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

巨噬细胞诱导的细胞毒性与异种移植物的长期存活有关，但其机制尚不清楚。最近的报道表明信号调节蛋白（SIRP）α是巨噬细胞上的一种重要的免疫抑制受体，其与SIRPα的配体CD 47的相互作用阻止自体吞噬。我们证实，种间不相容性的CD 47显着有助于异种细胞的排斥巨噬细胞。在猪细胞上遗传诱导人CD 47可以提供对人巨噬细胞上SIRPα的抑制性信号，为预防巨噬细胞介导的异种移植排斥提供了一种新的方法。CD 47-SIRPα信号系统在获得性免疫应答中也可能发挥重要作用。我们已经分析了频率和增殖活性的人T细胞响应无论是猪或同种异体PBMC通过使用体外混合淋巴细胞反应（MLR）与CFSE标记技术测定。频率 ...更多信息 同种异体反应性和异种反应性CD 4 ^+ T细胞前体的反应几乎相同，但是异种反应性CD 4 ^+ T细胞的刺激指数（SI）显著高于同种异体反应性，表明单个异种反应性CD 4 ^+ T细胞的反应更强。此外，当在MLR中从应答者中去除CD 4 ^+ T细胞时，异种反应性CD 8 ^+ T细胞的增殖显著低于同种异体反应性CD 8 ^+ T细胞，这表明人CD 4 ^+ 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，异种反应性CDC和CostT细胞的SI在人CD 47-Fc的存在下也被显著抑制。这些结果表明，由于CD 47的种间不相容性，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，基因操作猪细胞诱导人CD 47表达可能会减弱人T细胞介导的异种移植排斥反应。少

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