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Analysis of rejection mechanism, aiming for the establishment of novel immunosuppression in small bowel transplantation

分析排斥反应机制，旨在建立小肠移植新型免疫抑制药物

基本信息

批准号：
09307025
负责人：
INOMATA Yukihiro
金额：
$ 16.45万
依托单位：
KYOTO UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1998
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-09307025/
关键词：
small bowel transplantation pig rejection apoptosis Tacrolimus TUNEL法免疫抑制 FTY720

项目摘要

Background : The experience with clinical living donor SBT(small bowel transplantation) motivate us to research on the following problems, which have been the obstacles to the improvement of graft and/or patient survival.Earlier and definite diagnosis of rejectionMore sophisticated way to control rejectionPig SBT model : Pigs are adopted for our experiment because of the anatomical, physiological and immunological similarity between humans and pigs. We established one-staged orthotopic SBT model using donors and recipients which showed alloreactivity with mixed lymphocyte reaction.Sampling of specimens :a) drug administration and blood sampling through central lineb) fiberscopy (using clinical pediatric fiber) and biopsyWe established techniques above with pig SBT model and are performing these safely and regularly, which enable us to monitor the rejection process at the same level for clinical transplantation.Results : Based on the macroscopic and microscopic findings, severity of rej … More ection and its relationship to ABC (apoptotic body counts) were analyzed under the immunosuppression with Tacrolimus, which has been the key drug for clinical SBT.Samples from grafts with rejection presented higher ABC (6.59/l0crypts) than those from non-rejected grafts (ABC ; 0.773/l0crypts), which showed statistical difference. There was no correlation between the severity of rejection and ABC.Immunohistochemical studies were performed to analyze the induction pathway to apoptosis. Infiltration of CD8+ lymphocytes and FasL+ lymphocytes around crypts and increased expression of TNF receptor on epithelial cells were observed at the same time with, or prior to, macroscopic and/or histological rejection.Future prospects and plans : The rejection in pig SBT now can be analyzed more in detail with the indicators above. Using the indicators, we are moving on to the further research projects such as local administration of immunosuppressants or tolerance induction. These indicators will be applied for our coming clinical SBT cases for the diagnosis of rejection. Less

背景：临床活体供体SBT（小肠移植）的经验促使我们研究以下问题，这些问题一直是提高移植物和/或患者存活率的障碍。排斥反应的早期和明确诊断更复杂的排斥反应控制方法猪SBT模型：由于人类和猪之间的解剖学、生理学和免疫学相似性，因此采用猪进行实验。我们使用显示出混合淋巴细胞反应的同种异体反应的供体和受体建立了一阶段原位SBT模型。样本取样：a）通过中心线给药和血液采样b）纤维镜检（使用临床儿科纤维）和活检我们用猪SBT模型建立了上述技术，并安全、定期地执行这些技术，这使我们能够同时监测排斥过程结果：根据宏观和微观结果，分析了他克莫司免疫抑制下的排斥严重程度及其与ABC（凋亡小体计数）的关系，他克莫司一直是临床SBT的关键药物。排斥反应的移植物样本呈现出比来自移植物的样本更高的ABC（6.59/l0crypts）。非排斥移植物（ABC；0.773/l0crypts），显示出统计学差异。排斥反应的严重程度与ABC之间没有相关性。通过免疫组织化学研究来分析细胞凋亡的诱导途径。在肉眼和/或组织学排斥的同时或之前，观察到隐窝周围 CD8+ 淋巴细胞和 FasL+ 淋巴细胞的浸润以及上皮细胞上 TNF 受体表达的增加。未来的前景和计划：现在可以用上述指标更详细地分析猪 SBT 的排斥反应。利用这些指标，我们正在开展进一步的研究项目，例如免疫抑制剂的局部给药或耐受诱导。这些指标将应用于我们即将到来的临床SBT病例，以诊断排斥反应。较少的