Recombinant IL-33 prolongs leflunomide-mediated graft survival by reducing IFN- gamma and expanding CD4 super(+)Foxp3 super(+) T cells in concordant heart transplantation

• Published in: Laboratory investigation 2016-08, Vol.96 (8), p.820-829
• Main Authors: Dai, Chen, Lu, Fang-Na, Jin, Ning, Yang, Bo, Gao, Chang, Zhao, Bin, Fu, Jia-Zhao, Hong, Shi-Fu, Liang, Han-Ting, Chen, Li-Hong, Chen, Zhi-Shui, Chen, Jie, Qi, Zhong-Quan
• Format: Article
• Language: English
• ISSN: 0023-6837
• DOI: 10.1038/labinvest.2016.54

Interleukin (IL)-33 is a novel IL-1 family member, and its administration has been associated with promotion of T helper type-2 (Th2) cell activity and cytokines, particularly IL-4 and IL-5 in vivo. Recently, IL-33 was shown to increase CD4 super(+)Foxp3 super(+) regulatory T cells (Tregs) and to suppress levels of the Th1-type cytokine IFN- gamma in allogeneic heart transplantation in mice. Therefore, we hypothesized that IL-33 and leflunomide (Lef) could prolong graft survival in the concordant mouse-to-rat heart transplantation model. In this model, xenografts undergo acute humoral xenograft rejection (AHXR) typically on day 3 or cell-mediated rejection approximately on day 7 if AHXR is inhibited by Lef treatment. Recipients were treated with Lef (n=6), IL-33 (n=6), IL-33 combined with Lef (n=6), or left untreated (n=6) for survival studies. Heart grafts were monitored until they stopped beating. Mouse heterotopic grafts were performed, and recipients were sacrificed on days 2 and 7 for histological and flow cytometric analyses. The combination of IL-33 and Lef significantly prolonged the grafts from 17.3 plus or minus 2.3 to 2.8 plus or minus 0.4 days, compared to untreated controls. IL-33 administration with Lef, while facilitating Th2-associated cytokines (IL-4 on day 2 but not day 7), also decreased IFN- gamma on day 2 and day 7, compared with Lef treatment only. Furthermore, IL-33 with Lef administration caused an expansion of suppressive CD4 super(+)Foxp3 super(+) Tregs in rats. The IL-33 and Lef combination therapy resulted in significantly prolonged graft survival, associated with markedly decreased Th1 cells and increased IL-10 levels. In addition, the combination therapy significantly decreased the percentage of CD-45 super(+) B cells on days 2 and 7, compared with monotherapy. These findings reveal a new immunoregulatory property of IL-33. Specifically, it facilitates regulatory cells, particularly functional CD4 super(+)Foxp3 super(+) Tregs that underlie IL-33-mediated cardiac xenograft survival. Moreover, it can decrease Th1 cells and cytokine expression of Th1 T cells in xenograft recipients, for example IFN- gamma .