The Immunomodulatory Effect of Triptolide on Mesenchymal Stromal Cells.

Haiping He,Arinobu Tojo,Miwako Narita,Tokiko Nagamura-Inoue,Atsuko Takahashi,Akiko Hori,Tonghua Yang,Takeo Mukai

doi:10.3389/fimmu.2021.686356

Abstract

Mesenchymal stromal cells (MSCs) are known to have immunosuppressive ability and have been used in clinical treatment of acute graft-versus-host disease, one of severe complications of the hematopoietic stem cell transplantation. However, MSCs are activated to suppress the immune system only after encountering an inflammatory stimulation. Thus, it will be ideal if MSCs are primed to be activated and ready to suppress the immune reaction before being administered. Triptolide (TPL) is a diterpene triepoxide purified from a Chinese herb-Tripterygium wilfordii Hook.f. It has been shown to possess anti-inflammatory and immunosuppressive properties in vitro. In this study, we aimed to use TPL to prime umbilical cord-derived MSCs (TPL-primed UC-MSCs) to enter a stronger immunosuppressive status. UC-MSCs were primed with TPL, which was washed out thoroughly, and the TPL-primed UC-MSCs were resuspended in fresh medium. Although TPL inhibited the proliferation of UC-MSCs, 0.01 μM TPL for 24 h was tolerable. The surface markers of TPL-primed UC-MSCs were identical to those of non-primed UC-MSCs. TPL-primed UC-MSCs exhibited stronger anti-proliferative effect for activated CD4+ and CD8+ T cells in the allogeneic mixed lymphocyte reaction assay than the non-primed UC-MSCs. TPL-primed UC-MSCs promoted the expression of IDO-1 in the presence of IFN-γ, but TPL alone was not sufficient. Furthermore, TPL-primed UC-MSCs showed increased expression of PD-L1. Conclusively, upregulation of IDO-1 in the presence of IFN-γ and induction of PD-L1 enhances the immunosuppressive potency of TPL-primed UC-MSCs on the proliferation of activated T cells. Thus, TPL- primed MSCs may provide a novel immunosuppressive cell therapy.

Highlights

Mesenchymal stromal cells (MSCs) are known to have immunosuppressive abilities and have been used clinically to treat the acute graft-versus-host disease (GVHD), which accounts as one of the most severe complications after hematopoietic stem cell transplantation (HSCT) [1]
The immunosuppressive potency of mesenchymal stromal cells (MSCs) depends on the inflammatory factors, including those responsible for allogeneic reactions in acute graftversus-host disease (GVHD) and autologous diseases
TPL was a likely candidate for clinical use, severe adverse events including myocardial damage, renal failure, and hypovolemic shock secondary to severe intestinal tract disturbances [27] resulted in the limitation of TPL on clinical applications

Summary

Introduction

Mesenchymal stromal cells (MSCs) are known to have immunosuppressive abilities and have been used clinically to treat the acute graft-versus-host disease (GVHD), which accounts as one of the most severe complications after hematopoietic stem cell transplantation (HSCT) [1]. MSCs are activated to suppress the immune system only upon their stimulation by inflammatory cytokines, while the clinical results of MSC-based therapies for acute GVHD are diverse [2, 3]. Those MSCs are not active forms and expected to be active after the administration. We previously reported that UC-MSCs secreted indoleamine 2,3-dioxygenase-1 (IDO-1), a key soluble factor to inhibit the activated T-cell proliferation, only upon the IFN-g stimulation or allogenic mixed lymphocyte reaction (MLR), while no IDO-1 expressed without inflammations [4]. Combining the hypoxia with IFN-g priming showed additive effect of IFN-g alone on T-cell proliferations in MLR, gene expression of IDO-1 and PD-L1 was slightly suppressed by hypoxia

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