Abstract
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.
Highlights
Tacrolimus, a calcineurin inhibitor (CNI), is one of the main immunosuppressive drugs used to prevent rejection after liver transplantation (LT) [1, 2]
We examined the changes in type 1 helper T (Th1) and type 17 helper (Th17) cells in the CD4+T cells derived from splenocytes of normal and graft-versus-host disease (GVHD) mice after CD3 stimulation
In normal mouse cells activated under CD3 stimulation, flow cytometry demonstrated that the combination of metformin and tacrolimus suppressed the development of Th1 and Th17 cells compared with control and tacrolimus monotherapy (Figure 1A)
Summary
Tacrolimus, a calcineurin inhibitor (CNI), is one of the main immunosuppressive drugs used to prevent rejection after liver transplantation (LT) [1, 2]. It has immunosuppressive effects by reducing interleukin-2 (IL-2) transcription, which results in inhibition of the proliferation of helper and cytotoxic T cells [2]. In our previous study, the serial increase of Treg/type 17 helper T (Th17) ratio during tapering immunosuppressive drugs may indicate tolerance after LT [4]. Metformin modulates the immune system by reducing type 17 helper T (Th17) cells and increasing the Treg population [7]
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