Elucidation of the mechanism on carbohydrate antigen recognition by B cells through CD1d mediated signaling and establishment of a method to regulate B cells responding to the carbohydrate antigens in ABO-incompatible transplantation and xe

阐明 B 细胞通过 CD1d 介导的信号识别碳水化合物抗原的机制，并建立在 ABO 不相容移植和 xe 中调节 B 细胞对碳水化合物抗原反应的方法

• 批准号: 18390349
• 负责人: ASAHARA Toshimasa
• 金额: $ 11.21万
• 依托单位: Hiroshima University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2006
• 资助国家: 日本
• 起止时间: 2006 至 2007
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-18390349/
• 关键词: Transplant immunology; ABO-blood group incompatible transplantation Xenot; Antibody mediated rejection; NKT cell; CD1d; ABO不適合移植; 抗体拒絶反応

In ABO-blood group incompatible transplantation and xenotransplantation, grafted organs will be rejected because antibody (Ab)-mediated rejection is induced in responses to blood group A/B antigens, Gal α 1-3Galb1-4GlcNAc (Gal) or N-glycolylneuraminic acid (NeuGc) carbohydrates, which are widely expressed on the organ vessel epithelia. We have attempted to establish a specific immunosuppressive method targeting B cells responding to A/B, Gal and NeuGc carbohydrate antigens.In this study, we have analyzed the role of natural killer T (NKT) cells in the differentiation of B cells responding to the transplant-related carbohydrates. In the wild-type (WT) control mice, anti-A IgM/IgG Ab production occurred and was accelerated after the immunization with human red blood cells (RBCs) and α Galactosylceramide ( α GalCer) (an unique carbohydrate antigen that is presented on CD1d molecules and activates NKT cells). On the other hand, in the CD1d (ligand to the V α 14 T cell receptors used predominantly in NKT cells) knockout (KO) mice, anti-A IgM production was significantly reduced and anti-A IgG-class switching could not be observed. There was no difference in anti-allogeneic MHC Ab production between WT and CD1dKO mice, and IgG-class switching could be normally observed in both background mice. Based on these findings, it is likely that the suppressive modulation of CD1d molecule-mediated signaling between NKT cells and B cells might lead to the avoidance of Ab-mediated rejection in ABO-incompatible transplantation, whereas this strategy could not prevent Ab production from B cells responding to allogeneic MHC antigens. In order to investigate further such roles of NKT cells in the differentiation of B cells responding to the xenogeneic carbohydrate antigens, we have now established Gal/CD1d double KO mice and NeuGc/CD1d double KO mice by mating either Gal KO or NeuGc KO mice with CD1dKO mice.

在ABO血型不合的移植和异种移植中，由于抗体（Ab）介导的排斥反应在对器官血管上皮广泛表达的血型A/B抗原、Gal α 1- 3Galb 1 -4GlcNAc（Gal）或N-羟乙酰神经氨酸（NeuGc）碳水化合物的应答中被诱导，因此移植器官将被排斥。本研究试图建立一种针对A/B、Gal和NeuGc糖抗原反应的B细胞的特异性免疫抑制方法，并分析了自然杀伤T（NKT）细胞在移植相关糖抗原反应的B细胞分化中的作用。在野生型（WT）对照小鼠中，抗A IgM/IgG Ab产生，并在用人红细胞（RBC）和α半乳糖神经酰胺（α GalCer）（一种独特的碳水化合物抗原，存在于CD 1d分子上并激活NKT细胞）免疫后加速。另一方面，在CD 1d（主要用于NKT细胞的V α 14 T细胞受体的配体）敲除（KO）小鼠中，抗A IgM的产生显著减少，并且未观察到抗A IgG类转换。WT和CD 1dKO小鼠之间的抗同种异体MHC Ab产生没有差异，在两种背景小鼠中可以正常观察到IgG类转换。基于这些发现，这是可能的，抑制调节CD 1d分子介导的NKT细胞和B细胞之间的信号传导可能会导致避免抗体介导的排斥反应，在ABO血型不合移植，而这种策略不能阻止抗体的生产从B细胞应答同种异体MHC抗原。为了进一步研究NKT细胞在应答异种碳水化合物抗原的B细胞分化中的作用，我们通过将Gal KO或NeuGc KO小鼠与CD 1dKO小鼠交配，建立了Gal/CD 1d双KO小鼠和NeuGc/CD 1d双KO小鼠。

项目成果

抗血液型抗体産生B細胞の分化様式の解明と血液型不適合腎移植への応用

抗血型抗体产生B细胞分化模式的阐明及其在血型不相容肾移植中的应用

• 发表时间: 2008
• 作者: E. Sato;E. Tanaka;H. Mori;J.Onagawa;他8名;伊禮 俊充
• 通讯作者: 伊禮 俊充

抗血液型抗体産生B細胞の分化様式に即したABO血液型不適合肝移植に対する治療戦略

基于抗血型抗体产生B细胞分化模式的ABO血型不合肝移植治疗策略

• 发表时间: 2007
• 作者: M. Masuda;S. Takeda;H. Mori;N. Mochizuki;他3名;伊禮 俊充
• 通讯作者: 伊禮 俊充

Human CD47 expression protects porcine cells from xenogeneic human macrophage phagocytosis through inhibitory CD47-SIRPa signaling (Young Investigator Award)

人 CD47 表达通过抑制性 CD47-SIRPa 信号传导保护猪细胞免受异种人巨噬细胞吞噬（青年研究员奖）

• 发表时间: 2007
• 作者: K.;Ide;H.;Wang;T.;Asahara;M.;Sykes;Y.G.;Yang;H.;Ohdan
• 通讯作者: Ohdan

Therapeutic strategy for ABO-incompatible liver transplantation based on the B cell developmental theory responding to blood group carbohydrates

基于B细胞发育理论响应血型碳水化合物的ABO血型不合肝移植治疗策略

• 发表时间: 2007
• 作者: T.;Irei;H.;Ohdan;K.;Ishiyama;Y.;Tanaka;K.;Ide;M.;Shishida;M.;Ohira;Y.;Igarashi;H.;Tahara;B.;Nabin;M.;Doskari;T.;Asahara
• 通讯作者: Asahara

Immunotoxin、シクロスポリンを用いた新しい抗血液型抗体産生B細胞の特異的排除法とABO不適合肝移植への応用の可能性

利用免疫毒素和环孢菌素特异性消除产生抗血型抗体的B细胞的新方法及其在ABO血型不相容肝移植中的潜在应用

• 发表时间: 2006
• 作者: Hattori K;Yamanouchi D;Banno H;Kobayashi M;Yamamoto K;Kajikuri J;Itoh T;Komori K;伊禮 俊充
• 通讯作者: 伊禮 俊充