Kozutsumi Daisuke, Tsunematsu Masako, Yamaji Taketo, Murakami Rika, Yokoyama Minehiko, Kino Kohsuke
Research and Development Section, Pharmaceuticals Development Department, Meiji Dairies Corporation, Kanagawa, Japan.
Immunology. 2006 Jul;118(3):392-401. doi: 10.1111/j.1365-2567.2006.02390.x.
Polysorbate 80 (PS80 or Tween-80) is often used as an additive to promote the rapid solubilization of pharmaceuticals in aqueous solutions. We investigated whether coinjection of a minimal amount of PS80 had a modulatory effect on the immunotherapeutic effects of Cry (Cryptomeria)-consensus peptide, a novel peptide developed for the therapeutic management of Japanese cedar pollinosis, using a Cry j 1-sensitized mouse model with experimental allergic rhinitis. Subcutaneous challenge with Cry-consensus peptide plus 50 microg/ml of PS80 did not affect the antigen-specific proliferation of splenocytes, but decreased the potency of Cry-consensus peptide to inhibit antigen-specific interleukin (IL)-5 production by the cells significantly in comparison with challenge with Cry-consensus peptide alone. However, there was no significant difference between the effect of Cry-consensus peptide administration on interferon (IFN)-gamma production in the presence and absence of PS80, indicating that PS80 interfered with the T helper 1 (Th1)-dominant T helper balance induced by Cry-consensus peptide challenge. Moreover, the increase in the level of antigen-specific immunoglobulin G2a (IgG2a) induced by Cry-consensus peptide challenge was inhibited slightly but unambiguously by PS80 coinjection. These in vitro experiments indicated that PS80 induces Th2-type differentiation of T helper cells through preferential inhibition of IFN-gamma expression relative to IL-5 expression in splenocytes in a concentration-dependent manner. In naïve mice, sensitization by Cry-consensus peptide with PS80 induced antigen-specific IL-5 production more potently than sensitization by Cry-consensus peptide alone, and when PS80 was added to bone marrow-derived dendritic cells, the endocytosis of fluorescence-labelled Cry-consensus peptide was dramatically inhibited in a concentration-dependent manner. Therefore, we conclude that PS80 has an immunomodulatory effect on the antigen-specific response resulting in a shift towards Th2 predominance with respect to the antigen recognition stage. Taken together, our findings suggest that PS80 might decrease the efficacy of Cry-consensus peptide through modulation of the efficiency of antigen endocytosis and/or of the direction of successive T helper cell differentiation.
聚山梨醇酯80(PS80或吐温80)常被用作添加剂,以促进药物在水溶液中的快速溶解。我们使用患有实验性变应性鼻炎的Cry j 1致敏小鼠模型,研究了注射极少量的PS80是否对Cry(柳杉)共有肽的免疫治疗效果具有调节作用,Cry共有肽是一种为治疗日本雪松花粉症而研发的新型肽。用Cry共有肽加50微克/毫升的PS80进行皮下激发,并不影响脾细胞的抗原特异性增殖,但与单独用Cry共有肽激发相比,显著降低了Cry共有肽抑制细胞产生抗原特异性白细胞介素(IL)-5的能力。然而,在有和没有PS80的情况下,Cry共有肽给药对干扰素(IFN)-γ产生的影响没有显著差异,这表明PS80干扰了Cry共有肽激发所诱导的以T辅助1(Th1)为主导的T辅助细胞平衡。此外,Cry共有肽激发所诱导的抗原特异性免疫球蛋白G2a(IgG2a)水平的升高,被同时注射PS80轻微但明确地抑制。这些体外实验表明,PS80以浓度依赖的方式,通过优先抑制脾细胞中相对于IL-5表达的IFN-γ表达,诱导T辅助细胞向Th2型分化。在未致敏小鼠中,用Cry共有肽与PS80致敏比单独用Cry共有肽致敏更有效地诱导抗原特异性IL-5产生,并且当将PS80添加到骨髓来源的树突状细胞中时,荧光标记的Cry共有肽的内吞作用以浓度依赖的方式被显著抑制。因此,我们得出结论,PS80对抗原特异性反应具有免疫调节作用,导致在抗原识别阶段向以Th2为主导转变。综上所述,我们的研究结果表明,PS80可能通过调节抗原内吞效率和/或连续T辅助细胞分化的方向,降低Cry共有肽的疗效。