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首页> 外文期刊>Journal of Leukocyte Biology: An Official Publication of the Reticuloendothelial Society >A GMCSF-neuroantigen fusion protein is a potent tolerogen in experimental autoimmune encephalomyelitis (EAE) that is associated with efficient targeting of neuroantigen to APC
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A GMCSF-neuroantigen fusion protein is a potent tolerogen in experimental autoimmune encephalomyelitis (EAE) that is associated with efficient targeting of neuroantigen to APC

机译：GMCSF-神经抗原融合蛋白是实验性自身免疫性脑脊髓炎（EAE）中的强效耐受原，与神经抗原有效靶向APC有关

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Cytokine-NAg fusion proteins represent an emerging platform for specific targeting of self-antigen to particular APC subsets as a means to achieve antigen-specific immunological tolerance. This study focused on cytokine-NAg fusion proteins that targeted NAg to myeloid APC. Fusion proteins contained GM-CSF or the soluble extracellular domain of M-CSF as the N-terminal domain and the encephalitogenic 69a€“87 peptide of MBP as the C-terminal domain. GMCSF-NAg and MCSF-NAg fusion proteins were a??1000-fold and 32-fold more potent than NAg in stimulating antigenic proliferation of MBP-specific T cells, respectively. The potentiated antigenic responses required cytokine-NAg covalent linkage and receptor-mediated uptake. That is, the respective cytokines did not potentiate antigenic responses when cytokine and NAg were added as separate molecules, and the potentiated responses were inhibited specifically by the respective free cytokine. Cytokine-dependent targeting of NAg was specific for particular subsets of APC. GMCSF-NAg and MCSF-NAg targeted NAg to DC and macrophages; conversely, IL4-NAg and IL2-NAg fusion proteins, respectively, induced an a??1000-fold enhancement in NAg reactivity in the presence of B cell and T cell APC. GMCSF-NAg significantly attenuated severity of EAE when treatment was completed before encephalitogenic challenge or alternatively, when treatment was initiated after onset of EAE. MCSF-NAg also had significant tolerogenic activity, but GMCSF-NAg was substantially more efficacious as a tolerogen. Covalent GMCSF-NAg linkage was required for prevention and treatment of EAE. In conclusion, GMCSF-NAg was highly effective for targeting NAg to myeloid APC and was a potent, antigen-specific tolerogen in EAE.
机译：细胞因子-NAg融合蛋白代表了一种新兴平台，可将自身抗原特异性靶向特定的APC亚群，以此作为实现抗原特异性免疫耐受的手段。这项研究的重点是将NAg靶向髓样APC的细胞因子-NAg融合蛋白。融合蛋白包含GM-CSF或M-CSF的可溶性细胞外结构域作为N末端域，MBP的致脑炎69a-87肽作为C末端域。 GMCSF-NAg和MCSF-NAg融合蛋白在刺激MBP特异性T细胞的抗原增殖方面分别比NAg强1000倍和32倍。增强的抗原反应需要细胞因子-NAg共价键和受体介导的摄取。即，当将细胞因子和NAg作为单独的分子添加时，各个细胞因子不增强抗原应答，并且各个游离细胞因子特异性地抑制了增强的应答。 NAg的细胞因子依赖性靶向特异性针对APC的特定子集。 GMCSF-NAg和MCSF-NAg将NAg靶向DC和巨噬细胞;相反，在存在B细胞和T细胞APC的情况下，IL4-NAg和IL2-NAg融合蛋白分别诱导NAg反应性提高了αβ1000倍。当在致脑源性攻击之前完成治疗，或者在EAE发作后开始治疗时，GMCSF-NAg可以显着降低EAE的严重程度。 MCSF-NAg也具有显着的致癌活性，但GMCSF-NAg作为致癌物的功效明显更高。预防和治疗EAE需要共价GMCSF-NAg连接。总之，GMCSF-NAg对于将NAg靶向髓样APC非常有效，并且是EAE中有效的抗原特异性耐受原。

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