Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells

• Published in: The FASEB journal Vol. 21; no. 13; pp. 3450 - 3457
• Main Authors: Lee, Soo Sun, Gao, Wenda, Mazzola, Silvia, Thomas, Michael N, Csizmadia, Eva, Otterbein, Leo E, Bach, Fritz H, Wang, Hongjun
• Format: Journal Article
• Language: English
• Published: United States The Federation of American Societies for Experimental Biology 01-11-2007; Federation of American Societies for Experimental Biology
• Subjects: allografl survival; Animals; Bilirubin - pharmacology; Carbon Monoxide - pharmacology; Forkhead Transcription Factors - metabolism; Heme Oxygenase (Decyclizing) - metabolism; Immune Tolerance; islet transplantation; Islets of Langerhans - immunology; Islets of Langerhans - metabolism; Islets of Langerhans Transplantation; Lymphocyte Culture Test, Mixed; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Inbred DBA; Reverse Transcriptase Polymerase Chain Reaction; T-Lymphocytes, Regulatory - immunology; Transforming Growth Factor beta - metabolism; Transplantation, Homologous
• ISSN: 0892-6638; 1530-6860
• DOI: 10.1096/fj.07-8472com

Heme oxygenase-1 (HO-1) induction in, or carbon monoxide (CO), or bilirubin administration to, donors and/or recipients frequently lead to long-term survival (>100 days) of DBA/2 islets into B6AF1 recipients. We tested here whether similar treatments show value in a stronger immunogenetic combination, i.e., BALB/c to C57BL/6, and attempted to elucidate the mechanism accounting for tolerance. Induction of HO-1, administering CO or bilirubin to the donor, the islets or the recipient, prolonged islet allograft survival to different extents. Combining all the above treatments (the "combined" protocol) led to survival for >100 days and antigen-specific tolerance to 60% of the transplanted grafts. A high level of forkhead box P3 (Foxp3) and transforming growth factor β (TGF-β) expression was detected in the long-term surviving grafts. With the combined protocol, significantly more T regulatory cells (Tregs) were observed surrounding islets 7 days following transplantation. No prolongation of graft survival was observed using the combined protocol when CD4⁺CD25⁺ T cells were predepleted from the recipients before transplantation. In conclusion, our combined protocol led to long-term survival and tolerance to islets in the BALB/c to C57BL/6 combination by promoting Foxp3⁺ Tregs; these cells played a critical role in the induction and maintenance of tolerance in the recipient.--Lee, S. S., Gao, W., Mazzola, S., Thomas, M. N., Csizmadia, E., Otterbein, L. E., Bach, F. H., and Wang, H. Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells.