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

建立一种新的方法，用于持续消除对移植相关的碳含碳水解的B细胞：我们已经证明，在SIGM^+ CD11B^+ CD11b^+ CD11b^+ CD5^+ CD5^+ B-1中，具有识别血液组A碳氢化的B细胞仅在Blops o grous o或B中进行B-1的疾病，以表明B-1的cy型。用胸腺独立于2型抗原刺激。我们规定，环孢菌素A（CSA）和他克莫司（TAC）阻止了这种隔离到B-1细胞，尽管CSA对产生AB的细胞或分化的B-1细胞没有影响。基于这些事实，我们假设具有抗A/B特异性和随后的CSA/TAC治疗的特异性消除产生AB的细胞和分化的B-1细胞可能会导致对ABO不合时宜的器官移植中抗A/B AB产生的持久抑制作用。 BALB/c小鼠类似于……更多的血液组O或B，因为小鼠对人类血液A碳含有天然ABS的血清中的碳水化合物。 B细胞带有识别这些A中这些A碳水解的受体也属于CD5^+ CD11b^+ B-1子集。在体外研究了与BSA和兔抗BSA ABS共轭复制抗A IgM产生的细胞的合成A（GalNACα1-3FUCα1-2GAL）的能力。首先将BALB/C小鼠注射A-BSA，然后在6小时后用抗BSA ABS注射。在接受A-BSA/抗BSA ABS注射的小鼠中，抗A IgM的血清水平降低到第14天。但是，第14天对人类RBC进行免疫，导致抗A ABS的血清水平升高。相比之下，当与A-BSA/抗BSA ABS的CSA治疗和治疗结合时，即使在免疫后，小鼠的抗A ABS的血清水平也持续无法检测到。这些结果与A-BSA/抗BSA ABS治疗的假设一致，暂时耗尽了对确定剂反应的B细胞，并且CSA/TAC治疗可防止这些细胞的补充。建立了对N-糖基因神经氨酸反应的B细胞分析模型的建立：针对N-甘糖醇基因神经氨酸的天然抗体的存在（NeugC）表位对猪血管内皮的效果可能会在抗抗体抗体中的抗体抗体 - 抗抗激素与抗固定性粘合。尚未有用于分析B细胞对Neugcso的分析的动物模型。我们已经使用Neugc缺陷小鼠建立了一个体内模型。较少的