Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
J Immunol. 2011 Nov 15;187(10):5090-8. doi: 10.4049/jimmunol.1100608. Epub 2011 Oct 5.
Allergic diseases, including asthma and food allergies, are an increasing health concern. Immunotherapy is an effective therapeutic approach for many allergic diseases but requires long dose escalation periods and has a high risk of adverse reactions, particularly in food allergy. New methods to safely induce Ag-specific tolerance could improve the clinical approach to allergic disease. We hypothesized that Ag-specific tolerance induced by the i.v. injection of Ags attached to the surface of syngeneic splenic leukocytes (Ag-coupled splenocytes [Ag-SPs]) with the chemical cross-linking agent ethylene-carbodiimide, which effectively modulate Th1/Th17 diseases, may also safely and efficiently induce tolerance in Th2-mediated mouse models of allergic asthma and food allergy. Mice were tolerized with Ag-SP before or after initiation of OVA/alum-induced allergic airway inflammation or peanut-induced food allergy. The effects on disease pathology and Th2-directed cytokine and Ab responses were studied. Ag-SP tolerance prevented disease development in both models and safely tolerized T cell responses in an Ag-specific manner in presensitized animals. Prophylactically, Ag-SP efficiently decreased local and systemic Th2 responses, eosinophilia, and Ag-specific IgE. Interestingly, Ag-SP induced Th2 tolerance was found to be partially dependent on the function of CD25(+) regulatory T cells in the food allergy model, but was regulatory T cell independent in the model of allergic airway inflammation. We demonstrate that Ag-SP tolerance can be rapidly, safely, and efficiently induced in murine models of allergic disease, highlighting a potential new Ag-specific tolerance immunotherapy for Th2-associated allergic diseases.
变应性疾病，包括哮喘和食物过敏，是一个日益严重的健康问题。免疫疗法是许多变应性疾病的有效治疗方法，但需要长时间的剂量递增期，并且具有很高的不良反应风险，尤其是在食物过敏中。安全诱导 Ag 特异性耐受的新方法可以改善变应性疾病的临床治疗方法。我们假设通过将 Ag 附着在同种脾白细胞（Ag 偶联脾细胞 [Ag-SP]）表面并用化学交联剂乙二醛二胺处理，静脉注射 Ag 可有效调节 Th1/Th17 疾病，也可以安全有效地诱导 Th2 介导的变应性哮喘和食物过敏的小鼠模型中的耐受。在 OVA/明矾诱导的过敏性气道炎症或花生诱导的食物过敏开始之前或之后，用 Ag-SP 对小鼠进行耐受。研究了对疾病病理和 Th2 定向细胞因子和 Ab 反应的影响。Ag-SP 耐受可预防两种模型中的疾病发展，并以 Ag 特异性的方式安全耐受致敏动物的 T 细胞反应。预防性地，Ag-SP 有效地降低了局部和全身 Th2 反应、嗜酸性粒细胞增多和 Ag 特异性 IgE。有趣的是，发现 Ag-SP 诱导的 Th2 耐受部分依赖于食物过敏模型中 CD25(+)调节性 T 细胞的功能，但在过敏性气道炎症模型中，调节性 T 细胞不依赖。我们证明了 Ag-SP 耐受可以在变应性疾病的小鼠模型中快速、安全、有效地诱导，突出了一种针对 Th2 相关变应性疾病的潜在新型 Ag 特异性耐受免疫疗法。
