Treatment of autoimmune anterior uveitis with recombinant TCR ligands
Treatment of autoimmune anterior uveitis with recombinant TCR ligands
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DOI：
10.1167/iovs.05-1242
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发表时间：
2006-06-01
影响因子：
4.4
通讯作者：
Offner, H
中科院分区：
文献类型：
--
作者：
Adamus, G;Burrows, GG;Offner, H
目的。目的探讨重组TCR配体（RTLs）作为实验性自身免疫性葡萄膜前炎（AU）的新治疗方法的保护特性。rtl包括大鼠RT1。B β 1 α 1结构域与豚鼠MBP69-89肽（RTL201）、相应的大鼠MBP69-89肽（RTL200）或心肌球蛋白肽CM-2 （RTL203）相连。Lewis大鼠通过注射完全弗氏佐剂（CIA）乳化的髓鞘碱性蛋白或通过致病性T细胞的转移被动诱导实验性自身免疫性脑脊髓炎（EAE）相关的AU。大鼠每天静脉注射5次300kg RTL201盐水。对照大鼠接受相同剂量的RTL203或“空”β 1 α 1蛋白（无肽）。对大鼠的临床和组织学征象进行了评价。RTL201预防主动和被动AU，减轻已建立AU的临床症状。与未治疗大鼠或“空”结构治疗大鼠的疾病进展相比，RTL201完全阻止了治疗大鼠的临床和组织学AU。临床AU的抑制与rtl201治疗大鼠眼部炎症细胞的显著减少相关。此外，与未治疗的大鼠相比，RTL201抑制眼内T细胞增殖、DTH反应和细胞因子mRNA表达。与RTL201相比，RTL200在保护眼睛免受AU的效果较差。RTL203对临床AU也有显著抑制作用，但对eae无显著抑制作用。RTL通过抑制特异性T细胞的全身激活和阻止炎症细胞进入眼睛来构建抑制临床和组织学上的AU。这些发现表明，这种新型多肽/MHC II类构建物在AU患者中的临床应用可能是由t细胞对已知抗原肽的反应介导的。
PURPOSE. To determine protective properties of recombinant TCR ligands (RTLs) as a new treatment for experimental autoimmune anterior uveitis (AU). RTLs comprise the rat RT1.B beta 1 alpha 1 domains, linked either to the guinea pig MBP69-89 peptide (RTL201), to the corresponding rat MBP69-89 peptide (RTL200), or to the cardiac myosin peptide CM-2 (RTL203).METHODS. AU associated with experimental autoimmune encephalomyelitis (EAE) was actively induced in Lewis rats by injection of myelin basic protein emulsified in complete Freund's adjuvant (CIA) or passively by the transfer of pathogenic T cells. Rats received five daily doses each of 300 kg RTL201 in saline, intravenously. Control rats received the same dose of RTL203 or an "empty" beta 1 alpha 1 protein (no peptide). The rats were evaluated for the suppression of clinical and histologic signs of AU.RESULTS. RTL201 prevented active and passive AU and reduced the clinical symptoms of established AU. RTL201 completely prevented clinical and histologic AU in the treated rats, compared with disease progression in the untreated rats or those treated with an "empty" construct. The suppression of clinical AU correlated with a significant reduction in inflammatory cells infiltrating the eyes of the RTL201-treated rats. Furthermore, RTL201 inhibited T cell proliferation, DTH responses, and cytokine mRNA expression in the eye, in contrast to the untreated rats. In comparison with RTL201, RTL200 was less effective in protecting the eye from AU. RTL203 also significantly inhibited clinical AU, but not EAE.CONCLUSIONS. RTL constructs suppressed clinical and histologic AU by inhibiting the systemic activation of specific T cells and preventing the recruitment of inflammatory cells into the eye. These findings suggest a possible clinical application of this novel class of peptide/MHC class II constructs in patients with AU that is mediated by T-cell responses to known antigenic peptides.