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EXPERIMENTAL ANALYSIS OF VASCULER CHANGES IN CHRONIC ALLOGRAFT REJECTION USING HUMANIZED SCID MOUSE MODEL.

使用人源化 SCID 小鼠模型对慢性同种异体移植排斥中的血管变化进行实验分析。

基本信息

批准号：
14571526
负责人：
SHIROKI Ryoichi
金额：
$ 2.18万
依托单位：
FUJITA HEALTH UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-14571526/
关键词：
organ transplantation chronic rejection SCID mouse

项目摘要

Chronic allograft nephropathy (CAN) is the most common cause to graft failure in clinical kidney transplantation. The appropriate therapeutic strategies to CAN, however, is yet to be established because of the various etiology and rationale of CAN. Basic pathophysiology of CAN is accounted for vascular inflammation leading to fibrosis and screlosis. Our study goal was to analyze and characterize CAN in animal model using hu-PBL-SCOD mouse. Humanized severe combined immunodeficient (SCID) mice, which exhibited human immunological environment, were established by administration of human peripheral blood lymphocytes (PBL). These huPBL-SCID mice were also demonstrated to involve functional human lymphocyte and immunoglobulin in their circulation. To display the real CAN of human allotransplant circumstances in mouse, human mesenteric arterior was applied for direct bypass of abdominal aorta in hu-PBL-SCID. Analysis of recovered vascular graft revealed lymphocytes invasion on the endothelium of the vascular graft. Pathological analysis indicated these graft-infiltrating-lymphocytes (GIL) belonged to CD3+CD4+ in staining. Next, we tried to determine the optimal time to see the cellular rejection by changing the recovering time of graft. Stable model of the cellular rejection were, however, difficult to establish due to the inter-individual differences. We also tried to establish the GIL cell line in vitro by recovering these grafts to tissue culture. This experiment, however, resulted in discontinued because of the contaminations and slow growing GILs. Messenger RNA expression of TNF-alpha and IFN-gamma were noted in recovered human mesenteric arterior using PCR analysis applying the appropriate anti-sense oligonucleotides. On the other hand, no particular messenger expression of adhesion molecules associated with cell migration or chemokines in our experimental condition.

慢性移植肾肾病（CAN）是临床肾移植中最常见的移植肾衰竭原因.然而，由于CAN的病因和理论基础多种多样，因此CAN的适当治疗策略尚未建立。CAN的基本病理生理学是血管炎症导致纤维化和硬化。我们的研究目的是分析和表征在动物模型中使用hu-PBL-SCOD小鼠的CAN。采用人外周血淋巴细胞（PBL）诱导建立了人源化严重联合免疫缺陷（SCID）小鼠模型。这些huPBL-SCID小鼠也被证明在其循环中涉及功能性人淋巴细胞和免疫球蛋白。为了在小鼠体内展示人同种异体移植的真实的CAN情况，应用人肠系膜动脉直接转流于hu-PBL-SCID的腹主动脉。对回收的血管移植物的分析显示淋巴细胞侵入血管移植物的内皮。病理学分析表明，这些移植物浸润淋巴细胞（GIL）均为CD 3 + CD 4+细胞。其次，我们试图通过改变移植物的恢复时间来确定观察细胞排斥反应的最佳时间。然而，由于个体间差异，难以建立稳定的细胞排斥模型。我们还尝试通过将这些移植物恢复到组织培养来建立体外GIL细胞系。然而，由于污染和生长缓慢的GIL，该实验导致中断。使用应用适当的反义寡核苷酸的PCR分析，在恢复的人肠系膜动脉中观察到TNF-α和IFN-γ的信使RNA表达。另一方面，在我们的实验条件下，没有与细胞迁移或趋化因子相关的粘附分子的特定信使表达。