B cell survival in intragraft tertiary lymphoid organs after rituximab therapy.
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.
Thaunat
Olivier
O
Renal Transplantation and Clinical Immunology Department, Edouard Herriot Hospital, HCL, Université Claude Bernard Lyon I, INSERM U851, Lyon, France. olivier.thaunatpastu@free.fr
Patey
Natacha
N
Gautreau
Chantal
C
Lechaton
Sophie
S
Fremeaux-Bacchi
Véronique
V
Dieu-Nosjean
Marie-Caroline
MC
Cassuto-Viguier
Elisabeth
E
Legendre
Christophe
C
Delahousse
Michel
M
Lang
Philippe
P
Michel
Jean-Baptiste
JB
Nicoletti
Antonino
A
D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D053264:B-Cell Activating Factor / Q000096:biosynthesis / Q000235:genetics; D001402:B-Lymphocytes / Q000187:drug effects / Q000473:pathology*; D001706:Biopsy; D002470:Cell Survival / Q000187:drug effects; D002908:Chronic Disease; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D015870:Gene Expression; D006084:Graft Rejection / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use*; D007518:Isoantibodies / Q000276:immunology; D016030:Kidney Transplantation / Q000276:immunology / Q000473:pathology*; D008297:Male; D011446:Prospective Studies; D012313:RNA / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000069283:Rituximab; D014184:Transplantation, Homologous; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D058846:Antibodies, Monoclonal, Murine-Derived; D018951:Antigens, CD20; D053264:B-Cell Activating Factor; D007155:Immunologic Factors; D007518:Isoantibodies; D000069283:Rituximab; D012313:RNA