Veterinary Molecular Biology, Montana State University, Bozeman, Montana, United States of America.
PLoS One. 2010 Jan 14;5(1):e8720. doi: 10.1371/journal.pone.0008720.
Conventional methods to induce tolerance in humans have met with limited success. Hence, efforts to redirect tolerogen uptake using reovirus adhesin, protein sigma 1 (psigma1), may circumvent these shortcomings based upon the recent finding that when reovirus psigma1 is engineered to deliver chicken ovalbumin (OVA) mucosally, tolerance is obtained, even with a single dose. To test whether single-dose tolerance can be induced to treat EAE, proteolipid protein (PLP(130-151)) was genetically fused to OVA to psigma1 (PLP:OVA-psigma1) and shown to significantly ameliorate EAE, suppressing proinflammatory cytokines by IL-10(+) forkhead box P3 (FoxP3)(+) CD25(+)CD4(+) T(reg) and IL-4(+)CD25(-)CD4(+) Th2 cells. IL-10R or IL-4 neutralization reversed protection to EAE conferred by PLP:OVA-psigma1, and adoptive transfer of Ag-specific T(reg) or Th2 cells restored protection against EAE in recipients. Upon assessment of each relative participant, functional inactivation of CD25 impaired PLP:OVA-psigma1's protective capacity, triggering TGF-beta-mediated inflammation; however, concomitant inactivation of TGF-beta and CD25 reestablished PLP:OVA-psigma1-mediated protection by IL-28-producing FoxP3(+)CD25(-)CD4(+) T cells. Thus, psigma1-based therapy can resolve EAE independently of or dependently upon CD25 and assigns IL-28 as an alternative therapy for autoimmunity.
传统的人类诱导耐受方法取得的成效有限。因此，人们努力利用呼肠孤病毒黏附蛋白 sigma 1（psigma1）重新引导耐受原摄取，这可能会克服这些缺点。这是基于最近的发现，即当呼肠孤病毒 psigma1 被设计成经黏膜递呈鸡卵清白蛋白（OVA）时，即使单次给予，也能获得耐受。为了测试单次给予耐受原是否可以诱导来治疗实验性自身免疫性脑脊髓炎（EAE），我们将蛋白脂蛋白（PLP（130-151））基因融合到 OVA 上形成 psigma1（PLP：OVA-psigma1），并发现它能显著改善 EAE，通过 IL-10（+）叉头框 P3（FoxP3）（+）CD25（+）CD4（+）T（reg）和 IL-4（+）CD25（-）CD4（+）Th2 细胞抑制促炎细胞因子。IL-10R 或 IL-4 中和逆转了 PLP：OVA-psigma1 对 EAE 的保护作用，Ag 特异性 T（reg）或 Th2 细胞的过继转移在受体中恢复了对 EAE 的保护作用。在对每个相对参与者进行评估时，CD25 的功能失活损害了 PLP：OVA-psigma1 的保护能力，引发 TGF-β 介导的炎症；然而，TGF-β 和 CD25 的同时失活通过产生 IL-28 的 FoxP3（+）CD25（-）CD4（+）T 细胞重新建立了 PLP：OVA-psigma1 介导的保护作用。因此，基于 psigma1 的治疗可以独立或依赖于 CD25 来解决 EAE，并将 IL-28 作为自身免疫的替代治疗方法。
