Laboratory of Allergology and Pulmonary Diseases, Department of Pathology and Medical Biology, University Medical Center Groningen (UMCG), GRIAC Research Institute, University of Groningen, Groningen, the Netherlands.
Clin Exp Immunol. 2013 Apr;172(1):113-20. doi: 10.1111/cei.12041.
Allergen-specific immunotherapy (SIT) is the only treatment for allergic diseases that targets allergen-specific T helper type 2 (Th2) cells, which are the cause of the disease. There is an unmet requirement for adjuvants that increase the clinical efficacy of SIT allowing application of lower doses of the allergen, thereby reducing the risk of anaphylactic reactions. Cytotoxic T lymphocyte antigen 4-immunoglobulin (CTLA-4-Ig) has been shown to induce immunological tolerance in autoimmunity and allograft transplantation by blocking T cell co-stimulation and induction of the immunoregulatory enzyme indoleamine 2,3 dioxygenase (IDO). Previously, we showed that CTLA-4-Ig treatment at the time of allergen inhalation induced tolerance to subsequent allergen exposure in a mouse model of asthma. In this study, we test the hypothesis that CTLA-4-Ig acts as an adjuvant for experimental SIT. We evaluated the adjuvant effects of CTLA-4-Ig on SIT in a mouse model of ovalbumin-driven asthma. We used both wild-type and IDO-deficient mice to assess the role of IDO in the adjuvant effects of CTLA-4-Ig. Co-administration of CTLA-4-Ig strongly increased SIT-induced suppression of airway hyperreactivity (AHR), specific IgE in serum, airway eosinophilia and Th2 cytokine levels. Moreover, we found that CTLA-4-Ig, as an adjuvant for SIT, is equally effective in IDO-deficient and wild-type mice, demonstrating that the effect of CTLA-4-Ig is independent of IDO expression. We show that CTLA-4-Ig acts as a potent adjuvant to augment the therapeutic effects of SIT. As the adjuvant activity of CTLA-4-Ig is independent of IDO, we conclude that it acts by blocking CD28-mediated T cell co-stimulation.
变应原特异性免疫疗法（SIT）是唯一针对变应原特异性 T 辅助细胞 2（Th2）的治疗方法，而 Th2 细胞是疾病的病因。目前需要佐剂来提高 SIT 的临床疗效，使能够应用较低剂量的变应原，从而降低过敏反应的风险，但仍存在未满足的需求。细胞毒性 T 淋巴细胞相关抗原 4-免疫球蛋白（CTLA-4-Ig）已被证明通过阻断 T 细胞共刺激和诱导免疫调节酶吲哚胺 2,3 双加氧酶（IDO）来诱导自身免疫和同种异体移植中的免疫耐受。此前，我们表明 CTLA-4-Ig 在变应原吸入时的治疗可诱导哮喘小鼠模型中随后的变应原暴露的耐受。在这项研究中，我们检验了 CTLA-4-Ig 作为实验性 SIT 佐剂的假说。我们在卵清蛋白驱动的哮喘小鼠模型中评估了 CTLA-4-Ig 对 SIT 的佐剂作用。我们使用野生型和 IDO 缺陷型小鼠来评估 IDO 在 CTLA-4-Ig 的佐剂作用中的作用。CTLA-4-Ig 的共同给药强烈增加了 SIT 诱导的气道高反应性（AHR）、血清特异性 IgE、气道嗜酸性粒细胞和 Th2 细胞因子水平的抑制。此外，我们发现 CTLA-4-Ig 作为 SIT 的佐剂，在 IDO 缺陷型和野生型小鼠中同样有效，表明 CTLA-4-Ig 的作用独立于 IDO 表达。我们表明 CTLA-4-Ig 作为一种有效的佐剂，增强了 SIT 的治疗效果。由于 CTLA-4-Ig 的佐剂活性独立于 IDO，我们得出结论，它通过阻断 CD28 介导的 T 细胞共刺激起作用。
