| [objection]Mycophenolate mofetil (MMF) is a newly developed immunosuppressor, currently widely used in allogeneic bone marrow transplantation. MMF is the morpholinoethyl ester prodrug of its active metabolite mycophenolic acid (MPA), MPA is a noncompetitive, reversible inhibitor of the enzyme inosine 5'-monophosphate dehydrogenase, which plays a major role in the denovo synthesis of guanosine nucleotides, Unlike other cells that also use the salvage pathway for purine biosynthesis, proliferating B and T cells are singularly dependent on the de novo pathway for the generation of guanosine. Thus, MPA exerts its immunosuppressive effects of lymphocyte proliferation . Resently, some studies found that MPA could inhibit the immunologic function of antigen presenting cells . Dendritic cells (DCs), the mostpotent antigen presenting cells with the unique ability to prime naive T cells, play a central role in antigen processing and presentation to induce T cell response in vitro and in vivo. This study is to evaluate the effects of mycophenolate acid, the in vivo active metabolite of MMF, on the maturation and immunologic function of murine bone marrow-derived dendritic cells and the activity of NF-KB in DCs, and to explore the underlying mechanisms of MMF in graft versus host disease, [methods]Bone marrow-derived dendritic cells were cultured with GM-CSF and IL-4 in the presence of MPA at doses of 0.01 mol/L and 0.1 mol/L. Cultured DCs were categorized into three groups-controK MPA 0.01 and MPA0.1. The ability of antigen presentation of the DCs were tested. The ability of the allostimulatory activities of the DCs on allogeneic T cells as assessed by mixed lymphocyte reaction . IL-12 production in culture supernatant and the Th1/Th2 cytokines such as IL-2, IFN-y, IL-4 and IL-10 levels in mixed lymphocyte reaction supernatant were examined by ELISA assays. The protein expression of NF-icB p50 in DCs was measured with Western blot assays, [results]The results showed that DCs cultured in the presence of MPA expressed low levels of CD40, CD80 and CD86. DCs cultured in the presence of MPA exhibited weaker activity of stimulating the proliferation of allogeneic T cells and antigen presentingfunction with a concurrent reduction of IL-12 procuction. MPA-treated DCs stimulated allogeneic T cells to secrete higher levels of Th2 cytokines IL-4 and IL-10 but lower levels of Thl cytokines IL-2 and IFN-y than did DCs without MPA treatment. The protein expression of NF-кB p50 was found decreased in DCs treated with MPA in a dose-dependent manner, [conclusion]It is conclusioned that MPA, and hence MMF, exerts a negative effect on the maturation and immunologic function of in vitro cultured DCs, and drives a shift of Thl cytokines to Th2 cytokines in MLR. This negative effect is linked to a decrease of the activity of NF-кB in DCs. |
