Casey Eye Institute, Oregon Health & Science University, Portland, Oregon.
Invest Ophthalmol Vis Sci. 2013 Oct 23;54(10):6917-25. doi: 10.1167/iovs.13-12058.
Autoimmune inflammation of the retina causes vision loss in the majority of affected individuals. Th1 or Th17 cells initiate the disease on trafficking from the circulation into the eye across the retinal vascular endothelium. We investigated the ability of human Th1- and Th17-polarized cells to cross a simulated human retinal endothelium, and examined the role of IgG superfamily members in this process.
Th1- and Th17-polarized cell populations were generated from human peripheral blood CD4(+) T cells, using two Th1- and Th17-polarizing protocols. Transendothelial migration assays were performed over 18 hours in Boyden chambers, after seeding the transwell membrane with human retinal endothelial cells. In some assays intercellular adhesion molecule 1 (ICAM-1), vascular cell adhesion molecule 1 (VCAM-1), or activated leukocyte cell adhesion molecule (ALCAM) blocking antibody, or isotype- and concentration-matched control antibody, was added to the upper chambers.
Th1- and Th17-polarized cells migrated equally efficiently across the human retinal endothelial monolayer. The percentage of IL-17(+) IFN-γ(-) Th17-polarized cells was reduced following migration. Blocking ICAM-1, but not VCAM-1 or ALCAM, significantly reduced migration of Th1- and Th17-polarized cells for a majority of human donors.
Taken in the context of other literature on transendothelial migration, our results illustrate the importance of investigating the specific tissue and vascular endothelium when considering helper T cell migration in autoimmune inflammation. Our findings further indicate that while generalizations about involvement of specific adhesion molecules in uveitis and other autoimmune disease may be possible, these may not apply to individual patients universally. The observations are relevant to the use of adhesion blockade for therapeutic purposes.
视网膜自身免疫炎症会导致大多数受影响个体的视力丧失。Th1 或 Th17 细胞在从循环系统通过视网膜血管内皮迁移到眼内时引发疾病。我们研究了人类 Th1 和 Th17 极化细胞穿过模拟人视网膜内皮的能力，并研究了 IgG 超家族成员在该过程中的作用。
使用两种 Th1 和 Th17 极化方案，从人外周血 CD4+T 细胞中生成 Th1 和 Th17 极化细胞群体。在将人视网膜内皮细胞接种到 Transwell 膜上之后，在 Boyden 室中进行跨内皮迁移测定 18 小时。在某些测定中，在上室中加入细胞间黏附分子 1（ICAM-1）、血管细胞黏附分子 1（VCAM-1）或活化白细胞细胞黏附分子（ALCAM）阻断抗体或同型和浓度匹配的对照抗体。
Th1 和 Th17 极化细胞穿过人视网膜内皮单层的迁移效率相等。迁移后，IL-17（+）IFN-γ（-）Th17 极化细胞的百分比降低。阻断 ICAM-1，但不阻断 VCAM-1 或 ALCAM，可显著减少大多数供体的 Th1 和 Th17 极化细胞的迁移。
从跨内皮迁移的其他文献来看，我们的结果说明了在考虑辅助性 T 细胞迁移与自身免疫炎症时，研究特定组织和血管内皮的重要性。我们的研究结果进一步表明，虽然关于特定黏附分子在葡萄膜炎和其他自身免疫性疾病中的参与的概括可能是可能的，但这些概括可能不适用于所有患者。这些观察结果与粘附阻断的治疗用途有关。
