BACKGROUND: Rituximab is emerging as a potent therapeutic option in chronic inflammatory diseases associated with a prominent humoral component. Recent studies have demonstrated that chronic inflammatory infiltrate organize progressively themselves into ectopic lymphoid tissues (tertiary lymphoid organs; TLOs) supporting a local humoral immune response. In the present study, we evaluated the impact of rituximab therapy on TLOs associated with chronic active antibody-mediated rejection, a prototypic humoral chronic inflammatory condition. METHODS: Renal allografts removed for terminal chronic rejection were prospectively collected in four transplantation centers over 4 years. Among 38 grafts collected, two were explanted after rituximab therapy for chronic active antibody-mediated rejection. Clinical characteristics and circulating B cell count were recorded for these two patients. The composition and the microarchitecture of the inflammatory infiltrate were analyzed by flow cytometry and immunohistochemistry. Organotypic cultures were performed to evaluate the intragraft production of alloantibody. Levels of expression of BAFF (Blys, CD257) were evaluated by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: Despite the complete depletion of circulating B cells in peripheral blood, TLOs were evidenced in the interstitium of both explanted grafts. Their functionality was assessed by the demonstration of a persistent local production of alloantibody. BAFF, a potent survival factor for B cells, was found to be overexpressed (both at the gene and the protein levels) in chronically rejected grafts when compared with normal kidneys and lymph nodes. CONCLUSIONS: In certain patients, inflammatory microenvironment provides BAFF-dependent paracrine survival signal to B-cells in TLOs, allowing them to escape rituximab-induced apoptosis, thereby thwarting therapeutic efficiency.
BACKGROUND:Rituximab is emerging as a potent therapeutic option in chronic inflammatory diseases associated with a prominent humoral component. Recent studies have demonstrated that chronic inflammatory infiltrate organize progressively themselves into ectopic lymphoid tissues (tertiary lymphoid organs; TLOs) supporting a local humoral immune response. In the present study, we evaluated the impact of rituximab therapy on TLOs associated with chronic active antibody-mediated rejection, a prototypic humoral chronic inflammatory condition. METHODS: Renal allografts removed for terminal chronic rejection were prospectively collected in four transplantation centers over 4 years. Among 38 grafts collected, two were explanted after rituximab therapy for chronic active antibody-mediated rejection. Clinical characteristics and circulating B cell count were recorded for these two patients. The composition and the microarchitecture of the inflammatory infiltrate were analyzed by flow cytometry and immunohistochemistry. Organotypic cultures were performed to evaluate the intragraft production of alloantibody. Levels of expression of BAFF (Blys, CD257) were evaluated by quantitative reverse transcriptase-polymerase chain reaction. RESULTS: Despite the complete depletion of circulating B cells in peripheral blood, TLOs were evidenced in the interstitium of both explanted grafts. Their functionality was assessed by the demonstration of a persistent local production of alloantibody. BAFF, a potent survival factor for B cells, was found to be overexpressed (both at the gene and the protein levels) in chronically rejected grafts when compared with normal kidneys and lymph nodes. CONCLUSIONS: In certain patients, inflammatory microenvironment provides BAFF-dependent paracrine survival signal to B-cells in TLOs, allowing them to escape rituximab-induced apoptosis, thereby thwarting therapeutic efficiency.
Authors: Vijay G Bhoj; Dimitrios Arhontoulis; Gerald Wertheim; James Capobianchi; Colleen A Callahan; Christoph T Ellebrecht; Amrom E Obstfeld; Simon F Lacey; Jan J Melenhorst; Farzana Nazimuddin; Wei-Ting Hwang; Shannon L Maude; Mariusz A Wasik; Adam Bagg; Stephen Schuster; Michael D Feldman; David L Porter; Stephen A Grupp; Carl H June; Michael C Milone Journal: Blood Date: 2016-05-10 Impact factor: 22.113