de Vries J E, Yssel H
Human Immunology Dept, DNAX Research Institute for Molecular and Cellular Biology, Palo Alto, CA, USA.
Eur Respir J Suppl. 1996 Aug;22:58s-62s.
Studies on the immunological basis of allergic diseases have indicated that enhanced production of the cytokines interleukin (IL)-4 and IL-13 and the reduced production of interferon-gamma (IFN-gamma) by allergen-specific T-cells contribute to enhanced immunoglobulin E (IgE) synthesis and the development of allergic disease in certain individuals. Therefore, inhibition of IL-4 and IL-13 synthesis or blocking of activities of these cytokines would be one approach to inhibiting IgE production. In the present communication, novel approaches toward this goal are discussed. It is shown that an IL-4 mutant protein, in which the tyrosine residue at position 124 is replaced by aspartic acid (IL-4,Y124D), binds with high affinity to the IL-4 receptor, without receptor activation. IL-4,Y124D acts as a potent antagonist both of IL-4 and IL-13 activity in vitro, and inhibits immunoglobulin G4 (IgG4) and IgE production induced by these cytokines. These data are compatible with the notion that the IL-4 and IL-13 receptors are complex receptors, which share a common component, which is required for signal transduction. In addition, it has been demonstrated that allergen-specific T-cells, belonging to the T-helper 2 (Th2) subset can be rendered anergic after incubation with allergen-derived peptides representing minimal T-cell activation inducing epitopes. These anergic Th2 cells failed to produce IL-4 and IL-13, and failed to proliferate after activation with allergen and antigen-presenting cells (APC). The anergized T cells also failed to give B-cells help in IgE synthesis, although they expressed normal levels of the CD40 ligand (CD40L). Exogenous IL-4 and IL-13 failed to restore IgE synthesis, indicating that in addition to CD40L other co-stimulatory signals are required for productive T-cell/B-cell interactions, resulting in IgE synthesis. IgE production was restored by exogenous IL-2, demonstrating that IL-2 reverses the nonresponsive state and helper function of these nonresponsive T-cells. It is tempting to speculate that induction of T-cell nonresponsiveness by allergen-derived peptides may represent the underlying mechanisms for successful immunotherapy in allergenic patients.
对过敏性疾病免疫基础的研究表明，变应原特异性T细胞中细胞因子白细胞介素（IL）-4和IL-13的产生增加以及干扰素-γ（IFN-γ）的产生减少，在某些个体中会导致免疫球蛋白E（IgE）合成增加和过敏性疾病的发展。因此，抑制IL-4和IL-13的合成或阻断这些细胞因子的活性将是抑制IgE产生的一种方法。在本通讯中，讨论了实现这一目标的新方法。结果表明，一种IL-4突变蛋白，其中第124位的酪氨酸残基被天冬氨酸取代（IL-4，Y124D），能以高亲和力与IL-4受体结合，而不激活受体。IL-4，Y124D在体外作为IL-4和IL-13活性的有效拮抗剂，并抑制由这些细胞因子诱导的免疫球蛋白G4（IgG4）和IgE的产生。这些数据与IL-4和IL-13受体是复合受体的观点一致，它们共享一个信号转导所需的共同成分。此外，已经证明，属于辅助性T细胞2（Th2）亚群的变应原特异性T细胞在与代表最小T细胞激活诱导表位的变应原衍生肽孵育后可变为无反应状态。这些无反应的Th2细胞不能产生IL-4和IL-13，在用变应原和抗原呈递细胞（APC）激活后也不能增殖。无反应的T细胞在IgE合成中也不能为B细胞提供帮助，尽管它们表达正常水平的CD40配体（CD40L）。外源性IL-4和IL-13不能恢复IgE合成，这表明除了CD40L外，有效的T细胞/B细胞相互作用还需要其他共刺激信号，从而导致IgE合成。外源性IL-2可恢复IgE合成，这表明IL-2可逆转这些无反应T细胞的无反应状态和辅助功能。很容易推测，变应原衍生肽诱导T细胞无反应性可能代表了变应性疾病患者成功免疫治疗的潜在机制。
