Pharmazentrum Frankfurt/Zentrum für Arzneimittelforschung, Entwicklung und Sicherheit (ZAFES), Goethe University Hospital, Frankfurt am Main, Germany.
Front Endocrinol (Lausanne). 2020 Oct 19;11:591083. doi: 10.3389/fendo.2020.591083. eCollection 2020.
Type 1 diabetes (T1D) is mainly precipitated by the destruction of insulin-producing β-cells in the pancreatic islets of Langerhans by autoaggressive T cells. The etiology of the disease is still not clear, but besides genetic predisposition the exposure to environmental triggers seems to play a major role. Virus infection of islets has been demonstrated in biopsies of T1D patients, but there is still no firm proof that such an infection indeed results in islet-specific autoimmunity. However, virus infection results in a local inflammation with expression of inflammatory factors, such as cytokines and chemokines that attract and activate immune cells, including potential autoreactive T cells. Many chemokines have been found to be elevated in the serum and expressed by islet cells of T1D patients. In mouse models, it has been demonstrated that β-cells express chemokines involved in the initial recruitment of immune cells to the islets. The bulk load of chemokines is however released by the infiltrating immune cells that also express multiple chemokine receptors. The result is a mutual attraction of antigen-presenting cells and effector immune cells in the local islet microenvironment. Although there is a considerable redundancy within the chemokine ligand-receptor network, a few chemokines, such as CXCL10, seem to play a key role in the T1D pathogenesis. Studies with neutralizing antibodies and investigations in chemokine-deficient mice demonstrated that interfering with certain chemokine ligand-receptor axes might also ameliorate human T1D. However, one important aspect of such a treatment is the time of administration. Blockade of the recruitment of immune cells to the site of autoimmune destruction might not be effective when the disease process is already ongoing. By that time, autoaggressive cells have already arrived in the islet microenvironment and a blockade of migration might even hold them in place leading to accelerated destruction. Thus, an anti-chemokine therapy makes most sense in situations where the cells have not yet migrated to the islets. Such situations include treatment of patients at risk already carrying islet-antigen autoantibodies but are not yet diabetic, islet transplantation recipients, and patients that have undergone a T cell reset as occurring after anti-CD3 antibody treatment.
1 型糖尿病（T1D）主要是由胰岛自身反应性 T 细胞破坏胰岛中的胰岛素分泌β细胞引起的。该疾病的病因尚不清楚，但除了遗传易感性外，暴露于环境触发因素似乎也起着重要作用。胰岛病毒感染已在 T1D 患者的活检中得到证实，但尚无确凿证据表明这种感染确实会导致胰岛特异性自身免疫。然而，病毒感染会导致局部炎症，炎症会表达细胞因子和趋化因子等炎症因子，这些因子会吸引和激活免疫细胞，包括潜在的自身反应性 T 细胞。许多趋化因子已被发现存在于 T1D 患者的血清和胰岛细胞中表达。在小鼠模型中，已经证明β细胞表达参与最初将免疫细胞募集到胰岛的趋化因子。然而，大量趋化因子是由浸润的免疫细胞释放的，这些免疫细胞也表达多种趋化因子受体。结果是抗原呈递细胞和效应免疫细胞在局部胰岛微环境中相互吸引。尽管趋化因子配体-受体网络中有相当大的冗余，但少数趋化因子，如 CXCL10，似乎在 T1D 发病机制中发挥关键作用。用中和抗体进行的研究和趋化因子缺陷小鼠的研究表明，干扰某些趋化因子配体-受体轴也可能改善人类 T1D。然而，这种治疗的一个重要方面是给药时间。当疾病过程已经发生时，阻止免疫细胞向自身免疫破坏部位募集可能无效。此时，自身反应性细胞已经到达胰岛微环境，而迁移的阻断甚至可能使它们停留在原位，导致更快的破坏。因此，抗趋化因子疗法在细胞尚未迁移到胰岛的情况下最有意义。这种情况包括治疗已经携带胰岛抗原自身抗体但尚未患糖尿病的患者、胰岛移植受者，以及接受抗 CD3 抗体治疗后发生 T 细胞重置的患者。
