title: Tanshinol suppresses cardiac allograft rejection in a murine model.
abstract: BACKGROUND
  Achieving long-term cardiac allograft survival without continuous immunosuppression is highly desired in organ transplantation. Studies have shown that Salvia miltiorrhiza, an herb also known as danshen, improves microcirculation and is highly effective in treating coronary heart disease. Our objective is to determine whether tanshinol, an ingredient of danshen, improves cardiac allograft survival.
  
  
  METHODS
  Fully vascularized heterotopic heart transplantation was performed using BALB/c mice as donors and C57BL/6 mice as recipients, which were then treated with tanshinol and rapamycin. CD4+FoxP3+regulatory T cells (Tregs) were quantified by flow analyses, whereas CCL22 was measured by real-time polymerase chain reaction and Western blotting.
  
  
  RESULTS
  We found that tanshinol significantly delayed cardiac allograft rejection. It promoted long-term allograft survival induced by rapamycin, a mammalian target-of-rapamycin (mTOR) inhibitor. Tanshinol increased CD4+FoxP3+Treg numbers in cardiac allografts, but not spleens and lymph nodes, of recipient mice by enhancing chemokine CCL22 expression in cardiac allografts, especially cardiac dendritic cells. In contrast, rapamycin increased Treg numbers in both lymphoid organs and allografts, suggesting that it generally expands Tregs. Moreover, Tregs induced by rapamycin plus tanshinol were more potent in suppressing T-cell proliferation in vitro than those from untreated recipients. Neutralizing CCL22 hindered CD4+FoxP3+Treg migration to cardiac allografts and reversed long-term allograft survival induced by tanshinol plus rapamycin.
  
  
  CONCLUSIONS
  Tanshinol suppresses cardiac allograft rejection by recruiting CD4+FoxP3+Tregs to the graft, whereas rapamycin does so via expanding the Tregs. Thus, tanshinol cooperates with rapamycin to further extend cardiac allograft survival.
authors: Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China.
authors: Chuanjian
authors: C
authors: Lu
authors: Section of Nephrology, the Second Affiliated Hospital, Graduate School, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong, China.
authors: Yu-Qun
authors: YQ
authors: Zeng
authors: Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China.
authors: Huazhen
authors: H
authors: Liu
authors: Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China.
authors: Qingfeng
authors: Q
authors: Xie
authors: Center for Regenerative and Translational Medicine, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China.
authors: Shengmei
authors: S
authors: Xu
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi׳an, Shaanxi, China.
authors: Kangsheng
authors: K
authors: Tu
authors: Department of Hepatobiliary Surgery, First Affiliated Hospital of Xi'an Jiaotong University, Xi׳an, Shaanxi, China; Department of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA.
authors: Changwei
authors: C
authors: Dou
authors: Section of Immunology and Joint Immunology Program, Guangdong Provincial Academy of Chinese Medical Sciences, Guangzhou, Guangdong, China. Electronic address: zdai2009@outlook.com.
authors: Zhenhua
authors: Z
authors: Dai
mesh_terms: D064591:Allografts; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001707:Biopsy, Needle; D015153:Blotting, Western; D002109:Caffeic Acids / Q000494:pharmacology*; D054422:Chemokine CCL22 / Q000378:metabolism; D004195:Disease Models, Animal; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000009:adverse effects* / Q000379:methods; D007150:Immunohistochemistry; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011897:Random Allocation; D012680:Sensitivity and Specificity; D020123:Sirolimus / Q000494:pharmacology; D014019:Tissue Donors; D066027:Transplant Recipients; D014181:Transplantation Immunology / Q000502:physiology; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D002109:Caffeic Acids; C515483:Ccl22 protein, mouse; D054422:Chemokine CCL22; D007166:Immunosuppressive Agents; C585969:tanshinol; D020123:Sirolimus
keywords: Chinese medicine; allograft survival; chemokine; heart; regulatory T cells; transplantation