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Toll-like receptor 4 suppression leads to islet allograft survival

Alyssa Goldberg^*, Margherita Parolini, Beek Y. Chin^*, Eva Czismadia^*, Leo E. Otterbein^*, Fritz H. Bach^* and Hongjun Wang^*,1

^* Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA; and

Universita di Milano-Bicocca, Milan, Italy

¹Correspondence: Beth Israel Deaconess Medical Center, Harvard Medical School, 99 Brookline Ave., Boston, MA 02215, USA. E-mail: hwang3{at}bidmc.harvard.edu

Carbon monoxide (CO) exposure of an islet donor frequently leads to islet allograft long-term survival and tolerance in recipients. We show here that CO confers its protective effects at least in part by suppressing Toll-like receptor 4 (TLR4) up-regulation in pancreatic ß cells. TLR4 is normally up-regulated in islets during the isolation procedure; donor treatment with CO suppresses TLR4 expression in isolated islets as well as in transplanted grafts. TLR4 up-regulation allows initiation of inflammation, which leads to islet allograft rejection; islet grafts from TLR4-deficient mice survive indefinitely in BALB/c recipients and show significantly less inflammation at various days after transplantation compared with grafts from a control donor. Isolated islets preinfected with a TLR4 dominant negative virus before transplantation demonstrated prolonged survival in recipients. Despite the salutary effects of TLR4 suppression, HO-1 expression is still needed in the recipient for islet survival: TLR4-deficient islets were rejected promptly after being transplanted into recipients in which HO-1 activity was blocked. In addition, incubation of an insulinoma cell line, ßTC3, with an anti-TLR4 antibody protects those cells from cytokine-induced apoptosis. Our data suggest that TLR4 induction in ß cells is involved in ß cell death and graft rejection after transplantation. CO exposure protects islets from rejection by blocking TLR4 up-regulation.—Goldberg, A., Parolini, M., Chin, B. Y., Czismadia, E., Otterbein, L. E., Bach, F. H., Wang, H. Toll-like receptor 4 suppression leads to islet allograft survival.

Key Words: islet transplantation • carbon monoxide • inflammation • type 1 diabetes