A New Immunosuppressive Molecule Emodin Induces both CD4+FoxP3+ and CD8+CD122+ Regulatory T Cells and Suppresses Murine Allograft Rejection
Authors: Zhenhua Dai
Chun-Ling Liang
Feifei Qiu
Huazhen Liu
Golay D Nie
Journal: Frontiers in Immunology (2017)
Discipline: IMMUNOLOGY
Keywords: T cell; allograft rejection; immunosuppression; regulatory T cell; transplant immunology.
Affiliations: Section of Immunology, Guangdong Provincial Academy of Chinese Medical Sciences, Guangdong Provincial Hospital of Chinese Medicine, Guangzhou, China., School of Medicine, University of Texas Medical Branch, Galveston, TX, United States.

Abstract:  Due to vigorous alloimmunity, an allograft is usually rejected without any conventional immunosuppressive treatment. However, continuous global immunosuppression may cause severe side effects, including tumors and infections. Mounting evidence has shown that cyclosporine (CsA), a common immunosuppressant used in clinic, impedes allograft tolerance by dampening regulatory T cells (Tregs), although it inhibits allograft rejection at the same time. Therefore, it is necessary to seek an alternative immunosuppressive drug that spares Tregs with high efficiency in suppression but low toxicity. In this study, we investigated the capacity of emodin, an anthraquinone molecule originally extracted from certain natural plants, to prolong transplant survival in a mouse model and explored the cellular and molecular mechanisms underlying its action. We found that emodin significantly extended skin allograft survival and hindered CD3+ T cell infiltration in the allograft, accompanied by an increase in CD4+Foxp3+ and CD8+CD122+ Treg frequencies and numbers but a reduction in effector CD8+CD44highCD62Llow T cells in recipient mice. Emodin also inhibited effector CD8+ T cells proliferation in vivo. However, CD4+CD25+, but not CD8+CD122+, Tregs derived from emodin-treated recipients were more potent in suppression of allograft rejection than those isolated from control recipients, suggesting that emodin also enhances the suppressive function of CD4+CD25+ Tregs. Interestingly, depleting CD25+ Tregs largely reversed skin allograft survival prolonged by emodin while depleting CD122+ Tregs only partially abrogated the same allograft survival. Furthermore, we found that emodin hindered dendritic cell (DC) maturation and reduced alloantibody production posttransplantation. Finally, we demonstrated that emodin inhibited in vitro proliferation of T cells and blocked their mTOR signaling as well. Therefore, emodin may be a novel mTOR inhibitor that suppresses alloimmunity by inducing both CD4+FoxP3+ and CD8+CD122+ Tregs, suppressing alloantibody production, and hindering DC maturation. Thus, emodin is a newly emerging immunosuppressant and could be utilized in clinical transplantation in the future. 

Retracted: No

PubPeer comments:
  The authors regret to identify errors in Figure 1 (Page 290) and Figure 2 (Page 292) and in the titles of Table 1 and 2 of the published article [1]. The error in Figure 1 was an incorrect scale bar, the figure should be replaced by the new figure below. FIGURE 1. Outline of Planhoogenraadia wuchanica sp. nov. (1A, 1B) in ventral and lateral views. (1u20136 characters of the shell measured (see Table 1). Scale bar is 50 u03bcm. The error in Figure 2 was the inclusion of a different but close-related taxon in Figure 2 D, E, F. This is corrected in the new version of the figure below. FIGURE 2. SEM images showing Planhoogenraadia wuchanica sp. nov. (A) lateral view; (B) the upper cap like structure; (C) dorsal view.). Scale bars: A, C 50 u03bcm, B, 30 u03bcm. The error in the titles of table 1 and Table 2 was the mention of a second taxon not discussed in the published paper. These are corrected below. TABLE 1. Morphometric characteristics of Planhoogenraadia wuchanica sp. nov. Measurements in u03bcm. SDu2014 standard deviation; CVu2014coefficient of variation in %; Minu2014minimum; Maxu2014maximum; Nu2014number of individuals investigated. TABLE 2. Comparison of Planhoogenraadia wuchanica sp. nov. with related species (Lu2014length, Wu2014width) ,