Background: Intra-islet endothelial cells (IECs) express high levels of major histocompatibility complex (MHC) and are pivotal for posttransplant islet revascularization. We postulated that donor-specific sensitization would result in hyperacute rejection of IECs and prevent islet engraftment. Furthermore, ligation of endothelial cells with subsaturating concentrations of anti-MHC class I antibody (Ab) results in "accommodation" conferring protection against Ab/complement-mediated lysis. Therefore, we investigated whether accommodation of IECs would prevent hyperacute rejection of islets in sensitized recipients.
Methods: Islets were transplanted beneath the kidney capsule and allograft survival monitored using daily blood glucose (diabetes >300 mg/dL, normoglycemia <150 mg/dL). Recipients were presensitized with donor islets, splenocytes, or skin. Accommodation was induced by incubating human or murine islets with varying concentrations of anti-MHC class I Ab ex vivo.
Results: Isografts remained functional for >100 days, whereas allografts were rejected by day 14. Islet allo-transplantation induced donor-specific but not third-party anti-MHC Abs. Donor-specific, but not third-party, sensitization induced hyperacute rejection of subsequent islet allografts (median survival 1 day) associated with complement deposition. Preincubation of islets with subsaturating concentrations of anti-MHC-I Abs (1-100 ng/mL) up-regulated Bcl-2, Bcl-xl, and HO-1 within CD31+ IEC. These accommodated islets were resistant against hyperacute rejection when transplanted into donor-(splenocyte) sensitized recipients without any immunosuppression (median survival 6 days).
Conclusions: Pretransplant sensitization against donor antigens results in hyperacute rejection of murine islets. IECs may play a crucial role in development of donor-specific immunity after islet transplantation. Significantly, accommodation of IEC may confer resistance to hyperacute rejection in sensitized recipients.
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| http://dx.doi.org/10.1097/01.tp.0000288192.11396.70 | DOI Listing |
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