Blockade of IL-6/IL-6R Signaling Attenuates Acute Antibody-Mediated Rejection in a Mouse Cardiac Transplantation Model
Authors: Zhe Yang
Qipeng Sun
Xiujie Li
Zhengyu Huang
Yannan Zhang
Gengguo Deng
Fei Han
Youqiang Fang
Maolin Ma
Tao Liao
Qiquan Sun
Journal: Frontiers in Immunology (2021)
Discipline: IMMUNOLOGY
Keywords: IL-6; IL-6R; antibody-mediated rejection; cardiac transplantation; mouse model.
Affiliations: Organ Transplantation Research Institute, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China., Department of Kidney Transplantation, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong, China., Department of Obstetrics and Gynecology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China., Department of Urology, the Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.

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. 

Retracted: No

PubPeer comments:
 Dear authors, Please check Fig. 2A, NS group 1d and 2d have overlapping regions indicating that they are actually from the same sample. ![file] , 
 #1 Dear Dr. Heterochasta Lasioplaca Thanks for your comments on our published article, which we have checked very carefully and discussed. We regret that one image (Figure 2A, 1d in the NS group) was misincorporated during figure assembly when we were preparing for manuscript submission. After carefully checking the original data, the image 1d was misused by accident when we were preparing for manuscript submissions. During the immunohistochemical staining, we observed that all C4d staining in the NS group within 4 days after cardiac transplantation showed negative results. Accidentally, when the 2d images in the NS group were captured, partial images were saved by mistake in the folder named 1d, and then mistaken saved image in 1d folder was misincorporated in Figure 2A during figure assembly when we were preparing for manuscript submission. Due to the negative C4d staining results in the NS group within 4 days, this error does not cause the different results and conclusions of this manuscript. The corrected 1d and 2d C4d staining images in the NS group of Figure 2A appears below. We apologize for this error and state that this does not change the scientific conclusions of the article in any way. ![file] We immediately contacted with the Editorial Office of the journal, and have submitted a correction to the journal today. We apologize to our readers for any confusion this unintentional error might have caused. Thank you again for your attention. , 
 CORRECTION: In the original article, there was a mistake in Figure 2 as published. In Figure 2A, C4d staining results in the NS group 1d and 2d have overlapping regions indicating that they are from the same sample. After carefully checking the original data, the image 1d was misused by accident when we were preparing for manuscript submission. The corrected Figure 2 appears below. https: www.frontiersin.org articles 10.3389 fimmu.2021.808329 full ,