Analysis of the cellular mechanism underlying inhibition of EAE after treatment with anti-NKG2A F(ab′)2
Analysis of the cellular mechanism underlying inhibition of EAE after treatment with anti-NKG2A F(ab′)2
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DOI：
10.1073/pnas.0914732107
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发表时间：
2010-02-09
影响因子：
11.1
通讯作者：
Cantor, Harvey
中科院分区：
文献类型：
--
作者：
Leavenworth, Jianmei W.;Schellack, Carola;Cantor, Harvey
通过中断 Qa-1(b) 和 CD94/NKG2A 之间相互作用的突变，可以通过增强 NK 细胞介导的激活自身反应性 T 细胞的消除来通过实验改善自身免疫性脑脊髓炎。在这里，我们评估了抗 NKG2A F(ab')(2) Ab 增强自身反应性 T 细胞消除并减少实验性自身免疫性脑脊髓炎 (EAE) 的能力。抗 NKG2A F(ab')(2) 治疗可减少完整 C57BL/6 小鼠中髓磷脂少突胶质细胞糖蛋白 (MOG) 诱导的 EAE 以及致病 T 细胞过继转移后的进展。对潜在机制的分析表明，给予抗NKG2A F(ab')(2) Ab可减少CD4(+) T对MOG的回忆反应，并使产生IL-17和IFNγ的CD4(+) T细胞的比例偏向保护性分泌IL-4和IL-10的CD4(+) T细胞亚群。 CD94/NKG2A 依赖性脊髓炎症损伤抑制与中枢神经系统中 T 细胞浸润减少和小胶质细胞活化减少有关。由于抗 NKG2A F(ab')(2) 治疗对外周淋巴组织中 T 淋巴细胞和 B 淋巴细胞以及 NK 细胞的数量或活性没有可检测到的影响，因此这种基于抗 NKG2A 的方法可能是治疗这种 CNS 疾病的安全有效的方法。
Autoimmune encephalomyelitis may be ameliorated experimentally by enhancing NK cell-mediated elimination of activated auto-reactive T cells through a mutation that interrupts the interaction between Qa-1(b) and CD94/NKG2A. Here we evaluate the ability of an anti-NKG2A F(ab')(2) Ab to enhance elimination of autoreactive T cells and reduce experimental autoimmune encephalomyelitis (EAE). Anti-NKG2A F(ab')(2) treatment diminishes progression of both myelin oligodendrocyte glycoprotein (MOG)-induced EAE in intact C57BL/6 mice and after adoptive transfer of disease-causing T cells. Analyses of the underlying mechanism revealed that administration of anti-NKG2A F(ab')(2) Ab reduces CD4(+) T recall responses to MOG and skews the proportion of IL-17- and IFN gamma-producing CD4(+) T cells toward the protective IL-4- and IL-10-secreting CD4(+) T cell subpopulations. CD94/NKG2A-dependent inhibition of inflammatory damage to spinal cord is associated with decreased infiltration of T cells and reduced microglia activation in the central nervous system. Because anti-NKG2A F(ab')(2) treatment had no detectable effect on the numbers or activity of T and B lymphocytes and NK cells in peripheral lymphoid tissues, this anti-NKG2A-based approach may represent a safe and effective therapy for this CNS disorder.