Mycophenolate mofetil enhances the effects of tacrolimus on the inhibitory function of regulatory T cells in patients after liver transplantation via PD-1 and TIGIT receptors

Abstract

Objective

Regulatory T cells (Tregs) induce immune tolerance in patients after organ transplantation. Various immunosuppressors can affect Tregs function through different mechanisms. PD-1 and TIGIT are important receptors on Tregs surface. Here, we investigated the effects of Tacrolimus and mycophenolate mofetil (MMF) on the inhibitory function of Tregs and explored the regulatory mechanism in patients after liver transplantation.

Methods

Thirty patients that underwent a liver transplant and 15 healthy people were enrolled. Fifteen patients received Tacrolimus only, and 15 received a combination of Tacrolimus and MMF. Tregs and effector T cells (Teffs) were isolated using magnetic beads and were mixed at different ratios of 0:1, 1:4, 1:2 and 1:1. An inhibition assay was performed by adding anti-PD-1 and anti-TIGIT when the mixture ratio was 1:1. The Tregs inhibition rate was determined and the levels of IFN-γ and TNF-α were measured.

Results

As the ratios of Tregs to Teffs in the mixture increased, the Tregs inhibition rate increased and the levels of IFN-γ and TNF-α decreased. At each mixture ratio, Tacrolimus + MMF group had the highest Tregs inhibition rate compared to Tacrolimus and control group. At the specific mixture ratio of 1:1, the addition of both anti- PD-1 and anti-TIGIT led to lower Tregs inhibition rate and higher IFN-γ and TNF-α levels in all three groups as opposed to the addition of each antibody separately. Additionally, both the decrease in the Tregs inhibition rate and the increase in the IFN-γ and TNF-α levels were the most for Tacrolimus + MMF group among all cases, either adding antibodies alone or mixed.

Conclusion

Tacrolimus and MMF enhanced the function of Tregs by synergistically affecting PD-1 and TIGIT in liver transplant patients.

Keywords:

• Tacrolimus
• mycophenolate mofetil
• regulatory T cells
• PD-1
• TIGIT
• liver transplantation

Acknowledgement

The authors thank TopEdit (www.topeditsci.com) for its linguistic assistance during the preparation of this manuscript.

Ethics approval and consent to participate

The signed written consents were obtained from each patient and the study was approved by the Ethics Committee of The Third Hospital of Hebei Medical University.

Disclosure statement

The authors declare that they have no competing interests.

Additional information

Funding

This work was supported by National Key Technologies R&D Program [No.2015BAI13B09].