Modulation of Donor-Specific Antibody Production After Organ Transplantation by Valproic Acid: A Histone Deacetylase Inhibitor

Background. Antibody-mediated rejection, mediated by donor-specific antibodies, is emerging as a leading cause for allograft dysfunction in organ transplantation. Histone deacetylase inhibitors (HDACi) have potential immunosuppressive action, but their effects on antibody-mediated rejection and B cell function in organ transplantation have not been fully explored. Methods. The impacts of valproic acid (VPA), an HDACi, on isolated murine B cell proliferation, apoptosis, class switch recombination (CSR), differentiation, and secretion of immunoglobulin were investigated in vitro and in vivo. Molecular mechanisms were also explored by analyzing the expression of the activation-induced cytidinedeaminase, B lymphocyte-induced maturation protein-1 (Blimp-1/Pridm1), X-box-binding protein 1 and interferon-regulatory factor 4. Mouse cardiac transplant model was used to evaluate the regulatory effects of VPA on B cell response in vivo. Results. Valproic acid significantly inhibited B cell CSR, plasma cell differentiation, thereby reduced antibody generation in a dose-dependent manner without altering B cell proliferation and apoptosis in vitro and in vivo. Activation-induced cytidinedeaminase, Blimp-1/Pridm1 and X-box-binding protein 1 expression were repressed by VPA treatment in a dose-dependent manner, whereas no obvious changes were observed on interferon-regulatory factor 4 expression. Although VPA alone did not prolong the graft medium survival time after murine heart transplantation, the low levels of donor-specific antibody, especially IgG in serum and the less numbers of plasma cells in the spleen were observed in VPA-treated mice. Conclusions. Valproic acid inhibited B cell CSR and plasma cell differentiation in vitro and in nitrophenylchicken gamma globulin-immunized and heart transplant recipient mice. HDACi might be a therapeutic agent targeting B cell response after organ transplantation.