Swiss Hepato-Pancreato-Biliary Centre, Visceral and Transplantation Surgery, University Hospital Zurich, 8091 Zurich, Switzerland;
Swiss Hepato-Pancreato-Biliary Centre, Visceral and Transplantation Surgery, University Hospital Zurich, 8091 Zurich, Switzerland.
Immunohorizons. 2020 Nov 5;4(11):688-700. doi: 10.4049/immunohorizons.2000079.
Autoimmune pancreatitis (AIP) is a rare form of chronic pancreatitis, for which treatment options, especially the long-term management, are limited. The only therapy that has been established and accepted so far is corticosteroids, but the relapse rate is significant. In the current study, we discern the effector mechanisms of targeted LTβR pathway inhibition using LTβR-Ig. Furthermore, the efficacy of LTβR-Ig therapy is compared with the depletion of immune cell subsets (CD4 and CD20), which are suggested to play a pathological role in AIP development. Three well-established mouse models of AIP were used to examine treatment efficacies and mechanisms. (Ela1-Lta,b) mice represent a genetic model, in which AIP develops spontaneously. In MRL/Mp and IL-10 mice, AIP is induced by repeated polyinosinic:polycytidylic acid injection. Mice with AIP were treated with anti-CD20, anti-CD4 mAbs, or targeted LTβR-Ig. LTβR-Ig and anti-CD20 treatment led to significant improvement of AIP, including a decrease in autoantibody production and pancreatic inflammation in (Ela1-Lta,b) and IL-10 mice. The molecular mechanism of this beneficial effect possibly involves the downregulation of Stat3 and noncanonical NF-κb activation. Anti-CD4 treatment reduced Th1 and Th2 signature but did not alleviate AIP. Additionally, in contrast to anti-CD20 or anti-CD4 treatments, blocking LTβR signaling disrupted tertiary lymphoid organs in all three models. We demonstrate that treatment with LTβR-Ig or anti-CD20 Ab alleviated murine AIP. LTβR-Ig treatment for AIP was effective in both lymphotoxin-dependent and lymphotoxin-independent AIP models, possibly because of its dual anti-inflammatory and antiautoimmune mechanisms.
自身免疫性胰腺炎(AIP)是一种罕见的慢性胰腺炎,其治疗选择,特别是长期管理,受到限制。迄今为止,唯一被确立并被接受的治疗方法是皮质类固醇,但复发率很高。在本研究中,我们使用 LTβR-Ig 来辨别靶向 LTβR 通路抑制的效应机制。此外,将 LTβR-Ig 治疗的疗效与免疫细胞亚群(CD4 和 CD20)耗竭进行比较,这些亚群被认为在 AIP 发展中起病理作用。使用三种已建立的 AIP 小鼠模型来检查治疗效果和机制。(Ela1-Lta,b) 小鼠代表一种遗传模型,其中 AIP 自发发展。在 MRL/Mp 和 IL-10 小鼠中,AIP 是通过反复注射多聚肌苷酸:多聚胞苷酸诱导的。用抗 CD20、抗 CD4 mAb 或靶向 LTβR-Ig 治疗 AIP 小鼠。LTβR-Ig 和抗 CD20 治疗导致 AIP 显著改善,包括在(Ela1-Lta,b)和 IL-10 小鼠中减少自身抗体产生和胰腺炎症。这种有益效果的分子机制可能涉及 Stat3 的下调和非经典 NF-κb 激活。抗 CD4 治疗减少了 Th1 和 Th2 特征,但不能缓解 AIP。此外,与抗 CD20 或抗 CD4 治疗相比,阻断 LTβR 信号传导破坏了所有三种模型中的三级淋巴器官。我们证明 LTβR-Ig 或抗 CD20 Ab 治疗可缓解小鼠 AIP。LTβR-Ig 治疗 AIP 在依赖和不依赖淋巴毒素的 AIP 模型中均有效,可能是因为其具有双重抗炎和抗自身免疫机制。