Feng S, Quickel R R, Hollister-Lock J, McLeod M, Bonner-Weir S, Mulligan R C, Weir G C
Department of Genetics, Harvard Medical School and Howard Hughes Medical Institute, The Children's Hospital, Boston, Massachusetts 02115, USA.
Transplantation. 1999 Jun 27;67(12):1607-13. doi: 10.1097/00007890-199906270-00016.
Systemic administration of the inhibitor of costimulation, CTLA4Ig, has been shown to prolong islet graft survival. The purpose of this study was to compare local and systemic expression of murine CTLA4Ig in transplants of rat islets into mice.
Murine CTLA4Ig was made by joining two polymerase chain reaction products, the extracellular portion of CTLA4 and the Fc portion of IgG2a. Recombinant adenovirus expressing CTLA4Ig (AdCTLA4Ig) was generated using the strategy of Cre-lox recombination. Isolated rat islets infected with AdCTLA4Ig at multiplicities of infection (MOIs) ranging from 0.1 to 10 were transplanted into streptozocin diabetic male B6AF1 mice. Control islets were mock infected or infected with AdLacZ or AdsIg, a recombinant adenovirus expressing only the Fc portion of IgG2a. Also, AdCTLA4Ig and control viruses were injected intramuscularly into mouse transplant recipients at the time of islet transplantation to provide CTLA4Ig systemically.
Control islets transplanted into diabetic mice were rejected in 13-17 days. Islets infected with AdCTLA4Ig had dose-dependent prolongation of graft survival. Prolonged survival was even found with very low MOIs of 0.1 and 0.5, with survivals of 24+/-4.2 and 25+/-2.2 days, respectively. Survival with an MOI of 10 was 39+/-8.7 days. With intramuscular injection, no prolongation was found at the lowest relative MOIs of 0.2 and 1, but there was dose-dependent prolongation of graft survival with larger doses. At the highest relative MOI of 400, survival was prolonged to 58+/-10 days.
Rat islets infected with AdCTLA4Ig transplanted into mice had prolonged graft survival. Prolonged survival with MOIs as low as 0.1 and 0.5 indicates that only a minority of islet cells need to express CTLA4Ig to exert an effect. Moreover, the results suggest that the improved islet graft survival is due to a local influence of CTLA4Ig.
已证明共刺激抑制剂CTLA4Ig的全身给药可延长胰岛移植的存活时间。本研究的目的是比较大鼠胰岛移植到小鼠体内时小鼠CTLA4Ig的局部和全身表达情况。
通过连接两个聚合酶链反应产物（CTLA4的细胞外部分和IgG2a的Fc部分）制备小鼠CTLA4Ig。使用Cre-lox重组策略产生表达CTLA4Ig的重组腺病毒（AdCTLA4Ig）。将感染复数（MOI）范围为0.1至10的AdCTLA4Ig感染的分离大鼠胰岛移植到链脲佐菌素诱导的糖尿病雄性B6AF1小鼠体内。对照胰岛进行模拟感染或用AdLacZ或AdsIg感染，AdsIg是一种仅表达IgG2a的Fc部分的重组腺病毒。此外，在胰岛移植时将AdCTLA4Ig和对照病毒肌肉注射到小鼠移植受体中以全身提供CTLA4Ig。
移植到糖尿病小鼠体内的对照胰岛在13 - 17天内被排斥。感染AdCTLA4Ig的胰岛移植存活时间呈剂量依赖性延长。即使在非常低的MOI为0.1和0.5时也发现存活时间延长，分别为24±4.2天和25±2.2天。MOI为10时的存活时间为39±8.7天。通过肌肉注射，在最低相对MOI为0.2和1时未发现存活时间延长，但在较大剂量时移植存活时间呈剂量依赖性延长。在最高相对MOI为400时，存活时间延长至58±10天。
感染AdCTLA4Ig的大鼠胰岛移植到小鼠体内后移植存活时间延长。MOI低至0.1和0.5时存活时间延长表明仅少数胰岛细胞需要表达CTLA4Ig即可发挥作用。此外，结果表明胰岛移植存活时间的改善是由于CTLA4Ig的局部影响。
