Yang Zandong, Chen Meng, Ellett Justin D, Fialkow Lawrence B, Carter Jeffrey D, Nadler Jerry L
Division of Endocrinology and Metabolism, Department of Internal Medicine, University of Virginia, Charlottesville, VA 22908, USA.
Transplantation. 2004 Jan 15;77(1):55-60. doi: 10.1097/01.TP.0000104844.48064.81.
Pancreatic islet transplantation has become a promising treatment for type 1 diabetes. However, autoimmune reactivity destroys engrafted islets in type 1 diabetic recipients. The authors' previous studies demonstrated that a novel anti-inflammatory agent, lisofylline (LSF), suppressed autoimmune reactivity and protected nonobese diabetic (NOD) mice from diabetes. In this study, the authors investigated the potential of LSF in preventing autoimmune diabetes recurrence after islet transplantation.
Spontaneously diabetic NOD mice received NOD severe combined immunodeficiency islet transplants and were treated with daily LSF injections at 50 mg/kg for 3 weeks. Blood glucose levels were monitored. Serum cytokine levels were measured at 1 and 3 weeks after engraftment. Nephrectomy of the islet-implanted kidney was performed in LSF-treated recipients. Histology of islet grafts was assessed at the end of the study. The effect of LSF on beta-cell function was studied in vitro.
Without immunosuppressants and insulin, the LSF-treated recipient mice maintained euglycemia significantly longer than the saline-treated recipients (mean, >65 days in the LSF-treated group vs. 6 days in saline controls; P=0.0004). Serum levels of interferon-gamma were markedly reduced in LSF-treated recipients at 1 and 3 weeks posttransplant. Diabetes recurred in the LSF-treated recipients after removing the islet-implanted kidneys. Immunohistochemistry showed retention of insulin-positive cells in the grafts of the LSF-treated recipients. LSF preserved beta-cell insulin secretory function in the presence of inflammatory cytokines in vitro.
This study demonstrates that autoimmune diabetes recurrence after islet transplantation could be prevented by treatment with LSF. LSF and its analogues may have the potential to prevent islet autoimmune destruction in clinical transplantation.
胰岛移植已成为1型糖尿病一种有前景的治疗方法。然而，自身免疫反应会破坏1型糖尿病受体中植入的胰岛。作者之前的研究表明，一种新型抗炎药利索茶碱（LSF）可抑制自身免疫反应，并保护非肥胖糖尿病（NOD）小鼠不患糖尿病。在本研究中，作者调查了LSF在预防胰岛移植后自身免疫性糖尿病复发方面的潜力。
自发性糖尿病NOD小鼠接受NOD重度联合免疫缺陷胰岛移植，并每天以50mg/kg的剂量注射LSF，持续3周。监测血糖水平。在移植后1周和3周测量血清细胞因子水平。对接受LSF治疗的受体进行植入胰岛的肾脏切除术。在研究结束时评估胰岛移植的组织学情况。在体外研究LSF对β细胞功能的影响。
在没有免疫抑制剂和胰岛素的情况下，接受LSF治疗的受体小鼠维持血糖正常的时间明显长于接受生理盐水治疗的受体（平均而言，LSF治疗组>65天，生理盐水对照组为6天；P=0.0004）。移植后1周和3周，接受LSF治疗的受体血清干扰素-γ水平明显降低。切除植入胰岛的肾脏后，接受LSF治疗的受体糖尿病复发。免疫组织化学显示，接受LSF治疗的受体移植物中存在胰岛素阳性细胞。在体外，LSF在存在炎性细胞因子的情况下保留了β细胞的胰岛素分泌功能。
本研究表明用LSF治疗可预防胰岛移植后自身免疫性糖尿病复发。LSF及其类似物可能有预防临床移植中胰岛自身免疫破坏的潜力。
