Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA 02215, USA.
Cell Transplant. 2010;19(4):443-51. doi: 10.3727/096368909X484680. Epub 2009 Dec 18.
We have previously demonstrated that bilirubin administration to the recipient induces tolerance towards islet cell transplants across a complete MHC mismatch in a mouse model. Here we assess the mechanisms of such protection. Bilirubin treatment of recipients improved function of islet allografts by suppressing expressions of proinflammatory and proapoptotic genes in those islets and by increasing Foxp3(+) T regulatory (Treg) cells at the site of transplanted islets at various days after transplantation. No prolongation of graft survival was observed in recipients treated with bilirubin when CD4(+)CD25(+) T cells were predepleted from those recipients, indicating that Treg cells are necessary for the protective effect of bilirubin. Adoptive transfer of Treg cells from tolerant mice into Rag1(-/-) recipients resulted in long-term acceptance of skin allografts in an alloantigen-specific manner, suggesting that Treg cells are sufficient to induce tolerance. In addition, bilirubin treatment promoted de novo generation of Treg cells in Rag1(-/-) recipients. Thus, bilirubin treatment to the recipients prolongs islet allograft survival via a Treg-dependent manner in which CD4(+)CD25(+) Treg cells are both necessary and sufficient for tolerance induction and graft acceptance. Bilirubin treatment promotes de novo generation of Treg cells that might account for the protective effects of bilirubin given to recipients.
我们之前已经证明，在小鼠模型中，向受者输注胆红素可诱导其对完全 MHC 不匹配的胰岛细胞移植物产生耐受。在这里，我们评估了这种保护的机制。胆红素处理受者通过抑制这些胰岛中促炎和促凋亡基因的表达，并在移植后不同天数的移植胰岛部位增加 Foxp3(+)T 调节性（Treg）细胞，从而改善胰岛同种异体移植物的功能。当从受者中耗尽 CD4(+)CD25(+)T 细胞时，胆红素处理的受者中未观察到移植物存活时间延长，这表明 Treg 细胞是胆红素保护作用所必需的。从耐受小鼠中过继转移 Treg 细胞到 Rag1(-/-)受者中，导致皮肤同种异体移植物以同种抗原特异性方式长期接受，表明 Treg 细胞足以诱导耐受。此外，胆红素处理促进了 Rag1(-/-)受者中 Treg 细胞的新生。因此，胆红素处理通过 Treg 依赖性方式延长胰岛同种异体移植物的存活，其中 CD4(+)CD25(+)Treg 细胞是诱导耐受和移植物接受所必需和充分的。胆红素处理促进 Treg 细胞的新生，这可能解释了胆红素对受者的保护作用。
