Synergistic effects of Isatis tinctoria L. and tacrolimus in the prevention of acute heart rejection in mice

• Published in: Transplant immunology Vol. 22; no. 1; pp. 5 - 11
• Main Authors: Wang, Yongzhi, Qin, Qing, Chen, Jibing, Kuang, Xiaocong, Xia, Junjie, Xie, Baiyi, Wang, Feng, Liang, Hua, Qi, Zhongquan
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 01.12.2009
• Subjects: Acute rejection; Allergy and Immunology; Animals; Body Weight - drug effects; Cardiac transplantation; Cell Proliferation - drug effects; Compound K; Concanavalin A - pharmacology; Drug Synergism; Drugs, Chinese Herbal - chemistry; Fatty Acids, Unsaturated - administration & dosage; Fatty Acids, Unsaturated - chemical synthesis; Fatty Acids, Unsaturated - pharmacology; Fatty Acids, Unsaturated - therapeutic use; Female; FK-506; Gene Expression - immunology; Graft Rejection - blood; Graft Rejection - metabolism; Graft Rejection - pathology; Graft Rejection - prevention & control; Graft Survival - drug effects; Heart Transplantation - immunology; Heart Transplantation - pathology; Immunosuppressive Agents - administration & dosage; Immunosuppressive Agents - chemical synthesis; Immunosuppressive Agents - pharmacology; Immunosuppressive Agents - therapeutic use; Interferon-gamma - blood; Interferon-gamma - genetics; Interleukin-10 - blood; Interleukin-10 - genetics; Interleukin-2 - blood; Interleukin-2 - genetics; Isatis - chemistry; Isatis tinctoria; Lymphocyte; Lymphocyte Activation - drug effects; Lymphocyte Activation - immunology; Lymphocyte Culture Test, Mixed; Lymphocytes - cytology; Lymphocytes - drug effects; Lymphocytes - immunology; Lymphocytes - metabolism; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; T cells; T-Lymphocytes - cytology; T-Lymphocytes - drug effects; T-Lymphocytes - immunology; Tacrolimus - administration & dosage; Tacrolimus - pharmacology; Tacrolimus - therapeutic use; Transplantation, Homologous - immunology; Transplantation, Homologous - pathology; Acute rejection; Compound K; FK-506; Cardiac transplantation; T cells; Lymphocyte
• ISSN: 0966-3274; 1878-5492
• DOI: 10.1016/j.trim.2009.09.004

Abstract Although immunosuppressive treatments are available for acute cardiac rejection no viable treatment exists for long-term cardiac graft failure. Moreover, the extended use of calcineurin inhibitor immunosuppressants, the mainstay of current treatment for cardiac transplantation, leads to significant side effects such as nephrotoxicity and an increased risk of cardiac disease. Because some agents used in Traditional Chinese Medicine (TCM) have strong immunosuppressive effects coupled with low toxicity, we investigated the effect of Compound K (K), the synthesized analogue of highly unsaturated fatty acids from Isatis tinctoria L., either as a single treatment or combined with tacrolimus (FK-506) on acute cardiac allograft rejection. We compared the ability of K alone, or in combination with FK-506, to inhibit acute heart transplant rejection both in vitro and in vivo . We found that the inhibition of lymphocyte proliferation was positively correlated with K concentration. K significantly reduced IL-2 and IFN-γ expression levels and significantly inhibited lymphocyte proliferation in both a lymphocyte transformation test and a mixed lymphocyte reaction (MLR). We also found that the inhibitory effect of a combination of K and a sub-therapeutic dose of FK-506 (SubFK-506) was stronger than that of full-dose FK-506 alone. Oral administration of K reduced acute cardiac allograft rejection in mice and had no apparent toxicity. In vivo , the immunosuppressive effect of K combined with a half-dose of FK-506 was equivalent to that of a full-dose of FK-506 alone. K combined with a half-dose of FK-506 reduced the expression levels of IL-2 and IFN-γ (both within the graft and in the recipients' serum) more effectively than a full-dose of FK-506. These results show that K has significant immunosuppressive effects both in vitro and in vivo . When used as a combination therapy with FK-506 we see a powerful inhibition of rejection with no obvious toxic side effects. The mechanism of action is postulated to involve the inhibition of IL-2 and IFN-γ expressions by lymphocytes, rather than the activation of Tr1 cells via the production of IL-10.