Enhanced efficacy of regulatory T cell transfer against increasing resistance, by elevated foxp3 expression induced in arthritic murine hosts
Enhanced efficacy of regulatory T cell transfer against increasing resistance, by elevated foxp3 expression induced in arthritic murine hosts
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DOI：
10.1002/art.22846
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发表时间：
2007-09-01
影响因子：
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通讯作者：
Kohsaka, Hitoshi
中科院分区：
文献类型：
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作者：
Ohata, Junko;Miura, Tomoko;Kohsaka, Hitoshi
Objective.研究II型胶原反应性Foxp3表达T细胞转移在抑制与疾病进展相关的胶原诱导性关节炎（CIA）中的功效。用Foxp3基因逆转录病毒转导CD3活化的CD4 T细胞，并评估其对T细胞增殖的体外抑制活性与Foxp3水平的相关性。为了抑制CIA，将Foxp3转导的T细胞与II型胶原或卵清蛋白（OVA）脉冲的树突状细胞（DC）在不同时间点过继转移到小鼠体内。Foxp3转导细胞的体外抑制活性与Foxp3水平正相关。II型胶原蛋白反应性，但不OVA反应性，Foxp3转导细胞显着抑制CIA时，他们被转移免疫前，这种抑制伴随着减少抗II型胶原蛋白抗体的产生。当免疫后20天发生转移时，需要较大的细胞数量来抑制CIA，这表明宿主对抑制产生了抗性。转移1X 10（5）Foxp（3低）细胞对免疫宿主中的CIA抑制作用仅具有轻微影响，而转移较小剂量的Foxp（3高）细胞可显着抑制CIA。关节炎建立后移植I X 10（5）Foxp（3high）细胞可减缓疾病进展，但不能逆转关节肿胀。对Foxp3转导的T细胞的抵抗随着CIA的进展而进行，这表明晚期侵袭性关节炎对调节性T细胞转移更具抵抗力。Foxp3在II型胶原特异性T细胞中的表达水平升高改善了其在CIA中的抑制功能。因此，转移表达高水平Foxp3的T细胞可能是克服对调节性T细胞疗法的诱导抗性的策略。
Objective. To investigate the efficacy of type II collagen-reactive Foxp3-expressing T cell transfer in suppressing collagen-induced arthritis (CIA) in relation to disease progression.Methods. CD3-activated CD4 T cells were retro-virally transduced with the Foxp3 gene, and their in vitro suppressive activity on T cell proliferation was assessed for correlation with Foxp3 levels. To suppress CIA, Foxp3-transduced T cells generated with type II collagen- or ovalbumin (OVA)-pulsed dendritic cells (DCs), which were fractionated by Foxp3 levels, were adoptively transferred to mice at various time points.Results. The in vitro suppressive activity of Foxp3-transduced cells correlated positively with Foxp3 levels. Type II collagen-reactive, but not OVA-reactive, Foxp3-transduced cells significantly suppressed CIA when they were transferred before immunization, and this suppression was accompanied by decreased anti-type II collagen antibody production. Larger cell numbers were required to suppress CIA when transfer occurred 20 days after immunization, indicating that hosts became resistant to suppression. Transfer of I X 10(5) Foxp(3low) cells had only a marginal effect on CIA suppression in immunized hosts, while transfer of Foxp(3high) cells at smaller doses significantly suppressed CIA. Transfer of I X 10(5) Foxp(3high) cells after establishment of arthritis attenuated disease progression but did not reverse joint swelling.Conclusion. Resistance to Foxp3-transduced T cells proceeded as CIA progressed, suggesting that late-stage aggressive arthritis is more resistant to regulatory T cell transfer. An elevated expression level of Foxp3 in type II collagen-specific T cells improved their suppressive function in CIA. Thus, transfer of T cells expressing high levels of Foxp3 could be a strategy to overcome the induced resistance to regulatory T cell therapy.