Blockade of IL-6/IL-6R Signaling Attenuates Acute Antibody-Mediated Rejection in a Mouse Cardiac Transplantation Model.

Maolin Ma,Tao Liao,Zhe Yang,Zhengyu Huang,Gengguo Deng,Fei Han,Qipeng Sun,Yannan Zhang,Qiquan Sun,Xiujie Li,Youqiang Fang

doi:10.3389/fimmu.2021.778359

Abstract

Acute antibody-mediated rejection (AAMR) is an important cause of cardiac allograft dysfunction, and more effective strategies need to be explored to improve allograft prognosis. Interleukin (IL)-6/IL-6R signaling plays a key role in the activation of immune cells including B cells, T cells and macrophages, which participate in the progression of AAMR. In this study, we investigated the effect of IL-6/IL-6R signaling blockade on the prevention of AAMR in a mouse model. We established a mouse model of AAMR for cardiac transplantation via presensitization of skin grafts and addition of cyclosporin A, and sequentially analyzed its features. Tocilizumab, anti-IL-6R antibody, and recipient IL-6 knockout were used to block IL-6/IL-6R signaling. We demonstrated that blockade of IL-6/IL-6R signaling significantly attenuated allograft injury and improved survival. Further mechanistic research revealed that signaling blockade decreased B cells in circulation, spleens, and allografts, thus inhibiting donor-specific antibody production and complement activation. Moreover, macrophage, T cell, and pro-inflammatory cytokine infiltration in allografts was also reduced. Collectively, we provided a highly practical mouse model of AAMR and demonstrated that blockade of IL-6/IL-6R signaling markedly alleviated AAMR, which is expected to provide a superior option for the treatment of AAMR in clinic.

Highlights

Cardiac transplantation is the primary treatment for patients with heart failure and has achieved great success [1]; the median survival of transplant recipients is only 11 years [2]
We explored the efficacy of blockade of IL-6/IL-6R signaling using tocilizumab and recipient IL-6 knockout (IL-6-/-) in suppressing acute AMR (AAMR) from allograft survival, pathological changes, donor-specific antibody (DSA), and inflammatory cell infiltration
In the PS and PS + cyclosporin A (CsA) groups, DSA-IgG significantly increased 7 d after skin transplantation (8220 ± 2630 vs 12380 ± 2525, p < 0.05; 8880 ± 2018 vs 11860 ± 1708, p < 0.05, respectively), and cardiac transplantation was performed at this time point to induce AAMR

Summary

Introduction

Cardiac transplantation is the primary treatment for patients with heart failure and has achieved great success [1]; the median survival of transplant recipients is only 11 years [2]. Current immunosuppression strategies have remarkably decreased T cell-mediated rejection (CMR), but antibodymediated rejection (AMR) is common and has recognized as an important cause of lethal allograft loss [3,4,5]. Current therapeutic strategies for AMR mainly include elimination of DSA, depletion of B and plasma cells, and inhibition of complement activation [7]. These treatments are only partially effective, and may cause severe complications. This situation necessitates the development of a more effective approach for managing AMR

Methods

Results

Conclusion