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Regulatory mechanisms of graft rejection and graft recurrence of IDDM by NKT cells in pancreaticoduodenal transplantation.

NKT细胞在胰十二指肠移植中对IDDM移植物排斥和移植物复发的调节机制。

基本信息

批准号：
11671231
负责人：
ITO Toshinori
金额：
$ 2.24万
依托单位：
Osaka University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
1999
资助国家：
日本
起止时间：
1999 至 2000
项目状态：
已结题

项目摘要

We previously domonstrated that IDDM graft recurrence could be prevented with the administration of anti-ICAM-1/LFA-1 mAbs, resulting in the appearance of macrochimerism (34.3%) of donor-derived RT6^+ T cells (120 days postTx) in a Wistar-Furth (WF ; RT1^u RT6.2) to spontaneously diabetes prone (DP ; RT1^u, RT6.1 gene carrier)-BB whole pancreaticoduodenal transplantation (PDTx) model. As NKR-P1^+TCRαβ^+ (NKT) cells have recently been demonstrated to be involved in immunoregulatory functions such as the control of occurrence of autoimmune diseases, the purpose of this study was to clarify the relationship between NKT cells and IDDM recurrence in this model. In addition to the examination of cellular immune responses, the cells of the spleen and liver of these nonrecurrent DP rats were analyzed in terms of NKT cells by flow cytometric analysis, and serum cytokine levels (IL-4 ＆ IFN-γ were determined by ELISA, as comparing with those of recurrent PDTx-DP recipients (without mAbs), recurre … More rnt pancreas-alone transplanted DP (PATx-DP with mAbs), DP, and WF rats. In the spleen cells of the DP recipients that had accepted pancreatic grafts, 45.6 (35-55) % of the total splenic T cells were donor-derived RT6.2^+ T cells as early as 60 days postgrafting. A three color flow cytometric analysis showed that NKT cells had proliferated markedly, with the proportion of 20-30% in the total splenic T cells, accompanied by the increased population (absolute number) of RT6^+ NKT cells, though those of RT6^- NKT cells were similar in each group. The proliferation of donor-derived RT6.2^+ NKT cells wsa also observed in the liver of the non-recurrent DP recipients. On the other hand, macrochimerism (and the proliferation of NKT cells) was not detected in the spleen cells of the recurrent DP recipients. By ELISA, serum IFN-γ was not detected (<13 pg/ml) in all, but IL-4 was detected as 158.8 pg/ml in the non-recurrent DP recipients.With the same mAbs treatment, graft rejection (including IDDM recurrence) of Diabetic resistant (DR ; RT1^u, RT6.1)-BB rats could be also inhibited in the DP recipients by the similar mechanism of NKT cells in the reappearance of RT6+T cells.Our data indicate that donor-derived RT6^+ NKT cells which originated from the lymphoid tissues of the donor pancreaticoduodenal grafts might be related to the inhibition of IDDM recurrence and graft rejection with a Th2 deviation. Less

我们先前证实，应用抗ICAM-1/LFA-1单克隆抗体可预防IDDM移植物复发，导致巨嵌合体的出现。（34.3%）的供体来源的RT 6 ^+ T细胞（治疗后120天）在Wistar-Furth（WF ; RT1_u，RT6.2）至自发性糖尿病易感（DP ; RT1_u，RT6.1基因携带者）-BB全胰十二指肠移植（PDTx）模型。由于NKR-P1^+TCRαβ^+（NKT）细胞最近被证明参与免疫调节功能，如控制自身免疫性疾病的发生，本研究的目的是阐明NKT细胞与该模型中IDDM复发的关系。除检测细胞免疫反应外，还通过流式细胞术分析这些未复发DP大鼠的脾和肝细胞的NKT细胞，并通过ELISA测定血清细胞因子（IL-4和IFN-γ）水平，与复发PDTx-DP受体（未使用mAb）、复发PDTx-DP受体（未使用mAb）、复发PDTx-DP受体（未使用mAb）和复发PDTx-DP受体（未使用mAb）进行比较。 ...更多信息 rnt胰腺单独移植的DP（PATx-DP与mAb）、DP和WF大鼠。在接受胰腺移植的DP受体的脾细胞中，早在移植后60天，45.6%（35-55）的脾T细胞是供体来源的RT 6.2 ^+ T细胞。三色流式细胞术分析显示，NKT细胞明显增殖，占脾T细胞总数的20-30%，同时伴有RT 6 ^+ NKT细胞的数量（绝对数量）增加，但各组中RT 6 ^- NKT细胞的数量相似。在非复发DP受体的肝脏中也观察到供体来源的RT 6.2 ^+ NKT细胞的增殖。另一方面，在复发性DP受体的脾细胞中未检测到巨嵌合体（和NKT细胞的增殖）。ELISA法未检测到IFN-γ IL-4在非复发性DP受者中为158.8pg/ml，在相同的mAb治疗下，（包括胰岛素依赖型糖尿病复发）（DR ; RT1^u，在DP受体中，NKT细胞在RT 6 +T细胞的重现中也可以通过类似的机制抑制RT 6.1）-BB大鼠。来源于供胰十二指肠移植物淋巴组织的RT 6 ^+ NKT细胞可能与抑制IDDM复发和Th 2偏移的移植物排斥反应有关。少