同种异体胰岛移植免疫耐受的诱导

同种异体胰岛移植为1型糖尿病患者带来了治愈疾病的希望,临床应用的成功显示了胰岛移植良好的发展前景。但移植后患者需终身服用免疫抑制剂,使胰岛移植仅适合用药物难以控制的糖尿病或需进行肾移植的患者。显然,诱导免疫耐受无疑将大大扩展胰岛移植的指征,更多的1型糖尿病患者将从中得益,避免糖尿病远期并发症的发生并提高生活质量。本文综述了诱导免疫耐受、延长同种异体移植胰岛存活的最新实验进展,包括外周和中央型耐受的诱导。对一些细胞表面分子,如共刺激分子、黏附素及细胞因子受体等进行干预,均可延长移植于非自身免疫疾病背景小鼠的同种异体胰岛存活时间。去除同种异体反应性T细胞、诱导供体特异的调节性T细胞是建立外周耐受的重要途径,甚至对有抵抗耐受倾向的自身免疫性非肥胖糖尿病小鼠也有效。通过骨髓移植,结合无须清除原始粒细胞的方案,能获得造血细胞嵌合,使胰岛成功移植于自身免疫性糖尿病受体中,并尽可能减少移植物抗宿主疾病的发生。

Tolerance induction to islet allografts

Islet transplantation holds renewed promise as a cure for type 1 diabetes mellitus.Results of recent clinical trials have shown remarkable success.But the need for life-long immunosuppression of the recipient still limits islet transplantation to patients with poorly controlled diabetes or to those requiring kidney transplantation. It is obvious that the achievement of immunological tolerance would broaden the indication for islet transplantation to a much larger cohort of patients with type 1 diabetes mellitus,most likely preventing long-term complications and contributing to a significantly improved quality of life.This paper evaluates recent progress in promoting long-term allograft survival and tolerance in animal models of islet transplantation.Several approaches can induce tolerance,including peripheral tolerance and central tolerance to islet allografts.An increasing variety of cell surface molecules involved in costimulation,adhesion and cytokine responses have been proved useful as therapeutic targets for inducing indefinite islet allograft survival in non-autoimmune-prone rodent models.In some cases,treatment regimens can result in the generation of active,donor-specific regulatory tolerance.Novel and promising strategies are being developed to achieve deletion of alloreactive T cells and preservation of regulatory cells.Such strategies may be effective even in tolerance-resistant,autoimmune NOD mice.New strategies for achieving hematopoietic chimerism with nonmyeloablative regimens,including costimulation blockade,are being generated.Such chimerism allows the successful grafting of islets,even in autoimmune diabetic recipients,and could be used clinically,provided that the regimens used to achieve bone marrow engraftment and avoid graft-versus-host disease are extensively minimized.