Veneziani Irene, Landolina Nadine, Ricci Biancamaria, Rossi Oliviero, Moretta Lorenzo, Maggi Enrico
Department of Immunology, Bambino Gesù Children's Hospital, IRCCS, 00146 Rome, Italy.
Immunoallergology Unit, University Hospital of Careggi, 50100 Florence, Italy.
Biomedicines. 2022 Nov 5;10(11):2825. doi: 10.3390/biomedicines10112825.
IgE-mediated diseases represent a highly diversified and multifactorial group of disorders that can deeply impact the patients' quality of life. Currently, allergy immunotherapy (AIT) still remains the gold standard for the management of such pathologies. In this review, we comprehensively examine and discuss how AIT can affect both the innate and the adaptive immune responses at different cell levels and propose timing-scheduled alterations induced by AIT by hypothesizing five sequential phases: after the desensitization of effector non-lymphoid cells and a transient increase of IgE (phase 1), high doses of allergen given by AIT stimulate the shift from type 2/type 3 towards type 1 response (phase 2), which is progressively potentiated by the increase of IFN-γ that promotes the chronic activation of APCs, progressively leading to the hyperexpression of Notch1L (Delta4) and the secretion of IL-12 and IL-27, which are essential to activate IL-10 gene in Th1 and ILC1 cells. As consequence, an expansion of circulating memory Th1/Tr1 cells and ILC-reg characterizes the third phase addressed to antagonize/balance the excess of type 1 response (phase 3). The progressive increase of IL-10 triggers a number of regulatory circuits sustained by innate and adaptive immune cells and favoring T-cell tolerance (phase 4), which may also be maintained for a long period after AIT interruption (phase 5). Different administration approaches of AIT have shown a similar tailoring of the immune responses and can be monitored by timely, optimized biomarkers. The clinical failure of this treatment can occur, and many genetic/epigenetic polymorphisms/mutations involving several immunological mechanisms, such as the plasticity of immune responses and the induction/maintenance of regulatory circuits, have been described. The knowledge of how AIT can shape the immune system and its responses is a key tool to develop novel AIT strategies including the engineering of allergen or their epitopes. We now have the potential to understand the precise causes of AIT failure and to establish the best biomarkers of AIT efficacy in each phase of the treatment.
IgE介导的疾病是一组高度多样化且多因素的病症，会对患者的生活质量产生深远影响。目前，过敏免疫疗法（AIT）仍是此类病症管理的金标准。在本综述中，我们全面研究并讨论了AIT如何在不同细胞水平上影响先天性和适应性免疫反应，并通过假设五个连续阶段提出AIT诱导的时间安排改变：在效应非淋巴细胞脱敏和IgE短暂增加后（阶段1），AIT给予的高剂量变应原刺激从2型/3型反应向1型反应转变（阶段2），这一转变因促进APC慢性激活的IFN-γ增加而逐渐增强，进而逐渐导致Notch1L（Delta4）的过度表达以及IL-12和IL-27的分泌，这对于激活Th1和ILC1细胞中的IL-10基因至关重要。因此，循环记忆性Th1/Tr1细胞和ILC调节细胞的扩增是针对拮抗/平衡1型反应过量的第三阶段（阶段3）的特征。IL-10的逐渐增加触发了由先天性和适应性免疫细胞维持的一些调节回路，并有利于T细胞耐受（阶段4），这在AIT中断后也可能长期维持（阶段5）。不同的AIT给药方法已显示出对免疫反应的类似调整，并且可以通过及时、优化的生物标志物进行监测。这种治疗可能会出现临床失败，并且已经描述了许多涉及多种免疫机制的遗传/表观遗传多态性/突变，例如免疫反应的可塑性以及调节回路的诱导/维持。了解AIT如何塑造免疫系统及其反应是开发新型AIT策略（包括变应原或其表位工程）的关键工具。我们现在有潜力了解AIT失败的确切原因，并确定治疗各阶段中AIT疗效的最佳生物标志物。
