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Donor Treatment With Carbon Monoxide Can Yield Islet Allograft Survival and Tolerance

¹ Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts
² Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts

Treatment of animals or certain cells with carbon monoxide (CO), a product of heme degradation by heme oxygenase-1 (HO-1), has potent anti-inflammatory and antiapoptotic effects that contribute to the survival of transplanted organs. We report here that inducing HO-1 in, or administering CO to, only the donor can be used in a therapeutic manner to sustain the survival of transplanted allogeneic islets. Similar treatments of only the islets or only the recipient are also salutary. Administering CO only to the donor frequently leads to long-term survival of those islets in untreated allogeneic recipients, which are then antigen-specifically tolerant. Several proinflammatory and proapoptotic genes that are strongly induced in islets after transplantation in the untreated situation were significantly suppressed after administering CO to the donor without further treatment. These included tumor necrosis factor-, inducible nitric oxide synthase, monocyte chemoattractant protein-1, granzyme B, and Fas/Fas ligand, all of which contribute to the pathogenesis of the rejection of transplanted islets. This correlated with a lesser infiltration of recipient macrophages into the transplanted islets. Our present findings show that induction of HO-1 in, or administration of CO to, only the donor, islets, or the recipient or combinations of such treatments improve allogeneic islet survival.

Abbreviations: CoPP, cobalt protoporphyrin-IX; HO-1, heme oxygenase-1; IL, interleukin; iNOS, inducible nitric oxide synthase; MCP-1, monocyte chemoattractant protein-1; MST, mean survival time; TNF-, tumor necrosis factor-

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