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Development of synthetic immunotoxin that can enable ABC incompatible transplantation and xenotransplantation.

开发合成免疫毒素，可实现 ABC 不相容移植和异种移植。

基本信息

批准号：
16390364
负责人：
ASAHARA Toshimasa
金额：
$ 9.02万
依托单位：
HIR0SHIMA UNIVERSITY
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2004
资助国家：
日本
起止时间：
2004 至 2005
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-16390364/
关键词：
Xenotransplantation ABO-incompatible transplantation Rejection B cells Immunotoxin

项目摘要

The establishment of a novel method for persistent elimination of B cells responding to transplantation associated carbohydrates : We have demonstrated that B cells bearing receptors that recognize blood group A carbohydrates are found exclusively in the sIgM^+ CD11b^+ CD5^+ B-1 subset in the peripheral blood of humans with blood group O or B. Some reports suggest that the segregation to B-1 cells probably occurs via Ig gene rearrangement on stimulation with thymus-independent type 2 antigens. We have proved that cyclosporin A (CsA) and Tacrolimus (Tac) blocks such segregation to B-1 cells, although CsA has no effect on Ab-producing cells or differentiated B-1 cells. Based on these facts, we hypothesize that the specific elimination of both Ab-producing cells and differentiated B-1 cells with anti-A/B specificity and subsequent CsA/Tac therapy might lead to the long lasting inhibition of anti-A/B Ab production in ABO-incompatible organ transplantation. Balb/c mice resemble humans with … More blood group O or B in that the mice have natural Abs against human blood group A carbohydrates in their sera. B cells bearing receptors that recognize these A carbohydrates in mice also belong to the CD5^+ CD11b^+ B-1 subset. The ability of synthetic A carbohydrates (GalNAcα1-3Fucα1-2Gal) conjugated with BSA and rabbit anti-BSA Abs to deplete anti-A IgM-producing cells was studied in vitro. The Balb/c mice were first injected with A-BSA and then with anti-BSA Abs after 6 hours. In mice that received the injection of A-BSA/anti-BSA Abs, the serum levels of anti-A IgM reduced by day 14. However, immunization with human A RBCs on day 14 resulted in an increase in the serum levels of anti-A Abs. In contrast, when combined with the CsA treatment and treatment with A-BSA/anti-BSA Abs, the serum levels of anti-A Abs were persistently undetectable in the mice even after the immunization. These results are consistent with the hypotheses that treatment with A-BSA/anti-BSA Abs temporally depletes B cells responding to A determinants, and that CsA/Tac treatment prevents the replenishment of these cells. The establishment of a model for analyses of B cells responding to N-glycolylneuraminic acid : The presence in humans of natural antibodies directed against N-glycolylneuraminic acid (NeuGc) epitopes on pig vascular endothelium may provides another barrier in xenotransplantation, as antibody-antigen binding leads to rejection. There has been no animal model for analyses of B cells responding to NeuGcso far. We have established a in vivo model utilizing NeuGc-deficient mice. Less

持续清除对移植相关碳水化合物有反应的B细胞的新方法的建立：我们已经证明，携带识别血型A碳水化合物的受体的B细胞仅见于O型或B型人外周血中的sIgM^+ CD 11 B ^+ CD 5 ^+ B-1亚群。一些报道表明，分离到B-1细胞可能是通过IG基因重排与胸腺非依赖性2型抗原刺激发生的。我们已经证明，环孢菌素A（CsA）和他克莫司（Tac）阻断这种分离到B-1细胞，虽然CsA对抗体产生细胞或分化的B-1细胞没有影响。基于这些事实，我们推测，特异性消除抗体产生细胞和具有抗A/B特异性的分化B-1细胞以及随后的CsA/Tac治疗可能导致ABO血型不合器官移植中抗A/B Ab产生的持久抑制。Balb/c小鼠与人类相似， ...更多信息血型O或B，因为小鼠在其血清中具有抗人血型A碳水化合物的天然Ab。在小鼠中，携带识别这些A类碳水化合物的受体的B细胞也属于CD 5 ^+ CD 11 B ^+ B-1亚群。本文研究了人工合成的A型糖（GalNAcα1-3Fucα1-2Gal）与牛血清白蛋白（BSA）和兔抗牛血清白蛋白（BSA）抗体（Abs）偶联后对抗A IgM产生细胞的杀伤作用。Balb/c小鼠首先注射A-BSA，然后在6小时后注射抗BSA抗体。在接受A-BSA/抗-BSA Ab注射的小鼠中，抗-A IgM的血清水平在第14天降低。然而，在第14天用人A RBC免疫导致抗A Ab的血清水平增加。相反，当与CsA治疗和用A-BSA/抗-BSA Ab治疗组合时，即使在免疫后，小鼠中抗-A Ab的血清水平也持续检测不到。这些结果与以下假设一致：用A-BSA/抗BSA Ab处理暂时耗尽对A决定簇应答的B细胞，并且CsA/Tac处理阻止这些细胞的补充。B细胞对N-羟乙酰神经氨酸反应分析模型的建立：人体内存在针对猪血管内皮上N-羟乙酰神经氨酸（NeuGc）表位的天然抗体，这可能为异种移植提供另一个屏障，因为抗体-抗原结合导致排斥反应。迄今为止，尚无用于分析B细胞对NeuGc反应的动物模型。我们已经建立了一个体内模型，利用NeuGc缺陷小鼠。少