Leonard D K, Landry A S, Sollinger H W, Hullett D A
Department of Surgery, University of Wisconsin Hospital and Clinic, Madison 53792.
J Surg Res. 1989 Jun;46(6):625-32. doi: 10.1016/0022-4804(89)90033-4.
The limited clinical success of human fetal pancreas (HFP) transplantation may be related to graft toxicity caused by immunosuppressant agents. This study describes the effects of prednisone (PRED), azathioprine (AZA), and cyclosporine A (CSA) on HFP tissue in vitro and in vivo. To assess in vitro function, fresh HFP explants (1-2 mm3; 16-21 weeks gestational age) were prepared and cultured 72 hr in supplemented Ham's medium containing varying concentrations of each drug. Insulin release in response to high glucose (17 mM) and theophylline (10 mM) challenge was determined and compared to basal release in low glucose (3 mM) buffer. No significant difference in insulin release was observed between culture control tissue and drug-cultured tissue throughout the concentration range (10(-8) -10(-4) M; P greater than 0.05). To assess in vivo function, cyropreserved HFP explants were transplanted under the kidney capsule of streptozotocin-induced diabetic nude mice. Mice were immunosuppressed with PRED (1 mg/kg), AZA (1 mg/kg), CSA (30 mg/kg), or combined triple drug therapy (COMBO), and glucose levels followed weekly. Hyperglycemia reversal and insulin withdrawal were observed in all drug groups [PRED (4/6), AZA (4/6), CSA (2/4), COMBO, (2/4)] and were not statistically different from control (5/8; P greater than 0.8). Time to insulin withdrawal was significantly different from control (12.2 +/- 2.2 weeks; P less than 0.05) only for AZA (10 +/- 0 weeks; PRED, 12.3 +/- 2.6 weeks; CSA, 11 +/- 0 weeks; COMBO, 15 +/- 0 weeks). Additionally, oral glucose tolerance tests in all groups were equivalent to nondiabetic controls. We were unable to demonstrate PRED, AZA, or CSA toxicity on HFP.(ABSTRACT TRUNCATED AT 250 WORDS)
人胎胰腺（HFP）移植有限的临床成功率可能与免疫抑制剂引起的移植物毒性有关。本研究描述了泼尼松（PRED）、硫唑嘌呤（AZA）和环孢素A（CSA）在体外和体内对HFP组织的影响。为评估体外功能，制备新鲜的HFP外植体（1 - 2立方毫米；孕龄16 - 21周），并在含有不同浓度每种药物的补充Ham培养基中培养72小时。测定对高糖（17毫摩尔）和茶碱（10毫摩尔）刺激的胰岛素释放，并与低糖（3毫摩尔）缓冲液中的基础释放进行比较。在整个浓度范围（10⁻⁸ - 10⁻⁴摩尔/升；P大于0.05）内，培养对照组织和药物培养组织之间未观察到胰岛素释放的显著差异。为评估体内功能，将冷冻保存的HFP外植体移植到链脲佐菌素诱导的糖尿病裸鼠的肾包膜下。小鼠用PRED（1毫克/千克）、AZA（1毫克/千克）、CSA（30毫克/千克）或三联药物联合治疗（COMBO）进行免疫抑制，每周监测血糖水平。在所有药物组[PRED（4/6）、AZA（4/6）、CSA（2/4）、COMBO（2/4）]中均观察到高血糖逆转和胰岛素停用，且与对照组（5/8；P大于0.8）无统计学差异。仅AZA的胰岛素停用时间与对照组有显著差异（12.2±2.2周；P小于0.05）（PRED，12.3±2.6周；CSA，11±0周；COMBO，15±0周）。此外，所有组的口服葡萄糖耐量试验与非糖尿病对照组相当。我们未能证明PRED、AZA或CSA对HFP有毒性。（摘要截断于250字）
