BACKGROUND: Interleukin (IL)-6 is a pleiotropic cytokine that functions in both the innate and adaptive immune responses. However, the role of IL-6 in allograft rejection remains poorly understood. METHODS: In this study, we demonstrate a critical role for graft-produced IL-6 in allograft rejection in a murine model of cardiac allograft transplantation. RESULTS: The results show that IL-6-deficient grafts transplanted into allogeneic wild-type recipients have significantly prolonged survival, approximately three times the survival time of wild-type controls. In contrast, allogeneic cardiac transplants into IL-6-deficient recipients do not have prolonged graft survival, indicating that donor graft cells are the relevant source of IL-6. Our investigation of potential mechanisms shows that graft-produced IL-6 promotes the activation of peripheral CD4 and CD8 T cells. Furthermore, we show that IL-6 deficiency prolongs graft survival only in the presence of CD25+ T cells that have a phenotype consistent with regulatory T cells. Interestingly, IL-6 production by the graft is triggered by antigen-independent innate immune mechanisms. CONCLUSIONS: Thus, our results suggest the paradigm that graft rejection versus tolerance is determined by a balance between the activation of effector T cells versus immune suppression by regulatory T cells, and that after transplantation, IL-6 functions as a systemic danger signal that overcomes constitutive immune suppression mediated by regulatory T cells and promotes the activation of effector T cells.
BACKGROUND:Interleukin (IL)-6 is a pleiotropic cytokine that functions in both the innate and adaptive immune responses. However, the role of IL-6 in allograft rejection remains poorly understood. METHODS: In this study, we demonstrate a critical role for graft-produced IL-6 in allograft rejection in a murine model of cardiac allograft transplantation. RESULTS: The results show that IL-6-deficient grafts transplanted into allogeneic wild-type recipients have significantly prolonged survival, approximately three times the survival time of wild-type controls. In contrast, allogeneic cardiac transplants into IL-6-deficient recipients do not have prolonged graft survival, indicating that donor graft cells are the relevant source of IL-6. Our investigation of potential mechanisms shows that graft-produced IL-6 promotes the activation of peripheral CD4 and CD8 T cells. Furthermore, we show that IL-6 deficiency prolongs graft survival only in the presence of CD25+ T cells that have a phenotype consistent with regulatory T cells. Interestingly, IL-6 production by the graft is triggered by antigen-independent innate immune mechanisms. CONCLUSIONS: Thus, our results suggest the paradigm that graft rejection versus tolerance is determined by a balance between the activation of effector T cells versus immune suppression by regulatory T cells, and that after transplantation, IL-6 functions as a systemic danger signal that overcomes constitutive immune suppression mediated by regulatory T cells and promotes the activation of effector T cells.
Authors: Birgit Fogal; Tai Yi; Chen Wang; Deepak A Rao; Amir Lebastchi; Sanjay Kulkarni; George Tellides; Jordan S Pober Journal: J Immunol Date: 2011-11-14 Impact factor: 5.422
Authors: Kevin P Kennelly; Toby M Holmes; Deborah M Wallace; Cliona O'Farrelly; David J Keegan Journal: Cell Transplant Date: 2017-01-20 Impact factor: 4.064
Authors: Z Solhjou; M Uehara; B Bahmani; O H Maarouf; T Ichimura; C R Brooks; W Xu; M Yilmaz; A Elkhal; S G Tullius; I Guleria; M M McGrath; R Abdi Journal: Am J Transplant Date: 2017-04-18 Impact factor: 8.086
Authors: Shoichi Iida; Hidetoshi Tsuda; Toshiaki Tanaka; Danielle D Kish; Toyofumi Abe; Charles A Su; Ryo Abe; Kazunari Tanabe; Anna Valujskikh; William M Baldwin; Robert L Fairchild Journal: J Immunol Date: 2016-02-08 Impact factor: 5.422
Authors: M H Oberbarnscheidt; J S Obhrai; A L Williams; D M Rothstein; W D Shlomchik; G Chalasani; F G Lakkis Journal: Am J Transplant Date: 2009-11-24 Impact factor: 8.086