| Graft versus host disease (GVI-ID) is a major complication associated with allogeneic bone marrow transplantation (ahlo-BMT). It is caused by donor-derived alloreactive T lymphocytes and is a lethal adverse effect of alIo- BMT. Cyclosporin A (CsA) has been used as the basis of most immuno- suppressive regiments for the prevention of GVH1D, but has exhibited only limited effects and is hampered by nephrotoxicity, neurotoxicity, and hepatotoxicity. Several newer immunosuppressive drugs such as tacrolimus and rnycophenolic acid are available, and are used in transplantation for the rejection of allografl survival. Little is known about their harmful side effects upon longer periods of usage. Most toxic side effects of immunosuppressive drugs occur in relation to their applied concentrations. On the other hand, high concentrations are normally needed to ensure allografl survival in episodes of acute rejectioiv It may, therefore, be recommended that established drugs or new agents showing synergistic immunosuppressive effects are used simultaneously in order to reduce the effective concentrations of each single substance. The medicinal plant Sinomeniuni acuturn Rehd. et Wils. has been used in China for more than 2000 years, for the treatment of various diseases. The main active constituent has been identified as the alkaloid sinomenine (7, 8- didehydro-4-hydroxy-3, 7-dimethoxy- 1 7-methyl-9c, 13 c, 1 4c&.tnorphinan-6- one). Sinomenne is in clinical use in China and Japan due to its analgetic and anti-inflammatory activities. Its anti-rheumatic properties have been proved in clinical studies. In the recent years additional irnmunomodulatory effects of sinomenine have been revealed in vivo and in different animal models. On the cellular level, sinomenine was found to reduce the production of several inflammatory mediators such as prostaglandin E2 and nitric oxide from activated macrophages. Cell proliferation was dose-dependently decreased in murine spleen cells, rat thymocytes, human PBMC, and rat synovial fibroblasts. Galactosamine-sensitized mice were protected by si nomenine against endotoxin-induced fulminant hepatitis, and inflan1tnatory parameters as well as clinical signs were attenuated in rat adjuvant or antigen-induced arthritis following treatment with the drug. Very recently, it has been demonstrated that sinomenine exerts synegistic effects together with suboptimal concentrations of cyclosporin A in vitro (inhibition of rat thymocyte proliferation) and in vivo (prolongation of rat cardiac allografl survival). The aim of this study was to characterize the effectiveness of sinomenine in combination with subtherapeutic dose of CsA suppressing the development of GVIID in a MI-IC-mismatched murine BMT model (H2h anti H2d) when administered early in the course of desease. In the first part, we investigated the immunosuppressive effects of sinomenine on normal C57BL/6 mice in vivo. Sinomenine showed widely inhibitory effects on cells of the immune system including lymphocytes and antigen presenting cells (APC), such as T lymphocytes proliferation and IL-2 secretion, antigen presenting function of peritoneal macrophage (Mp) and splenic dendritic cells (sDC). By flow cytolnetry analysis, Ia, CD86 B72 and CD4O molecules expression on the surface of sDC were found to be down regulated. Expression level of Ia antigen of peritoneal M(p was also reduced. Secondly, we further demonstrated that sinomenine suppressed...
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