Long‐Term Allograft Tolerance Is Characterized by the Accumulation of B Cells Exhibiting an Inhibited Profile

• Published in: American journal of transplantation Vol. 11; no. 3; pp. 429 - 438
• Main Authors: Le Texier, L., Thebault, P., Lavault, A., Usal, C., Merieau, E., Quillard, T., Charreau, B., Soulillou, J. P., Cuturi, M. C., Brouard, S., Chiffoleau, E.
• Format: Journal Article
• Language: English
• Published: Malden, USA Blackwell Publishing Inc 01-03-2011; Wiley
• Subjects: Alloantibodies; Allografts; Animal models; Animals; B-Lymphocytes - immunology; Biological and medical sciences; Blotting, Western; B‐cell tolerance; Endothelial cells; Fc receptors; Flow Cytometry; Germinal centers; Graft Survival - immunology; Heart; Heart Transplantation - immunology; Helper cells; Immune Tolerance - immunology; Immunoenzyme Techniques; Immunoglobulin G; Immunoglobulin M; Immunoglobulin Switch Region - genetics; Immunological tolerance; Immunoregulation; Immunosuppression; Inflammation; Isoantibodies - immunology; Lymphocytes B; Lymphocytes T; Male; Medical sciences; Molecular modelling; Peripheral blood; Rats; Rats, Inbred Lew; Recombination; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Surgery (general aspects). Transplantations, organ and tissue grafts. Graft diseases; T-Lymphocytes, Regulatory - immunology; Th2 Cells - immunology; tolerance immune; Transplantation Tolerance - immunology; Transplantation, Homologous; Homograft; Tolerance; B-cell tolerance; B-Lymphocyte; Long term; Accumulation; Profile; tolerance immune; Alloantibody; Graft; Inhibitor; Alloantibodies; β Cell
• ISSN: 1600-6135; 1600-6143
• DOI: 10.1111/j.1600-6143.2010.03336.x

Numerous reports have highlighted the central role of regulatory T cells in long‐term allograft tolerance, but few studies have investigated the B‐cell aspect. We analyzed the B‐cell response in a rat model of long‐term cardiac allograft tolerance induced by a short‐term immunosuppression. We observed that tolerated allografts are infiltrated by numerous B cells organized in germinal centers that are strongly regulated in their IgG alloantibody response. Moreover, alloantibodies from tolerant recipients exhibit a deviation toward a Th2 isotype and do not activate in vitro donor‐type endothelial cells in a pro‐inflammatory way but maintained expression of cytoprotective molecules. Interestingly, this inhibition of the B‐cell response is characterized by the progressive accumulation in the graft and in the blood of B cells blocked at the IgM to IgG switch recombination process and overexpressing BANK‐1 and the inhibitory receptor Fcgr2b. Importantly, B cells from tolerant recipients are able to transfer allograft tolerance. Taken together, these results demonstrate a strong regulation of the alloantibody response in tolerant recipients and the accumulation of B cells exhibiting an inhibited and regulatory profile. These mechanisms of regulation of the B‐cell response could be instrumental to develop new strategies to promote tolerance.
The authors show, in a rat model of cardiac allograft tolerance, that the B cell response is strongly regulated, and characterized by a deviation of the alloantibody response, B cell accumulation in the graft, and accumulation of peripheral blood B cells blocked at the switch recombination process that overexpress inhibitory molecules and can transfer tolerance. See editorial by Newell and Chong on page 420.