期刊
DIABETES
卷 63, 期 8, 页码 2876-2887出版社
AMER DIABETES ASSOC
DOI: 10.2337/db13-1236
关键词
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资金
- Fund for Scientific Research Flanders (FWO-Vlaanderen) [G.0554.13N]
- KU Leuven [GOA 2009/10]
- Health Seventh Framework Programme of the European Community (FP7) [241447]
- JDRF [17-2011-524]
- Agency for Innovation by Science and Technology in Flanders [IWT-90702]
- KU Leuven
- Italian Ministry of Research
- Italian Ministry of Health
- Italian Foundation for Diabetes Research
Growing insight into the pathogenesis of type 1 diabetes (T1D) and numerous studies in preclinical models highlight the potential of antigen-specific approaches to restore tolerance efficiently and safely. Oral administration of protein antigens is a preferred method for tolerance induction, but degradation during gastrointestinal passage can impede such protein-based therapies, reducing their efficacy and making them cost-ineffective. To overcome these limitations, we generated a tolerogenic bacterial delivery technology based on live Lactococcus lactis (LL) bacteria for controlled secretion of the T1D autoantigen GAD65(370-575) and the anti-inflammatory cytokine interleukin-10 in the gut. In combination with short-course low-dose anti-CD3, this treatment stabilized insulitis, preserved functional beta-cell mass, and restored normoglycemia in recent-onset NOD mice, even when hyperglycemia was severe at diagnosis. Combination therapy did not eliminate pathogenic effector T cells, but increased the presence of functional CD4(+)Foxp3(+)CD25(+) regulatory T cells. These preclinical data indicate a great therapeutic potential of orally administered autoantigen-secreting LL for tolerance induction in T1D.
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