Thomas F T, Ricordi C, Contreras J L, Hubbard W J, Jiang X L, Eckhoff D E, Cartner S, Bilbao G, Neville D M, Thomas J M
Department of Surgery, University of Alabama at Birmingham, 35294, USA.
Transplantation. 1999 Mar 27;67(6):846-54. doi: 10.1097/00007890-199903270-00011.
Isolated pancreatic islet transplantation (IPITx) is an attractive alternative for treatment of insulin-dependent diabetes mellitus (IDDM). However, IPITx has been difficult to implement clinically because islets frequently fail to function, have a high incidence of rejection, and are susceptible to autoimmune recurrence and damage by chronic immunosuppressive therapy. Tolerance induction may be a rational approach to resolve several of these limitations. Because anti-CD3 immunotoxin (IT) has been successful in promoting stable primate kidney transplant tolerance in our experience, we considered that tolerance induction with IT might be duplicated in IPITx.
Three monkeys with spontaneous IDDM (two Macaca fascicularis and one Ceropithecus aethiops) were treated with xenogeneic pancreatic islets (Macaca mulatta). Intrahepatic islet transplantation was performed at a mean of 13136+/-3860 islet equivalents/kg. Islet xenograft acceptance was accomplished by tolerance induction with two injections of IT given on day 0 at 2 hr before transplantation and on day +1, respectively. IT treatment was supplemented with cyclosporine and steroids administered on days 0 through 4. No additional immunosuppression was given thereafter. Two additional control macaques with spontaneous IDDM received the immunosuppressive protocol without islet infusion.
All recipients were restored to stable euglycemia, off exogenous insulin, within 1-2 weeks after transplantation. Glucose tolerance, C-peptide, and glycosylated hemoglobin tests confirmed the restoration of normal glucose homeostasis after islet transplantation. All three islet recipients have remained euglycemic at 410, 255, and 100 days of follow-up despite recovery of peripheral T cells to normal levels. In contrast, none of the controls presented changes in the diabetic status 4 and 8 months after treatment.
These results represent the first demonstration in nonhuman primates of stable, long-term acceptance of nonencapsulated xenogeneic islets off all immunosuppression, suggesting operational tolerance. The findings have potential implications for islet transplantation as well as improved and more cost-effective therapy for IDDM.
孤立胰岛移植（IPITx）是治疗胰岛素依赖型糖尿病（IDDM）的一种有吸引力的替代方法。然而，IPITx在临床上一直难以实施，因为胰岛常常无法发挥功能，排斥发生率高，且易发生自身免疫复发以及受到慢性免疫抑制治疗的损害。诱导耐受可能是解决这些局限性的一种合理方法。鉴于根据我们的经验抗CD3免疫毒素（IT）已成功促进灵长类动物肾脏移植的稳定耐受，我们认为IT诱导耐受在IPITx中可能会取得同样效果。
对3只患有自发性IDDM的猴子（2只食蟹猴和1只埃塞俄比亚疣猴）进行了异种胰岛（恒河猴）移植治疗。肝内胰岛移植的平均剂量为13136±3860个胰岛当量/千克。通过在移植前2小时的第0天和第+1天分别注射两次IT诱导耐受，实现了胰岛异种移植的接受。IT治疗辅以在第0天至第4天给予环孢素和类固醇。此后不再给予额外的免疫抑制。另外2只患有自发性IDDM的对照猕猴接受了无胰岛输注的免疫抑制方案。
所有受体在移植后1 - 2周内恢复到稳定的正常血糖水平，无需外源性胰岛素。葡萄糖耐量、C肽和糖化血红蛋白检测证实胰岛移植后正常葡萄糖稳态得以恢复。尽管外周T细胞恢复到正常水平，但所有3只胰岛受体在随访的410、255和100天时仍保持正常血糖水平。相比之下，治疗后4个月和8个月，所有对照的糖尿病状态均未出现变化。
这些结果首次证明了在非人类灵长类动物中，在完全没有免疫抑制的情况下对非封装异种胰岛的稳定、长期接受，提示存在操作性耐受。这些发现对胰岛移植以及IDDM的改进和更具成本效益的治疗具有潜在意义。
