Treatment of. murine collagen-induced arthritis by the stress protein BiP via interleukin-4-producing regulatory T cells - A novel function for an ancient protein
Treatment of. murine collagen-induced arthritis by the stress protein BiP via interleukin-4-producing regulatory T cells - A novel function for an ancient protein
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DOI：
10.1002/art.21654
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发表时间：
2006-03-01
影响因子：
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通讯作者：
Thompson, SJ
中科院分区：
文献类型：
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作者：
Brownlie, RJ;Myers, LK;Thompson, SJ
Objective.在证明应激蛋白BiP在HILA-DRB*0101（+/+）（HLA-. DR 1（+/+））小鼠，研究BiP对HLA-DR 1（+/+）和DBA/1小鼠CIA活动期疾病的免疫抑制能力。在关节炎发作时，对DBA/1、HLA-DR 1 +/+或白细胞介素-4（IL-4）敲除小鼠皮下或静脉给予BiP。免疫细胞用于过继转移研究或在培养物中用BiP或II型胶原蛋白（CII）再刺激。测量增殖和细胞因子释放。此外，血清抗CII抗体测定酶联免疫吸附试验。采用视觉模拟量表对疾病进展进行评分。BiP成功地抑制了HLA-DR 1（+/+）和DBA/1小鼠中建立的CIA。BiP处理的小鼠血清抗胶原IgG抗体水平降低。来自BiP免疫小鼠的T细胞产生Th 2细胞因子，特别是IL-4。用BiP处理也显示在研究结束时增加CII特异性IL-5、IL-10和干扰素-γ的产生。通过在HLA-DR 1（+/+）小鼠中CIA诱导时静脉内转移BiP特异性细胞或在疾病发作时将BiP特异性细胞转移至DBA/1小鼠来预防严重CIA的发展。BiP对IL-4（-/-）、HLA-DR 1（+/+）小鼠CIA的发生发展无明显改善作用。这些新的结果表明，BiP可以通过诱导主要通过IL-4起作用的调节细胞来抑制活性CIA。因此，BiP是治疗类风湿关节炎患者的潜在免疫增强剂。
Objective. Following the demonstration that the stress protein, BiP, prevented induction of collagen-induced arthritis (CIA) in HILA-DRB*0101(+/+) (HLA-. DR1(+/+)) mice, we investigated the immunotherapeutic ability of BiP to suppress disease during the active phase of CIA in HLA-DR1(+/+) and DBA/1 mice.Methods. BiP was administered either subcutaneously or intravenously to DBA/1, HLA-DR1+/+, or interleukin-4 (IL-4)-knockout mice at the onset of arthritis. Immune cells were used in adoptive transfer studies or were restimulated in culture with BiP or type II collagen (CII). Proliferation and cytokine release were measured. In addition, serum anti-CII antibodies were measured by enzyme-linked immunosorbent assay. Disease progression was scored using a visual analog scale.Results. BiP was successful in suppressing established CIA in HLA-DR1(+/+) and DBA/1 mice. Serum levels of anticollagen IgG antibodies were reduced in BiP-treated mice. T cells from BiP-immunized mice produced Th2 cytokines, in particular, IL-4. Treatment with BiP was also shown to increase the production of CII-specific IL-5, IL-10, and interferon-gamma at the termination of the study. Development of severe CIA was prevented by the intravenous transfer of BiP-specific cells at the time of CIA induction in HLA-DR1(+/+) mice or by transferring BiP-specific cells to DBA/1 mice at the onset of disease. BiP failed to ameliorate the development of CIA in IL-4(-/-), HLA-DR1(+/+) mice.Conclusion. These novel results show that BiP can suppress active CIA by the induction of regulatory cells that act predominantly via IL-4. Thus, BiP is a potential immunotherapeutic agent for the treatment of patients with rheumatoid arthritis.