title: Mycophenolic acid inhibits maturation and function of human dendritic cells and B cells.
abstract: Mycophenolic acid (MPA) is considered an immunosuppressive compound mainly because of its inhibitory effects on lymphocyte proliferation. Here we studied specifically the effects of MPA on the ability of dendritic cells (DCs) to activate T cells via the indirect pathway and on the maturation and function of B-lineage cells. We demonstrated that DC cell-surface receptors, associated with antigen uptake and antigen processing and presentation (CD83 and CD205), were differentially downregulated in the presence of MPA, translating into a decreased uptake of alloantigens and reduced stimulation of T cells with decreased cytokine secretion (interleukin (IL)-1Ra and transforming growth factor (TGF)-alpha). Similarly, MPA significantly inhibited B-cell differentiation into memory and plasma cells in vitro and decreased secretion of TNF-alpha, IL-1Ra, and IL-10. We further demonstrated for the first time that not only the amount of antibody secretion was significantly lowered in the presence of MPA but also the total number of antibody-producing cells was reduced. Importantly, we provide direct evidence that HLA-specific antibody secretion was also affected using a newly developed HLA antibody-specific B-cell enzyme-linked immunospot assay. Our data indicate additional pathways by which MPA downregulates the immune system. This in turn may lead to improved conditions for allograft tolerance and control of allograft rejection.
authors.affiliation: Division of Organ Transplantation, Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611-3008, USA.
authors.forename: Persis P
authors.initials: PP
authors.lastname: Wadia
authors.forename: Nancy D
authors.initials: ND
authors.lastname: Herrera
authors.forename: Michael M
authors.initials: MM
authors.lastname: Abecassis
authors.forename: Anat R
authors.initials: AR
authors.lastname: Tambur
mesh_terms: D000328:Adult; D000917:Antibody Formation / Q000187:drug effects; D017951:Antigen Presentation / Q000187:drug effects; D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects; D006084:Graft Rejection / Q000188:drug therapy* / Q000276:immunology; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics / Q000378:metabolism; D007165:Immunosuppression Therapy; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism; D016753:Interleukin-10 / Q000235:genetics / Q000378:metabolism; D037181:Lectins, C-Type / Q000235:genetics / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D015778:Minor Histocompatibility Antigens; D009173:Mycophenolic Acid / Q000494:pharmacology* / Q000627:therapeutic use; D011956:Receptors, Cell Surface / Q000235:genetics / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016211:Transforming Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism; D000097802:CD83 Antigen
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D006680:HLA Antigens; D007136:Immunoglobulins; D053590:Interleukin 1 Receptor Antagonist Protein; D016753:Interleukin-10; D037181:Lectins, C-Type; D008562:Membrane Glycoproteins; D015778:Minor Histocompatibility Antigens; D009173:Mycophenolic Acid; D011956:Receptors, Cell Surface; D016211:Transforming Growth Factor alpha; D014409:Tumor Necrosis Factor-alpha; D000097802:CD83 Antigen; C093569:DEC-205 receptor