Long-term allograft tolerance is characterized by the accumulation of B cells exhibiting an inhibited profile.
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.
INSERM U643, CHU Nantes, Institut de Transplantation et de Recherche en Transplantation Urologie Nephrologie, Nantes, France.
L
L
Le Texier
P
P
Thebault
A
A
Lavault
C
C
Usal
E
E
Merieau
T
T
Quillard
B
B
Charreau
J P
JP
Soulillou
M C
MC
Cuturi
S
S
Brouard
E
E
Chiffoleau
D000818:Animals; D001402:B-Lymphocytes / Q000276:immunology*; D015153:Blotting, Western; D005434:Flow Cytometry; D006085:Graft Survival / Q000276:immunology*; D016027:Heart Transplantation / Q000276:immunology*; D007108:Immune Tolerance / Q000276:immunology*; D007124:Immunoenzyme Techniques; D007134:Immunoglobulin Switch Region / Q000235:genetics; D007518:Isoantibodies / Q000276:immunology*; D008297:Male; D012333:RNA, Messenger / Q000235:genetics; D051381:Rats; D011917:Rats, Inbred Lew; D020133:Reverse Transcriptase Polymerase Chain Reaction; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
D007518:Isoantibodies; D012333:RNA, Messenger