Shapiro A M J, Suarez-Pinzon W L, Power R, Rabinovitch A
Department of Surgery, University of Alberta, Edmonton, Canada.
Diabetologia. 2002 Feb;45(2):224-30. doi: 10.1007/s00125-001-0745-x.
AIMS/HYPOTHESIS: Sirolimus and tacrolimus are immunosuppressive drugs that prevent rejection of pancreatic islet allografts transplanted into patients with Type I (insulin-dependent) diabetes mellitus. This study aimed to determine whether sirolimus and tacrolimus can prevent autoimmune beta-cell destruction, and if so, what the mechanisms of action are.
Sirolimus and tacrolimus were given separately and together to female non-obese diabetic (NOD) mice from age 12 to 35 weeks. Diabetes incidence was determined and pancreatic insulitis and insulin content were measured. Sirolimus and tacrolimus were also given separately and together to diabetic NOD mice from the time of syngeneic islet transplantation until the reappearance of hyperglycaemia. Islet grafts were examined by RT-PCR assay for expression of interferon (IFN)- gamma, interleukin (IL)-2, IL-4, IL-10 and transforming growth factor (TGF)- beta1.
Low doses of sirolimus (0.1 mg/kg) and tacrolimus (0.1 mg/kg) were synergistic in reducing insulitis, preserving pancreatic insulin content and preventing diabetes in female NOD mice (8 % diabetes incidence at 35 weeks vs 66 % in vehicle-treated mice). Also, the combination of sirolimus and tacrolimus prolonged syngeneic islet graft survival (median 34 days vs 13 days for vehicle-treated mice). Islet grafts from sirolimus plus tacrolimus-treated mice expressed significantly decreased mRNA contents of Th1-type cytokines (IFN- gamma and IL-2) and the highest ratio of TGF- beta1/IFN- gamma mRNA.
CONCLUSION/INTERPRETATION: These findings suggest that combination therapy with sirolimus and tacrolimus prevent autoimmune beta-cell destruction by upregulating expression of the immunoregulatory cytokine, TGF- beta1 and reducing Th1 cytokines (IFN- gamma and IL-2) expressed in the islets. Low-dose sirolimus and tacrolimus combination therapy could warrant consideration for prevention or early treatment of human Type I diabetes.
目的/假设：西罗莫司和他克莫司是免疫抑制药物，可防止移植到1型（胰岛素依赖型）糖尿病患者体内的胰岛同种异体移植被排斥。本研究旨在确定西罗莫司和他克莫司是否能预防自身免疫性β细胞破坏，若能预防，其作用机制是什么。
从12周龄至35周龄，分别单独及联合给予雌性非肥胖糖尿病（NOD）小鼠西罗莫司和他克莫司。测定糖尿病发病率，并测量胰腺炎症和胰岛素含量。从同基因胰岛移植时起至血糖再次升高，也分别单独及联合给予糖尿病NOD小鼠西罗莫司和他克莫司。通过逆转录聚合酶链反应（RT-PCR）检测胰岛移植中干扰素（IFN）-γ、白细胞介素（IL）-2、IL-4、IL-10和转化生长因子（TGF）-β1的表达。
低剂量西罗莫司（0.1mg/kg）和他克莫司（0.1mg/kg）联合使用可协同减轻雌性NOD小鼠的胰岛炎，维持胰腺胰岛素含量并预防糖尿病（35周时糖尿病发病率为8%，而载体处理小鼠为66%）。此外，西罗莫司和他克莫司联合使用可延长同基因胰岛移植的存活时间（中位存活时间为34天，而载体处理小鼠为13天）。西罗莫司加他克莫司处理的小鼠的胰岛移植中，Th1型细胞因子（IFN-γ和IL-2）的mRNA含量显著降低，且TGF-β1/IFN-γ mRNA的比例最高。
结论/解读：这些发现表明，西罗莫司和他克莫司联合治疗可通过上调免疫调节细胞因子TGF-β1的表达并减少胰岛中表达的Th1细胞因子（IFN-γ和IL-2）来预防自身免疫性β细胞破坏。低剂量西罗莫司和他克莫司联合治疗可能值得考虑用于预防或早期治疗人类1型糖尿病。
