Regulation of innate and adaptive immune responses in xenotransplantation by modulating CD47sirp α signaling

通过调节 CD47sirp α 信号调节异种移植中的先天性和适应性免疫反应

• 批准号: 18390348
• 负责人: OHDAN Hideki
• 金额: $ 10.96万
• 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-18390348/
• 关键词: xenotransplantation; macrophage; T cell immune response; self-recognition system

It has been reported that macrophage-induced cytotoxicity is involved in lon-term xenograft survival, however, the mechanism has remained unknown. A recent report indicates that the signal regulatory protein (SIRP) α is a critical immune inhibitory receptor on macrophages, and its interaction with CD47, a ligand for SIRPα, prevents autologous phagocytosis. We confirmed that interspecies incompatibility of CD47 significantly contributes to the rejection of xenogeneic cells by macrophages. Genetic induction of human CD47 on porcine cells could provide inhibitory signaling to SIRPα on human macrophages, providing a novel approach to preventing macrophage-mediated xenograft rejection. CD47-SIRPα signaling system may also play an important role in adaptive immune response. We have analyzed the frequency and proliferative activity of human T cells responding to either porcine or allogenic PBMCs by using in vitro mixed lymphocyte reaction (MLR) assay with a CFSE-labeling technique. The freque … More ncies of alloreactive and xenoreactive CD4^+ T cell precursors were almost identical, however, the Stimulation Index (SI) of xenoreactive CD4^+ T cells was significantly higher than that of alloreactive, indicating a stronger reaction by a single xenoreactive CD4^+ T cell. Moreover, when CD4^+ T cells were depleted from the responders in the MLR, the proliferation of xenoreactive CD8^+ T cells was significantly less than that of alloreactive CD8^+ T cells, indicating that the human CD4^+ T cells, but not CDS, T cells, are sufficient to induce porcine xenograft rejection. Further, The SI of xenoreactive CDC and Cost T cells was also significantly suppressed in the presence of human CD47-Fc. These results suggest that the human T cell responses to porcine cells are stronger than those to allogeneic cells because of the interspecies incompatibility of CD47. Moreover, genetic manipulation of porcine cells to induce human CD47 expression might attenuate human T cell-mediated xenograft rejection. Less

有报道称巨噬细胞诱导的细胞毒性参与了异种移植物的长期存活，但其机制尚不清楚。最近的研究表明，信号调节蛋白α是巨噬细胞上一种重要的免疫抑制受体，它与信号调节蛋白α的配体CD47相互作用可阻止自体吞噬。我们证实了CD47的种间不相容显著促进了巨噬细胞对异种细胞的排斥。人CD47在猪细胞上的遗传诱导可以为人巨噬细胞上的Sirpα提供抑制信号，为预防巨噬细胞介导的异种移植排斥反应提供了一种新的途径。CD47Sirpα信号系统也可能在获得性免疫反应中发挥重要作用。我们用体外混合淋巴细胞反应(MLR)结合CFSE标记技术分析了人T细胞对猪和同种异体PBMCs的反应频率和增殖活性。The First…异种反应和异种反应的CD4^+T细胞前体细胞的数量几乎相同，但异种反应的CD4^+T细胞的刺激指数(SI)显著高于异种反应的T细胞，表明单个异种反应的CD4^+T细胞反应较强。此外，当MLR中反应者的CD4^+T细胞被耗尽时，异种反应性CD8^+T细胞的增殖明显低于同种反应性CD8^+T细胞，这表明人的CD8^+T细胞而不是CDS，T细胞足以诱导猪异种移植排斥反应。此外，在人CD47-Fc存在的情况下，异种反应性CDC和COST T细胞的SI也被显著抑制。这些结果表明，由于CD47的种间不相容，人T细胞对猪细胞的反应比对同种异体细胞的反应更强。此外，对猪细胞进行基因操作以诱导人CD47的表达可能会减弱人类T细胞介导的异种移植排斥反应。较少

项目成果

Characterization of anti-Gal antibody-producing cells of baboons and humans

狒狒和人类抗 Gal 抗体产生细胞的表征

• 发表时间: 2006
• 期刊: Transplantation 27, 81(6)
• 作者: Y.,Xu;Y.,C.,Yang;H.,Ohdan;D.Ryan,D.,Harper;C.Wu;H.S.,Kruge-Grey;A.D.Thall;M.;Awwad;M.;Sykes
• 通讯作者: Sykes

Liver sinusoidal endothwlial cells that endocytose allogeneic cells suppress T cells with indirect allospecificity

内吞同种异体细胞的肝窦内皮细胞以间接同种异体特异性抑制 T 细胞

• 发表时间: 2006
• 期刊: The Journal of Immunology 177・6
• 作者: Tokita Daisuke;et al.
• 通讯作者: et al.

Mechanism of avoidance of xenogeneic rejection by macrophages through intracellular inhibitory CD47-SHIPα signaling

通过细胞内抑制性 CD47-SHIPα 信号传导避免巨噬细胞异种排斥的机制

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

Human CD47 expression protects porcine cells from xenogeneic human macrophage phagocyrtosis through inhibitory CD47-S1RPα signaling

人 CD47 表达通过抑制性 CD47-S1RPα 信号传导保护猪细胞免受异种人巨噬细胞吞噬作用

• 发表时间: 2006
• 作者: K.;Ide;H.;Wang;T.;Asahara;M.;Sykes;Y.G.;Yang;H.;Ohdan
• 通讯作者: Ohdan

Immunogenicity of xenogeneic antigen N-glycolylneuraminic acid (NeuGc)

异种抗原 N-羟乙酰神经氨酸 (NeuGc) 的免疫原性

• 发表时间: 2007
• 作者: H.;Tahara;H.;Ohdan;K.;Ide;N.;Basnet;K.;Ishiyama;M.;Shishida;Y.;Tanaka;T.;Irei;M.;Ohira;Y.;Igarashi;M.;Doskali;H.;Takematsu;Y.;Kozutsumi;T.;Asahara
• 通讯作者: Asahara