Frontiers in Immunology (Jan 2021)

Combination Treatment With Metformin and Tacrolimus Improves Systemic Immune Cellular Homeostasis by Modulating Treg and Th17 Imbalance

  • Soon Kyu Lee,
  • Min-Jung Park,
  • Joo Yeon Jhun,
  • Jin-Ah Beak,
  • Jeong Won Choi,
  • Jae-Yoon Rye,
  • Jeong Won Jang,
  • Si Hyun Bae,
  • Seung Kew Yoon,
  • Ho Joong Choi,
  • Young Kyoung You,
  • Mi-La Cho,
  • Jong Young Choi

DOI
https://doi.org/10.3389/fimmu.2020.581728
Journal volume & issue
Vol. 11

Abstract

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We examined the effect of combination therapy with metformin and tacrolimus on immune parameters including T regulatory (Treg) and type 17 helper T (Th17) cells in vitro and in vivo in mice and in liver transplantation (LT) patients. T cell proliferation and subtypes after in vitro T cell activation or allogeneic stimulation were evaluated. RNA sequencing and microarray analysis were used to evaluate differences in gene expression. Metformin and tacrolimus were administered to mice with graft-versus-host disease (GVHD) and the effects in vivo were assessed. Five LT patients were treated with metformin and the changes in Treg and Th17 cells examined. Combination therapy decreased Type 1 helper T (Th1) and Th17 cells present after in vitro T cell activation, whereas genes associated with Treg were overexpressed. During in vitro allogeneic stimulation, combination therapy increased Treg cells and decreased T cell proliferation and pro-inflammatory markers. In mice with GVHD, combination treatment decreased the clinical and pathological severity of GVHD. In LT patients, addition of metformin increased the peripheral percentage of CD4+Treg and CD8+Treg cells and decreased CD4+Th17. Our study suggests that the addition of metformin to tacrolimus may improve immunological balance by increasing Treg cells and decreasing Th17 cells.

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