Interleukin-21 is critically required in autoimmune and allogeneic responses to islet tissue in murine models.
Interleukin-21 is critically required in autoimmune and allogeneic responses to islet tissue in murine models.
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作者：
McGuire HM;Walters S;Vogelzang A;Lee CM;Webster KE;Sprent J;Christ D;Grey S;King C
1型糖尿病是一种无法治愈的慢性自身免疫性疾病。虽然胰岛移植可以作为胰岛素的替代来源，但受者受到免疫抑制的生活。白介素21对于NOD小鼠的1型糖尿病是必需的。我们研究了IL-21靶向治疗联合同基因胰岛移植预防NOD小鼠糖尿病的效果。此外，我们评估了IL-21在小鼠同种异体胰岛移植排斥反应中的作用。NOD小鼠接受IL-21中和嵌合蛋白IL-21R/Fc的治疗。该方法与同基因胰岛移植联合治疗糖尿病NOD小鼠。IL-21R缺陷小鼠的同种异体胰岛移植物的存活率也被评估。有证据表明，自身免疫渗入持续需要IL-21，从而在临床前的晚期通过中和IL-21减轻和逆转了胰腺炎，并抑制了糖尿病。自身免疫性糖尿病的康复是通过中和IL-21与胰岛移植相结合实现的。此外，CD8+T细胞对IL-21的反应性足以介导同种异体胰岛移植排斥反应。中和NOD小鼠的IL-21可以抑制糖尿病，当与胰岛移植配对时，这种治疗方法可以恢复正常血糖。IL-21对移植物上的免疫反应的影响是强烈的，因为缺乏IL-21信号可以防止同种异体胰岛移植排斥反应。这些发现表明，IL-21的治疗性操作可能是一种适合1型糖尿病患者的治疗方法。
Type 1 diabetes is an incurable chronic autoimmune disease. Although transplantation of pancreatic islets may serve as a surrogate source of insulin, recipients are subjected to a life of immunosuppression. Interleukin (IL)-21 is necessary for type 1 diabetes in NOD mice. We examined the efficacy of an IL-21–targeted therapy on prevention of diabetes in NOD mice, in combination with syngeneic islet transplantation. In addition, we assessed the role of IL-21 responsiveness in islet allograft rejection in mouse animal models. NOD mice were treated with IL-21R/Fc, an IL-21–neutralizing chimeric protein. This procedure was combined with syngeneic islet transplantation to treat diabetic NOD mice. Survival of allogeneic islet grafts in IL-21R–deficient mice was also assessed. Evidence is provided that IL-21 is continually required by the autoimmune infiltrate, such that insulitis was reduced and reversed and diabetes inhibited by neutralization of IL-21 at a late preclinical stage. Recovery from autoimmune diabetes was achieved by combining neutralization of IL-21 with islet transplantation. Furthermore, IL-21–responsiveness by CD8+ T-cells was sufficient to mediate islet allograft rejection. Neutralization of IL-21 in NOD mice can inhibit diabetes, and when paired with islet transplantation, this therapeutic approach restored normoglycemia. The influence of IL-21 on a graft-mounted immune response was robust, since the absence of IL-21 signaling prevented islet allograft rejection. These findings suggest that therapeutic manipulation of IL-21 may serve as a suitable treatment for patients with type 1 diabetes.