目前对于自身免疫性糖尿病的干预措施还不能在充分的有效性、最小的副作用，以及避免普遍的免疫抑制之间取得平衡。通过肠道引入抗原是一种吸引人的诱导抗原特异性免疫耐受的方法。本文作者及同事的研究小组设计了通过在小鼠的粘膜导入具有分泌胰岛素原自身抗原（PINS）和免疫调节细胞因子白细胞介素10（IL-10）转基因的乳酸乳球菌来恢复免疫耐受的方法。研究发现在给予具有分泌PINS和IL-10转基因的乳酸乳球菌进行治疗后，13例新诊断糖尿病的NOD小鼠中约15%的小鼠可长期恢复正常血糖。如果联合低剂量CD3单克隆抗体进行治疗，在61例新诊断糖尿病小鼠中约59%的小鼠可以平稳地逆转糖尿病。同时研究发现治愈的小鼠仍然保持着对糖尿病非相关性抗原的反应，这防止了过度免疫抑制的发生。他们还发现胰岛局部调节性T细胞的数量增加，这可能与自身抗原特异性免疫反应的抑制有关。这项研究实现了糖尿病相关抗原和一种生物活性免疫调节细胞因子IL-10在肠道粘膜的导入，并且在与低剂量系统性抗CD3联合应用时表现出了很好的耐受性，诱导了自身抗原特异性的长期耐受，从而逆转了新诊断的自身免疫性糖尿病，这将为人类1型糖尿病提供一种安全有效的治疗策略。

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

链接：http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3336982/?tool=pubmed