NOVEL APPROACHES TOWARD EARLY DIAGNOSIS OF ISLET ALLOGRAFT REJECTION1
NOVEL APPROACHES TOWARD EARLY DIAGNOSIS OF ISLET ALLOGRAFT REJECTION1
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早期诊断胰岛移植排斥的新方法1
作者：
A. M. Shapiro;E. Hao;J. Lakey;W. J. Yakimets;T. Churchill;P. Mitlianga;G. Papadopoulos;J. Elliott;R. Rajotte;N. Kneteman
背景不能诊断胰岛移植物的早期排斥反应以前已被证明是临床胰岛移植进展的主要障碍。随着新的耐受诱导方案在临床上的评估，检测早期排斥反应的需要将变得更加重要。我们探索了三种新的方法，以发展胰岛移植后胰岛排斥反应的早期诊断标志物。方法. (a)犬胰岛同种异体移植受者免疫抑制1个月，然后停止治疗。血清谷氨酸脱羧酶抗原（GAD 65），内源性胰岛蛋白，每天监测与CO2释放试验。(b)啮齿动物胰岛基因工程表达一种独特的外源蛋白（-半乳糖苷酶），通过使用腺病毒载体，同种异体移植后，血清中的病毒特异性蛋白质进行了测量，使用光学发光。(c)接受胰岛同种异体移植的啮齿动物暂时受到免疫抑制，并每天进行葡萄糖耐量测试，直到移植失败。结果(a)尽管在初步研究中GAD 65抗原的血清监测显示在移植物功能丧失之前水平升高，但该效应在所有动物中不可重现。(b)基因工程啮齿动物胰岛在体外表现出正常的胰岛素动力学（胰岛素刺激指数2.57±0.2对对照胰岛的2.95±0.3，P =ns），并且纯化的病毒蛋白产物在体内具有8小时的稳定半衰期。同种异体胰岛移植后，血清病毒蛋白有两个峰值升高，证实在急性排斥反应期间可以通过血清学检测到胰岛内的“哨兵信号”。然而，高血糖症的发生并没有提前时间。(c)每日序贯静脉葡萄糖耐量（IVGT）试验证实了移植物功能障碍（KG下降）的证据，高血糖的提前时间为2天（分别为2.58±0.3和1.63±0.2%/min，P <0.001），准确性为89%，敏感性为78%，特异性为95%。结论.在这三种诊断试验中，用简化的IVGT进行代谢评估是证明早期胰岛功能障碍的最有效方法。
Background. The inability to diagnose early rejection of an islet allograft has previously proved to be a major impediment to progress in clinical islet transplantation. The need to detect early rejection will become even more relevant as new tolerance-inducing protocols are evaluated in the clinic. We explored three novel approaches toward development of early diagnostic markers of islet rejection after islet allotransplantation. Methods. (a) Canine islet allograft transplant recipients were immunosuppressed for 1 month, then therapy was withdrawn. Serum glutamic acid decarboxylase antigen (GAD65), an endogenous islet protein, was monitored daily with a CO2 release assay. (b) Rodent islets were genetically engineered to express a unique foreign protein (&bgr;-galactosidase) by using adenoviral vectors, and after allograft transplantation, the viral-specific protein was measured in serum using optical luminescence. (c) Rodents receiving islet allografts were immunosuppressed temporarily, and daily glucose tolerance tests were followed until graft failure occurred. Results. (a) Although serum monitoring of GAD65 antigen demonstrated elevated levels preceding loss of graft function in preliminary studies, the effect was not reproducible in all animals. (b) Genetically engineered rodent islets demonstrated normal insulin kinetics in vitro (insulin stimulation index 2.57±0.2 vs. 2.95±0.3 for control islets, P =ns), and purified viral protein products had a stable half-life of 8 hr in vivo. After islet allotransplantation, there were two peak elevations in serum viral proteins, confirming that an intra-islet “sentinel signal” could be detected serologically during acute rejection. There was no lead-time ahead of hyperglycemia, however. (c) Daily sequential intravenous glucose tolerance (IVGT) tests demonstrated evidence of allograft dysfunction (decline in KG) with a 2-day lead time to hyperglycemia (2.58±0.3 vs. 1.63±0.2%/min, respectively, P <0.001), with an accuracy of 89%, sensitivity of 78%, and specificity of 95%. Conclusions. Of the three diagnostic tests, metabolic assessment with an abbreviated IVGT was the most effective method of demonstrating early islet dysfunction due to rejection.
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DOI：
--
发表时间：
1998
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Krams,SM;Hayashi,M;Fox,CK;Villanueva,JC;Whitmer,KJ;Burns,W;Esquivel,CO;Martinez,OM
通讯作者：
Martinez,OM
影响因子：
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作者：
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影响因子：
6.2
作者：
Ricordi,C;Tzakis,A;Alejandro,R;Zeng,YJ;Demetris,AJ;Carroll,P;Mintz,DH;Starzl,TE
通讯作者：
Starzl,TE
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DOI：
10.1210/jcem.80.3.7883841
发表时间：
1995
期刊：
The Journal of clinical endocrinology and metabolism
影响因子：
--
作者：
Vandewalle,CL;Falorni,A;Svanholm,S;Lernmark,A;Pipeleers,DG;Gorus,FK
通讯作者：
Gorus,FK
细胞凋亡作为肝同种异体移植排斥中细胞死亡的机制。
DOI：
--
发表时间：
1995
期刊：
Transplantation.
影响因子：
--
作者：
Krams,SM;Egawa,H;Quinn,MB;Villanueva,JC;Garcia-Kennedy,R;Martinez,OM
通讯作者：
Martinez,OM