Thomas J M, Contreras J L, Smyth C A, Lobashevsky A, Jenkins S, Hubbard W J, Eckhoff D E, Stavrou S, Neville D M, Thomas F T
Division of Transplantation, Department of Surgery, University of Alabama Medical Center, Birmingham, AL 35294, USA.
Diabetes. 2001 Jun;50(6):1227-36. doi: 10.2337/diabetes.50.6.1227.
The recent focus on islet transplantation as primary therapy for type 1 diabetes has heightened interest in the reversal of type 1 diabetes in preclinical models using minimal immunosuppression. Here, we demonstrated in a preclinical rhesus model a consistent reversal of all measured glycemic patterns of streptozotocin-induced type 1 diabetes. The model used single-donor islet transplantation with induction of operational tolerance. The term "operational tolerance" is used to indicate durable survival of single-donor major histocompatibility complex (MHC)-mismatched islet allografts without maintenance immunosuppressive therapy and without rejection or loss of functional islet mass or insulin secretory reserve. In this operational tolerance model, all immunosuppression was discontinued after day 14 posttransplant, and recipients recovered with excellent health. The operational tolerance induction protocol combined peritransplant anti-CD3 immunotoxin to deplete T-cells and 15-deoxyspergualin to arrest proinflammatory cytokine production and maturation of dendritic cells. T-cell deficiency was specific but temporary, in that T-cell-dependent responses in long-term survivors recovered to normal, and there was no evidence of increased susceptibility to infection. Anti-donor mixed lymphocyte reaction responses were positive in the long-term survivors, but all showed clear evidence of systemic T-helper 2 deviation, suggesting that an immunoregulatory rather than a deletional process underlies this operational tolerance model. This study provides the first evidence that operational tolerance can protect MHC nonhuman primate islets from rejection as well as loss of functional islet mass. Such an approach has potential to optimize individual recipient recovery from diabetes as well as permitting more widespread islet transplantation with the limited supply of donor islets.
最近，将胰岛移植作为1型糖尿病的主要治疗方法成为焦点，这激发了人们对在临床前模型中使用最小免疫抑制来逆转1型糖尿病的兴趣。在此，我们在一个临床前恒河猴模型中证明，链脲佐菌素诱导的1型糖尿病的所有测量血糖模式都能持续逆转。该模型采用单供体胰岛移植并诱导操作性耐受。术语“操作性耐受”用于表示单供体主要组织相容性复合体（MHC）不匹配的胰岛同种异体移植物在没有维持免疫抑制治疗、没有排斥反应且没有功能性胰岛团块或胰岛素分泌储备丧失的情况下持久存活。在这个操作性耐受模型中，移植后第14天停用所有免疫抑制，受体恢复良好。操作性耐受诱导方案结合移植前抗CD3免疫毒素以耗尽T细胞，以及15-脱氧精胍菌素以阻止促炎细胞因子的产生和树突状细胞的成熟。T细胞缺陷是特异性的但也是暂时的，因为长期存活者中依赖T细胞的反应恢复正常，并且没有证据表明对感染的易感性增加。长期存活者中抗供体混合淋巴细胞反应呈阳性，但都显示出明显的系统性辅助性T细胞2型偏移证据，这表明这种操作性耐受模型的基础是免疫调节过程而非删除过程。这项研究提供了首个证据，即操作性耐受可以保护MHC非人灵长类胰岛免受排斥以及功能性胰岛团块的丧失。这种方法有可能优化个体受体从糖尿病中恢复，同时在供体胰岛供应有限的情况下允许更广泛的胰岛移植。
