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Mechanism(s) of prolonged attenuation of allergic responses after modulation of idiotypic regulatory network.
Allergy, Asthma & Clinical Immunology ( IF 2.6 ) Pub Date : 2019-12-04 , DOI: 10.1186/s13223-019-0393-7
R M Gorczynski 1, 2, 3 , T Maqbool 4 , G Hoffmann 2
Affiliation  

Background We showed previously that allergic reactivity to ovalbumin (OVA) could be regulated in mice following perturbation of immune networks using combinations of an immune Ig along with anti-idiotypic Ig. We have explored features of this regulation including: its persistence after cessation of administration of combined Igs; the ability of heterologous Igs to produce immunoregulation; a role for Treg induction in regulation; and the ability to attenuate responses in mice pre-sensitized to an allergic stimulus. Methods BALB/c mice were sensitized to OVA. Mice also received 5 weekly injections of immune Ig or anti-idiotype Ig (at separate sites) from either homologous (mouse) or heterologous (human) sources. In the latter case pooled IVIG (given IM, hence hereafter IMIG) was used as a source of anti-idiotype Ig, and human anti-Tet as immune Ig. Injections of the Ig were given from the time of OVA sensitization (to attenuate development of immunity), or after pre-sensitization of mice (to attenuate existing allergic responses). All mice were assayed for development of OVA-specific serum IgE and IgG, as well as the production of OVA-induced IL-2, IL-4, IL-13, IL-31 and IL-33 in splenocytes cultured for 72 h. In studies examining possible mechanism(s) responsible for inhibition of immunity mice received, in addition to the Ig treatments described, infusion of depleting anti-CD4, and/or anti-CD8 antibodies, or a mAb to TNFSFR25, known to expand Tregs implicated in regulation of Allo immunity. Results Combinations of both heterologous and homologous immune Igs and anti-idiotype Igs attenuated OVA allergic responses in both naïve and pre-sensitized mice. This attenuation persisted in mice greater than 14 weeks after cessation of treatment with the Igs used. Finally, depletion of either CD4 or CD8 cells ameliorated the suppressive effect seen, while the combination of anti-CD4 and anti-CD8 essentially abolished suppression. Suppression was further enhanced by anti-TNFSFR25 mAb. Conclusions We conclude that the combine Ig treatment protocols used produced a long-lasting suppression of allergic immunity, even in pre-sensitized animals. The effects seem to depend upon induction and expansion of Tregs and represents a novel approach to treatment of allergic disease in humans and other animals.

中文翻译:

调节独特型调节网络后过敏反应延长减弱的机制。

背景我们之前表明,使用免疫 Ig 和抗独特型 Ig 的组合,可以在免疫网络扰动后在小鼠中调节对卵白蛋白 (OVA) 的过敏反应。我们探索了该法规的特点,包括:停止联合 Igs 给药后的持续性;异源 Igs 产生免疫调节的能力;Treg 诱导在调节中的作用;以及减弱对过敏刺激预敏的小鼠的反应的能力。方法 BALB/c小鼠对OVA致敏。小鼠还接受来自同源(小鼠)或异源(人)来源的免疫 Ig 或抗独特型 Ig(在不同部位)每周注射 5 次。在后一种情况下,合并的 IVIG(给定 IM,因此以下称为 IMIG)用作抗独特型 Ig 的来源,和人类抗 Tet 作为免疫 Ig。Ig 的注射从 OVA 致敏时开始(以减弱免疫的发展),或在小鼠预致敏后(以减弱现有的过敏反应)。测定所有小鼠在培养 72 小时的脾细胞中 OVA 特异性血清 IgE 和 IgG 的发展,以及 OVA 诱导的 IL-2、IL-4、IL-13、IL-31 和 IL-33 的产生。在检查抑制免疫的可能机制的研究中,除了所描述的 Ig 治疗外,小鼠还接受了输注消耗性抗 CD4 和/或抗 CD8 抗体或 TNFSFR25 的 mAb,已知可扩展 Tregs在 Allo 免疫调节中。结果 异源和同源免疫 Igs 和抗独特型 Igs 的组合减弱了幼稚和预致敏小鼠的 OVA 过敏反应。在停止用所用 Igs 治疗后,这种衰减在小鼠中持续超过 14 周。最后,CD4 或 CD8 细胞的消耗改善了所见的抑制作用,而抗 CD4 和抗 CD8 的组合基本上消除了抑制。抗 TNFSFR25 mAb 进一步增强了抑制作用。结论 我们得出结论,使用的联合 Ig 治疗方案产生了对过敏性免疫的长期抑制,即使在预致敏动物中也是如此。效果似乎取决于 Treg 的诱导和扩增,代表了一种治疗人类和其他动物过敏性疾病的新方法。而抗CD4和抗CD8的组合基本上消除了抑制。抗 TNFSFR25 mAb 进一步增强了抑制作用。结论 我们得出结论,使用的联合 Ig 治疗方案产生了对过敏性免疫的长期抑制,即使在预致敏动物中也是如此。效果似乎取决于 Treg 的诱导和扩增,代表了一种治疗人类和其他动物过敏性疾病的新方法。而抗CD4和抗CD8的组合基本上消除了抑制。抗 TNFSFR25 mAb 进一步增强了抑制作用。结论 我们得出结论,使用的联合 Ig 治疗方案产生了对过敏性免疫的长期抑制,即使在预致敏动物中也是如此。效果似乎取决于 Treg 的诱导和扩增,代表了一种治疗人类和其他动物过敏性疾病的新方法。
更新日期:2020-04-22
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