Kaminitz Ayelet, Ash Shifra, Askenasy Nadir
The Leah and Edward M. Frankel Laboratory of Experimental Bone Marrow Transplantation, 14 Kaplan Street, Petach Tikva, Israel, 49202.
Clin Rev Allergy Immunol. 2017 Jun;52(3):460-472. doi: 10.1007/s12016-016-8587-y.
As physiological pathways of intercellular communication produced by all cells, cytokines are involved in the pathogenesis of inflammatory insulitis as well as pivotal mediators of immune homeostasis. Proinflammatory cytokines including interleukins, interferons, transforming growth factor-β, tumor necrosis factor-α, and nitric oxide promote destructive insulitis in type 1 diabetes through amplification of the autoimmune reaction, direct toxicity to β-cells, and sensitization of islets to apoptosis. The concept that neutralization of cytokines may be of therapeutic benefit has been tested in few clinical studies, which fell short of inducing sustained remission or achieving disease arrest. Therapeutic failure is explained by the redundant activities of individual cytokines and their combinations, which are rather dispensable in the process of destructive insulitis because other cytolytic pathways efficiently compensate their deficiency. Proinflammatory cytokines are less redundant in regulation of the inflammatory reaction, displaying protective effects through restriction of effector cell activity, reinforcement of suppressor cell function, and participation in islet recovery from injury. Our analysis suggests that the role of cytokines in immune homeostasis overrides their contribution to β-cell death and may be used as potent immunomodulatory agents for therapeutic purposes rather than neutralized.
作为所有细胞产生的细胞间通讯的生理途径，细胞因子参与炎症性胰岛炎的发病机制，也是免疫稳态的关键介质。促炎细胞因子包括白细胞介素、干扰素、转化生长因子-β、肿瘤坏死因子-α和一氧化氮，它们通过放大自身免疫反应、对β细胞的直接毒性以及使胰岛对凋亡敏感，促进1型糖尿病中的破坏性胰岛炎。细胞因子中和可能具有治疗益处这一概念在少数临床研究中得到了验证，但这些研究未能诱导持续缓解或实现疾病缓解。治疗失败的原因是单个细胞因子及其组合的冗余活性，在破坏性胰岛炎过程中它们相当可有可无，因为其他细胞溶解途径能有效补偿它们的不足。促炎细胞因子在炎症反应调节中的冗余性较小，通过限制效应细胞活性、增强抑制细胞功能以及参与胰岛损伤后的恢复发挥保护作用。我们的分析表明，细胞因子在免疫稳态中的作用超过了它们对β细胞死亡的影响，并且可以用作治疗目的的有效免疫调节剂，而不是将其中和。
