title: Kaempferol Promotes Transplant Tolerance by Sustaining CD4+FoxP3+ Regulatory T Cells in the Presence of Calcineurin Inhibitor.
abstract: Calcineurin inhibitor cyclosporine is widely used as an immunosuppressant in clinic. However, mounting evidence has shown that cyclosporine hinders tolerance induction by dampening Tregs. Therefore, it is of paramount importance to overcome this pitfall. Kaempferol was reported to inhibit DC function. Here, we found that kaempferol delayed islet allograft rejection. Combination of kaempferol and low-dose, but not high-dose, of cyclosporine induced allograft tolerance in majority of recipient mice. Although kaempferol plus either dose of cyclosporine largely abrogated proliferation of graft-infiltrating T cells and their CTL activity, both proliferation and CTL activity in mice treated with kaempferol plus low-dose, but not high-dose, cyclosporine reemerged rapidly upon treatment withdrawal. Kaempferol increased CD4+FoxP3+ Tregs both in transplanted mice and in vitro, likely by suppressing DC maturation and their IL-6 expression. Reduction in Tregs by low dose of cyclosporine was reversed by kaempferol. Kaempferol-induced Tregs exhibited both allospecific and non-allospecific suppression. Administering IL-6 abrogated allograft tolerance induced by kaempferol and cyclosporine via diminishing CD4+FoxP3+ Tregs. Thus, for the first time, we demonstrated that kaempferol promotes transplant tolerance in the presence of low dose of cyclosporine, which allows for sufficient Treg generation while minimizing side effects, resulting in much-needed synergy between kaempferol and cyclosporine.
authors: Department of Nephrology, the Second Clinical College, Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P. R. China.
authors: Y Q
authors: YQ
authors: Zeng
authors: Department of Nephrology, the Second Clinical College, Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P. R. China.
authors: X S
authors: XS
authors: Liu
authors: Center for Regenerative and Translational Medicine, the Second Clinical College, Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P. R. China.
authors: S
authors: S
authors: Wu
authors: Department of Nephrology, the Second Clinical College, Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P. R. China.
authors: C
authors: C
authors: Zou
authors: Center for Regenerative and Translational Medicine, the Second Clinical College, Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P. R. China.
authors: Q
authors: Q
authors: Xie
authors: Center for Regenerative and Translational Medicine, the Second Clinical College, Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P. R. China.
authors: S M
authors: SM
authors: Xu
authors: Center for Regenerative and Translational Medicine, the Second Clinical College, Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P. R. China.
authors: X W
authors: XW
authors: Jin
authors: Center for Regenerative and Translational Medicine, the Second Clinical College, Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P. R. China.
authors: W
authors: W
authors: Li
authors: The Cardiovascular Research Center, Warren Alpert Medical School of Brown University, Providence, RI.
authors: A
authors: A
authors: Zhou
authors: Center for Regenerative and Translational Medicine, the Second Clinical College, Guangzhou University of Chinese Medicine, and Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, P. R. China.
authors: Z
authors: Z
authors: Dai
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000378:metabolism*; D065095:Calcineurin Inhibitors / Q000494:pharmacology*; D016572:Cyclosporine / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D016381:Islets of Langerhans Transplantation; D044949:Kaempferols / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D008810:Mice, Inbred C57BL; D011183:Postoperative Complications; D060888:Real-Time Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000473:pathology; D023001:Transplantation Tolerance / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D065095:Calcineurin Inhibitors; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D044949:Kaempferols; C006552:kaempferol; D016572:Cyclosporine
keywords: basic (laboratory) research / science; calcineurin inhibitor (CNI); immune regulation; immunobiology; immunosuppressant; immunosuppression / immune modulation; tolerance: experimental