JCI：基因工程改造肠道细菌治疗糖尿病

胰岛素对血糖水平的调节非常重要。在I型糖尿病中，免疫系统会破坏产生胰岛素的细胞。

鲁汶大学的Chantal Mathieu和同事试图想让免疫系统接受外来肠道细菌的刺激来规避上述问题。Mathieu研究团队基因改造肠道细菌，使得它们能产生一种胰岛素，并研究这些细菌是否能使得I型糖尿病小鼠的免疫系统不影响产生胰岛素的细胞。

他们发现与单靠传统疗法相比，这些特殊的细菌能增加小鼠治愈的概率，同时又似乎不带来不良影响。传统的方法即抑制免疫系统，这会带来不利后果如增加感染。事实上，Mathieu研究团队确认小鼠接受新疗法后，免疫系统能发挥作用。他们的研究在扭转I型糖尿病以及其他自身免疫性疾病的治疗道路上迈出了可喜的一步。

论文题目为“Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice”。

doi:10.1172/JCI60530

Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice

Tatiana Takiishi1, Hannelie Korf1, Tom L. Van Belle1, Sofie Robert1, Fabio A. Grieco2, Silvia Caluwaerts3, Letizia Galleri2, Isabella Spagnuolo2, Lothar Steidler3, Karolien Van Huynegem3, Pieter Demetter4, Clive Wasserfall5, Mark A. Atkinson5, Francesco Dotta2, Pieter Rottiers3, Conny Gysemans1 and Chantal Mathieu1

Current interventions for arresting autoimmune diabetes have yet to strike the balance between sufficient efficacy, minimal side effects, and lack of generalized immunosuppression. Introduction of antigen via the gut represents an appealing method for induction of antigen-specific tolerance. Here, we developed a strategy for tolerance restoration using mucosal delivery in mice of biologically contained Lactococcus lactis genetically modified to secrete the whole proinsulin autoantigen along with the immunomodulatory cytokine IL-10. We show that combination therapy with low-dose systemic anti-CD3 stably reverted diabetes in NOD mice and increased frequencies of local Tregs, which not only accumulated in the pancreatic islets, but also suppressed immune response in an autoantigen-specific way. Cured mice remained responsive to disease-unrelated antigens, which argues against excessive immunosuppression. Application of this therapeutic tool achieved gut mucosal delivery of a diabetes-relevant autoantigen and a biologically active immunomodulatory cytokine, IL-10, and, when combined with a low dose of systemic anti-CD3, was well tolerated and induced autoantigen-specific long-term tolerance, allowing reversal of established autoimmune diabetes. Therefore, we believe this method could be an effective treatment strategy for type 1 diabetes in humans.