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Induction of B cell tolerance against Gal-alpha(1-3)Gal Ag in Cyclophosphamide (CP)-induced tolerance

在环磷酰胺 (CP) 诱导的耐受中诱导 B 细胞对 Gal-alpha(1-3)Gal Ag 的耐受

基本信息

批准号：
15390419
负责人：
TOMITA Yukihiro
金额：
$ 9.41万
依托单位：
KYUSHU UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-15390419/
关键词：
tolerance xenotransplantation natural antibody alpha-Gal knockout mice Cyclophosphamide chimerism B cell tolerance heart graft 薬剤誘導性免疫寛容 B cell tolernace clonal destrution 皮膚移植心移植

项目摘要

We have previously reported a method of tolerance induction that comprises an i.v. injection of 1x10^8 allogeneic spleen cells (SC) followed, 2 days later, by an i.p. administration of 200mg/kg of CP. By using this method, we were able to induce a long-lasting skin graft (SG) tolerance in H-2 identical combinations. By using alpha-Gal knockout mice which are preimmunized with alpha-Gal Ag and have anti-alpha Gal nAb, we evaluated the effectiveness of this tolerance system to induce B cell tolerance against Gal-alpha(1-3)Gal. <Method> alpha-Gal knockout (alpha-Gal KO ; H-2^<b/d>) and AKR (H-2^k) mice were used as recipients and donors. Group 1 : untreated alpha Gal KO mice. Group 2: alpha-Gal KO mice were injected with 1x10^8 AKR SC on day -2. Group 3 : alpha-Gal KO mice were injected with 1x10^8 AKR SC on day -2 and CP on day 0. The level of anti-alpha-Gal IgM, IgG1, IgG2a, IgG2b, IgG3 was measured by FACS. The kinetics of alpha-Gal nAb-producing Bcells were evaluated with flow cytomet … More ry. AKR heart grafts (HG) were transplanted 2 weeks after the treatments. Histological examination was performed in the transplanted HG. <Result> The production of anti-alpha-Gal IgM and IgG2a was increased two weeks after injection of AKR SC alone. However, the production of anti-alpha-Gal Ab was completely inhibited after treatment with SC and CP during the observation. AKR heart grafts were rejected within 7 days after transplantation in untreated or AKR SC injected alpha-Gal KO mice. Histological analysis showed the hemorrhage within the cardiac muscle and thromboembolism in the coronary artery, i.e., the evidence of humoral rejection. In recipients treated with SC and CP, on the other hand, survival of AKR HG were significantly prolonged and 70% of them survived over 100 days. Histological analysis showed no evidence of humoral rejection. <Conclusion> Our studies confirmed the effectiveness of our cyclophosphamide-induced tolerance system in the induction of humoral tolerance in alpha Gal-knockout mice. Less

我们之前已经报道了一种诱导耐受的方法，包括静脉注射1x10^8个同种异体脾细胞（SC），2天后腹腔注射200 mg/kg CP。通过使用这种方法，我们能够在H-2相同的组合中诱导持久的皮肤移植（SG）耐受性。通过使用预先用α-Gal Ag免疫并具有抗α-Gal nAb的α-Gal敲除小鼠，我们评估了这种耐受系统诱导B细胞对Gal-α（1-3）Gal耐受的有效性。<Method>α-Gal敲除（α-Gal KO ; H-2^<B/d>）和AKR（H-2 ^k）小鼠用作受体和供体。第1组：未处理的α Gal KO小鼠。第2组：在第-2天对alpha-Gal KO小鼠皮下注射1 × 10^8 AKR。第3组：在第-2天对alpha-Gal KO小鼠皮下注射1x10^8 AKR，在第0天注射CP。用流式细胞仪检测抗α-Gal IgM、IgG 1、IgG 2a、IgG 2b、IgG 3的水平。用流式细胞仪检测β细胞产生α-Gal nAb的动力学 ...更多信息 ry。治疗2周后移植AKR心脏移植物（HG）。对移植的HG进行组织学检查。<Result>在单独注射AKR SC后两周，抗α-Gal IgM和IgG 2a的产生增加。然而，在观察期间，用SC和CP处理后，抗α-Gal Ab的产生被完全抑制。在未治疗或AKR SC注射的α-Gal KO小鼠中，AKR心脏移植物在移植后7天内被排斥。组织学分析显示心肌内出血和冠状动脉血栓栓塞，即，体液排斥反应的证据另一方面，在SC和CP治疗的受者中，AKR HG的存活时间显著延长，70%的受者存活超过100天。组织学分析显示没有体液排斥的证据。<Conclusion>我们的研究证实了我们的环磷酰胺诱导的耐受系统在α Gal敲除小鼠中诱导体液耐受的有效性。少