通过经鼻给予关节炎相关热休克蛋白60 T细胞表位的肽类似物诱导的白细胞介素-10驱动的调节性细胞对佐剂诱导的关节炎的抑制作用。

Inhibition of adjuvant-induced arthritis by interleukin-10-driven regulatory cells induced via nasal administration of a peptide analog of an arthritis-related heat-shock protein 60 T cell epitope.

作者信息

Prakken Berent J, Roord Sarah, van Kooten Peter J S, Wagenaar Josée P A, van Eden Willem, Albani Salvatore, Wauben Marca H M

机构信息

University of California San Diego, La Jolla, California, USA.

出版信息

Arthritis Rheum. 2002 Jul;46(7):1937-46. doi: 10.1002/art.10366.

DOI:10.1002/art.10366

PMID:12124879

Abstract

OBJECTIVE

To prevent and treat experimental arthritis via nasal administration of an altered peptide ligand (APL) from the major arthritogenic epitope in adjuvant-induced arthritis (AIA) and to explore the mechanisms involved.

METHODS

Peptides were administered nasally before and after induction of arthritis. Splenocytes and lymph node cells draining both the site of inflammation and the site of tolerance induction were used for cell transfer and were studied for antigen-specific T cell characteristics. In addition, attempts were made to stop T cell tolerance in vitro, using anticytokine antibodies.

RESULTS

Nasal administration of a modulatory APL of the heat-shock protein 60 (Hsp60) 180-188 T cell epitope, alanine 183, had a suppressive effect in AIA that far exceeded that of the wild-type epitope. In addition to its effectiveness in preventing AIA, alanine 183 may be effective in the treatment of ongoing AIA. The protective effect of alanine 183 can be passively transferred using activated splenocytes. Nasal administration of alanine 183 did not lead to detectable T cell proliferation or interleukin-2 (IL-2) production in mandibular lymph node cells, while transforming growth factor beta (TGF beta), IL-10, and IL-4 were readily produced. Likewise, after nasally induced tolerance, followed by induction of arthritis, inguinal lymph node cells produced IL-4, TGF beta, and IL-10. After neutralizing in vitro the individual cytokines with anticytokine antibodies, only blocking of IL-10 production led to reversal of tolerance, at the site of tolerance induction and the site of inflammation.

CONCLUSION

Nasal administration of an APL of Hsp60 180-188 induces highly effective protection against AIA through generation of regulatory cells that produce IL-4, TGF beta, and IL-10, whereas the induced tolerance is driven mainly by production of IL-10.

摘要

目的

通过鼻腔给予佐剂性关节炎（AIA）中主要致关节炎表位的变构肽配体（APL）来预防和治疗实验性关节炎，并探讨其相关机制。

方法

在关节炎诱导前后经鼻腔给予肽。引流炎症部位和耐受诱导部位的脾细胞和淋巴结细胞用于细胞转移，并研究其抗原特异性T细胞特征。此外，尝试使用抗细胞因子抗体在体外终止T细胞耐受。

结果

经鼻腔给予热休克蛋白60（Hsp60）180 - 188 T细胞表位丙氨酸183的调节性APL，对AIA具有抑制作用，其效果远超过野生型表位。除了预防AIA有效外，丙氨酸183对正在发生的AIA治疗也可能有效。丙氨酸183的保护作用可通过活化的脾细胞被动转移。经鼻腔给予丙氨酸183不会导致下颌淋巴结细胞中可检测到的T细胞增殖或白细胞介素-2（IL - 2）产生，而转化生长因子β（TGFβ）、IL - 10和IL - 4则很容易产生。同样，经鼻腔诱导耐受后再诱导关节炎，腹股沟淋巴结细胞会产生IL - 4、TGFβ和IL - 10。在体外使用抗细胞因子抗体中和单个细胞因子后，只有阻断IL - 10的产生会导致在耐受诱导部位和炎症部位的耐受逆转。