Huber Andrea, Diedrichs-Möhring Maria, Wildner Gerhild
Section of Immunobiology, Department of Ophthalmology, Klinikum der Universität, Mathildenstr. 8, 80336 München, Germany.
Section of Immunobiology, Department of Ophthalmology, Klinikum der Universität, Mathildenstr. 8, 80336 München, Germany.
Mol Immunol. 2015 Feb;63(2):215-26. doi: 10.1016/j.molimm.2014.07.009. Epub 2014 Jul 30.
Antigen-specific tolerance induction is a desired therapy for uveitis patients. Our relapsing-remitting rat model of experimental autoimmune uveitis (EAU) induced with IRBP peptide R14 enables us to test the effect of oral tolerance on the prevention of relapsing uveitis. We investigated several peptides overlapping the sequence of R14 for prevention and different doses of R14 for therapy to determine the tolerogenic epitope and the most effective therapeutic regimen for uveitis. Lewis rats were immunized with R14-CFA to induce EAU. Oral tolerance was induced prior to immunization (prevention) or after onset of EAU to prevent relapses (therapy). Therapeutic feeding was performed with high and/or low doses of oral antigen for clonal deletion of effector and induction of regulatory T cells. Uveitis was determined clinically and histologically; mesenteric lymph node (mLN) cells of tolerized rats were tested for surface markers, cytokines and Foxp3 expression. Preventive feeding of R14 and its major epitope R16, but none of the overlapping peptides significantly suppressed EAU and also prevented relapses, irrespective of their pathogenicity. Therapeutic feeding with R14 dramatically reduced relapses, while only the consecutive feeding of high and low-dose R14 had an ameliorating effect on the first course of disease. IL-10-producing T cells from mLN decreased after oral tolerization, and with R14-stimulation in vitro the TCRαβ+/Foxp3+ population increased in the low-dose fed group. No mLN population could be clearly assigned to successful oral tolerance induction during active autoimmune uveitis.
抗原特异性耐受诱导是葡萄膜炎患者理想的治疗方法。我们用IRBP肽R14诱导的复发性实验性自身免疫性葡萄膜炎（EAU）大鼠模型，使我们能够测试口服耐受对预防复发性葡萄膜炎的效果。我们研究了几种与R14序列重叠的肽用于预防，以及不同剂量的R14用于治疗，以确定致耐受性表位和葡萄膜炎最有效的治疗方案。用R14 - 完全弗氏佐剂免疫Lewis大鼠以诱导EAU。在免疫前（预防）或EAU发作后诱导口服耐受以预防复发（治疗）。用高剂量和/或低剂量的口服抗原进行治疗性喂食，以克隆清除效应细胞并诱导调节性T细胞。通过临床和组织学方法确定葡萄膜炎；检测耐受大鼠肠系膜淋巴结（mLN）细胞的表面标志物、细胞因子和Foxp3表达。预防性喂食R14及其主要表位R16，但没有一种重叠肽能显著抑制EAU，也能预防复发，无论其致病性如何。用R14进行治疗性喂食可显著减少复发，而只有连续喂食高剂量和低剂量的R14对疾病的第一个病程有改善作用。口服耐受后，mLN中产生IL - 10的T细胞减少，在体外R14刺激下，低剂量喂食组中TCRαβ + / Foxp3 +细胞群增加。在活动性自身免疫性葡萄膜炎期间，没有mLN细胞群可明确归因于成功的口服耐受诱导。
