抗胸腺基质淋巴细胞生成素治疗在2型炎症通路相关疾病的应用及展望

Anti-thymic stromal lymphopoietin therapy in type 2 inflammatory pathway-related diseases:Applications and perspectives

胸腺基质淋巴细胞生成素(TSLP)是IL-7家族成员,有两种亚型,长亚型(lfTSLP)作用于2型炎症通路上游,参与过敏性疾病级联反应,短亚型(sfTSLP)则起到维持稳态作用。长短两亚型还在炎症性肠病、肿瘤等疾病中发挥不同作用。TSLP单克隆抗体特泽鲁单抗被FDA批准用于中重度药物控制不良哮喘患者的附加治疗,临床试验证明特泽鲁单抗不仅针对2型炎症型哮喘,对其他表型的哮喘也有效,且有望应用于其他2型炎症相关疾病,如特应性皮炎的治疗。抗TSLP疗法在其他疾病的应用也正在开发中。目前大多数针对TSLP的药物研究并未区分lfTSLP和sfTSLP,理想状态下,用于中和TSLP的单克隆抗体不应相互作用或阻碍sfTSLP的稳态作用。此外,TSLP的不同亚型在肿瘤和自身免疫性疾病中的作用及机制尚存在争议。目前仍需要更多研究阐明TSLP对免疫系统的影响,并探讨如何拓宽抗TSLP临床应用和抗TSLP治疗潜在的不良反应。

Thymic stromal lymphopoietin(TSLP)is a member of interleukin-17(IL-7)family,which owns two isoforms.The long isoform TSLP(lfTSLP)targets upstream pathway of type 2 inflammatory,contributing to cascade reaction of allergy diseases;whereas the short isoform TSLP(sfTSLP)contributes to maintaining homeostasis.Additionally,long and short isoforms demonstrate diverse functions under different conditions such as tumors and inflammatory bowel disease(IBD).Tezepelumab,a monoclonal antibody to TSLP had been approved by FDA as an adjunctive therapy for patients with moderate to severe uncontrolled asthma.Results of clinical trials demonstrated that tezepelumab was of benefit not only for type 2 inflammatory asthma but also for other phenotypes of asthma.Tezepelumab is also expected to be applied in treatment of the other type 2 inflammation-related diseases such as atopic dermatitis.Anti-TSLP therapies are also being developed for treatment of non-allergic diseases such as tumors and autoimmune diseases.Ideal anti-TSLP antibodies should not interact with or hinder the role sfTSLP in homeostasis,whereas majority of current studies on TSLP were not lfTSLP or sfTSLP specific.Additionally,it is still controversialin function and mechanisms of various TSLP isoforms in tumors and autoimmune diseases.Further investigation should be done to explore the role of TSLP in immune system and to expand our knowledge of clinical use and potential side effects of anti-TSLP therapy.