Proteasome Inhibition Causes Apoptosis of Normal Human Plasma Cells Preventing Alloantibody Production

作者：D.K. Perry, Justin M. Burns, Harrison S. Pollinger, Bruce P. Amiot, J.M. Gloor, Greg J. Gores, Mark D. Stegall · 发表于：American Journal of Transplantation · 年份：2008 · DOI：10.1111/j.1600-6143.2008.02461.x · 被引用次数：329 · 研究领域：T-cell and B-cell Immunology、Multiple Myeloma Research and Treatments、Complement system in diseases

Antibody production by normal plasma cells (PCs) against human leukocyte antigens (HLA) can be a major barrier to successful transplantation. We tested four reagents with possible activity against PCs (rituximab, polyclonal rabbit antithymocyte globulin (rATG), intravenous immunoglobulin (IVIG) and the proteasome inhibitor, bortezomib) to determine their ability to cause apoptosis of human bone marrow-derived PCs and subsequently block IgG secretion in vitro. IVIG, rituximab and rATG all failed to cause apoptosis of PCs and neither rituximab nor rATG blocked antibody production. In contrast, bortezomib treatment led to PC apoptosis and thereby blocked anti-HLA and antitetanus IgG secretion in vitro. Two patients treated with bortezomib for humoral rejection after allogeneic kidney transplantation demonstrated a transient decrease in bone marrow PCs in vivo and persistent alterations in alloantibody specificities. Total IgG levels were unchanged. We conclude that proteasome activity is important for PC longevity and its inhibition may lead to new techniques of controlling antibody production in vivo.