Modulation of MS-like disease by a multi epitope protein is mediated by induction of CD11c+ CD1lb+ Grl+ myeloid-derived dendritic cells
Modulation of MS-like disease by a multi epitope protein is mediated by induction of CD11c+ CD1lb+ Grl+ myeloid-derived dendritic cells
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DOI：
10.1016/j.jneuroim.2019.04.013
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发表时间：
2019-08-15
影响因子：
3.3
通讯作者：
Ben-Nun, A.
中科院分区：
文献类型：
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作者：
Kaushansky, N.;Kaminitz, A.;Ben-Nun, A.
特异性中和致病的自身免疫细胞是多发性硬化(MS)治疗的最终目标。然而，MS的致病性自身免疫可以针对几个主要的靶抗原，因此针对单个靶抗原的致病T细胞不太可能有效。为了克服MS致病自身反应的多样性和潜在的复杂性，我们提出了伴随的多抗原/多表位靶向AS的概念，这是一种可以想象的更有效的免疫治疗方法。我们构建了一个实验自身免疫性脑炎(EAE)/MS相关的合成人类靶标自身抗原基因(MS-shMultiTAG)，旨在串联编码所有已知脑源性蛋白的EAE/MS相关表位。MS相关蛋白产物(命名为Y-MSPC)具有免疫功能，耐受性给药后可有效抑制和逆转单一脑源性蛋白诱导的EAE。此外，Y-MSPC还完全消除了由五种脑源性T细胞株混合诱导的“复合型EAE”的发展，每种细胞系针对不同的脑源性表位MBP、MOG、PLP、MOBP和OSP。值得注意的是，Y-MSPC在抑制“经典”或“复杂”EAE的发展和改善持续疾病方面始终比单一疾病特异性多肽或多肽鸡尾酒治疗更有效。总体而言，Y-MSPC对EAE的调节与抑制致病的自身反应性T细胞、下调Th1/Th17细胞因子的分泌和上调TGF-β的分泌有关。此外，我们还表明，通过给予Y-MSPC耐受性注射抑制和治疗正在进行的EAE，还与治疗小鼠脾和中枢神经系统中一种独特的树突状细胞(DC)亚群CD11c+CD11b+GRL+髓系来源的DC显著增加有关。这些DC具有较强的免疫调节特性，具有下调MS样病的功能，表现为IL-4、IL-10和转化生长因子-β的产生增加，而IL-12的产生减少。在功能上，这些髓系树突状细胞抑制了髓鞘特异性T细胞的体外增殖，更重要的是，这些细胞在体内是有功能的，因为它们过继转移到EAE诱导的小鼠体内后，对疾病有很强的抑制作用，并伴随着显著的CD4+FoxP3+调节细胞的诱导。这些结果突显了“多表位靶向”试剂在诱导功能调节CD11c+CD1lb+GRL+髓系树突状细胞方面的有效性，进一步表明这些树突状细胞在维持外周耐受方面的潜在作用，以及它们参与下调MS样疾病的调控。
Specific neutralization of the pathogenic autoimmune cells is the ultimate goal in therapy of Multiple Sclerosis (MS). However, the pathogenic autoimmunity in MS, can be directed against several major target antigens, and therefore targeting pathogenic T-cells directed against a single target antigen is unlikely to be effective. To overcome this multiplicity and the potential complexity of pathogenic autoreactivities in MS, we have put forward the concept of concomitant multi-antigen/multiepitope targeting as, a conceivably more effective approach to immunotherapy of MS. We constructed an (Experimental Autoimmune Encephalomeylitis (EAE)/MSrelated synthetic human Target Autoantigen Gene (MS-shMultiTAG) designed to encode in tandem only EAE/MS related epitopes of all known encephalitogenic proteins. The MS related protein product (designated Y-MSPc) was immunofunctional and upon tolerogenic administration, it effectively suppressed and reversed EAE induced by a single encephalitogenic protein. Furthermore, Y-MSPc also fully abrogated the development of "complex EAE" induced by a mixture of five encephalitogenic T-cell lines, each specific for a different encephalitogenic epitope of MBP, MOG, PLP, MOBP and OSP. Strikingly, Y-MSPc was consistently more effective than treatment with the single disease -specific peptide or with the peptide cocktail, both in suppressing the development of "classical" or "complex" EAE and in ameliorating ongoing disease. Overall, the modulation of EAE by Y-MSPc was associated with anergizing the pathogenic autoreactive T-cells, downregulation of Thl/Th17 cytokine secretion and upregulation of TGF-beta secretion. Moreover, we show that both suppression and treatment of ongoing EAE by tolerogenic administration of Y-MSPc is associated also with a remarkable increase in a unique subset of dendritic-cells (DCs), CD11c + CD11b+ Grl+-myeloid derived DCs in both spleen and CNS of treated mice. These DCs, which are with strong immunoregulatory characteristics and are functional in down-modulation of MS-like-disease displayed increased production of IL-4, IL-10 and TGF-beta and low IL-12. Functionally, these myeloid DCs suppress the in-vitro proliferation of myelin-specific T-cells and more importantly, the cells were functional in-vivo, as their adoptive transfer into EAE induced mice resulted in strong suppression of the disease, associated with a remarkable induction of CD4 + FoxP3 + regulatory cells.These results, which highlight the efficacy of "multi-epitope-targeting" agent in induction of functional regulatory CD11c + CD1lb + Grl + myeloid DCs, further indicate the potential role of these DCs in maintaining peripheral tolerance and their involvement in downregulation of MS-like-disease.