| Background:Allogeneic bone marrow transplantation (BMT) has a wide range of current and potential applications, including the treatment of leukemia and other malignancies as well as a variety of autoimmune diseases. To date, the major obstacle to the development of this is graft-versus-host disease (GVHD), and in particular acute GVHD, which is most severe in patients receiving matched unrelated donor transplants.GVHD is caused by mature donor T lymphocytes that react against disparate major and minor histocompatibility complex present on host tissues. The occurrence and severity of GVHD is influenced by several factors, such as the degree of disparity of histocompatibility between donor and recipient; the number of T lymphocytes in the graft et al. Because of difficulties in combating acute GVHD once it has developed, attention has been directed toward its prevention. One of the most effective methods used for decreasing the incidence and severity of GVHD is in vitro depletion of T cells from the donor bone marrow before transplantation. This method of GVHD prevention, however, has adverse side effects such as an increased risk of graft failure, a higher relapse rate, a delayed recovery of the immune system associated with an increased frequency of infections and of EBV-induced lymphomas. The standard prophylaxis for GVHD, methotrexate (MTX) combined with cyclosporine (CSA) or glucocorticoids such as prednisolone, is effective at controlling the disease in related donor transplants, but results are often disappointing when applied to the matched unrelated donor setting. In addition, this regimen can lead to serious side effects such as nuphrotoxicity, hypertension, bone marrow suppression, and an increased risk of liver damage.Mycophenolate mofetil (MMF), an ester prodrug of the immunosuppressive agent mycophenolic acid (MPA) is developed recently. MPA is an antimetabolite with a broadrange of activaties that include antitumor, antifungal, antibacterial, antiviral activities, and immunosuppression. MPA selectively inhibits inodine 5'-monophosphate dehydrogenase (IMPDH), the key enzyme that controls the de novo synthesis of guanosine monophosphate (GMP). Lymphocyte activation and proliferation depends on the supply of guanine nucleotides (GTP) for protein and nucleic acid synthesis through the de novo pathway while other cells have a salvage biosynthesis pathway. MPA blocks T- and B-cell proliferation in response to antigens and mitogens, thereby suppressing cellular and thmoral immune responses. In addition, MPA inhibits lymphocyte binding and downregulates expression of adhesion molecules, and that way reducds lymphocyte migration and interation with macrophages. MMF, a semisynlhetic derivative of MPA has been studied in solid organ transplants and has been shown to prolong allografts of skin, lung, small intestine, heart, liver, and kidney in animals. This drug has also been successfully tested for the prevention of rejection in renal transplantation, and for prevention of GVHD in a small bowel transplant model and in a parent to Fl splenocyte injection model.There were only four literatures oversea about the effect of MMF for prophylaxis or treatment of acute GVHD in bone marrow transplant recipients. In china MMF combinated with CSA and MTX had been first used by proferssor He Huang of our unit as the prophylaxis of aGVHD arising from MHC-matched unrelated donor bone marrow transplant since 1998. The effect was wonderful. In this study, we reported on the effect of MMF against aGVHD in a full H-2mismatched murine BMT model, and explored the immunosuppression mechanism of MPA to T lymphocytes activation and proliferation.PART I Mycophenolate mofetil as acute graft-versus-host disease prophylaxis after allogeneic bone marrow transplantation in a murine modelMethods:The immunosuppressive drugs mycophenolate mofetil (MMF), cyclosporine A (CSA) and methotraxate (MTX) were used for the prevention of acute graft-versus-host disease (aGVHD). Acute GVHD was induced in BALB/C mice by... |
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