Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice
Open Access
- 1 May 2012
- journal article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 122 (5), 1717-1725
- https://doi.org/10.1172/jci60530
Abstract
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.Keywords
This publication has 39 references indexed in Scilit:
- Anti-CD3 antibodies for type 1 diabetes: beyond expectationsThe Lancet, 2011
- Teplizumab for treatment of type 1 diabetes (Protégé study): 1-year results from a randomised, placebo-controlled trialThe Lancet, 2011
- Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trialThe Lancet, 2011
- Immunotherapy of Type 1 Diabetes: Where Are We and Where Should We Be Going?Immunity, 2010
- Developing combination immunotherapies for type 1 diabetes: recommendations from the ITN–JDRF Type 1 Diabetes Combination Therapy Assessment GroupClinical and Experimental Immunology, 2010
- Partial and transient modulation of the CD3–T‐cell receptor complex, elicited by low‐dose regimens of monoclonal anti‐CD3, is sufficient to induce disease remission in non‐obese diabetic miceImmunology, 2010
- Interleukin 10 acts on regulatory T cells to maintain expression of the transcription factor Foxp3 and suppressive function in mice with colitisNature Immunology, 2009
- Proinsulin peptide immunotherapy in type 1 diabetes: report of a first-in-man Phase I safety studyClinical and Experimental Immunology, 2008
- Innate immunity and intestinal microbiota in the development of Type 1 diabetesNature, 2008
- CD3-specific antibodies: a portal to the treatment of autoimmunityNature Reviews Immunology, 2007