, concentration and the type of inflammatory model used. Recently, another study also showed that the level of Tim-3 in Th1 cells reduced in patients with maculopapular exanthema and the exogenous recombinant Gal-9 significantly increased Treg proliferation and decreased Th1 proliferation, not differences in the proliferation of Th1 cells after blocking Tim-3 (37). It is certified that Tregs play a prominent role in terminating the immune response.…”