The DOI matches its Crossref record; 7 of the 7 references it cites were found in a registry or an index.
Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice
Open accessAbstract
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.
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Cites
Innate immunity and intestinal microbiota in the development of Type 1 diabetes
Wen, L., Ley, R. E., Volchkov, P. Y., Stranges, P. B., Avanesyan, L., Stonebraker, A. C., Hu, C., Wong, F. S., Szot, G. L., Bluestone, J. A., et al. (2008) · Nature · doi:10.1038/nature07336 · Cited by 1,921
Genetics, pathogenesis and clinical interventions in type 1 diabetes
Bluestone, J. A., Herold, K., & Eisenbarth, G. (2010) · Nature · doi:10.1038/nature08933 · Cited by 1,265
Anti-CD3 monoclonal antibody in new-onset type 1 diabetes mellitus
Herold, K. C., Hagopian, W., Auger, J. A., Poumian-Ruiz, E., Taylor, L., Donaldson, D., Gitelman, S. E., Harlan, D. M., Xu, D., Zivin, R. A., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa012864 · Cited by 1,222
Insulin needs after CD3-antibody therapy in new-onset type 1 diabetes
Keymeulen, B., Vandemeulebroucke, E., Ziegler, A. G., Mathieu, C., Kaufman, L., Hale, G., Gorus, F., Goldman, M., Walter, M., Candon, S., et al. (2005) · New England Journal of Medicine · doi:10.1056/nejmoa043980 · Cited by 1,099
Self-citationType 1 Diabetes: Etiology, Immunology, and Therapeutic Strategies
Van Belle, T. L., Coppieters, K. T., & Von Herrath, M. G. (2011) · Physiological Reviews · doi:10.1152/physrev.00003.2010 · Cited by 1,022
Vandenbroucke, K., Hans, W., Van Huysse, J., Neirynck, S., Demetter, P., Remaut, E., Rottiers, P., & Steidler, L. (2004) · Gastroenterology · doi:10.1053/j.gastro.2004.05.020 · Cited by 277
Self-citationAnti-CD3 antibodies for type 1 diabetes: beyond expectations
Bach, J.-F. (2011) · The Lancet · doi:10.1016/s0140-6736(11)60980-x · Cited by 59
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Swanson, K. S., Gibson, G. R., Hutkins, R., Reimer, R. A., Reid, G., Verbeke, K., Scott, K. P., Holscher, H. D., Azad, M. B., Delzenne, N. M., et al. (2020) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-020-0344-2 · Cited by 2,196
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Metadata
- Authors
- Takiishi, T., Korf, H., Van Belle, T. L., Robert, S., Grieco, F. A., Caluwaerts, S., Galleri, L., Spagnuolo, I., Steidler, L., Van Huynegem, K., Demetter, P., Wasserfall, C., Atkinson, M. A., Dotta, F., Rottiers, P., Gysemans, C., & Mathieu, C.
- Venue
- Journal of Clinical Investigation
- Published
- 2012-05-01
- Volume
- 122
- Issue
- 5
- Pages
- 1717-1725
- ISSN
- 0021-9738 (ISSN-L)
- OpenAlex
- W2127051809
- Cited by
- 201
- References
- 7
- FWCI
- 9.21
- Type
- journal article
- Language
- en
- Open access
- bronze
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- CoChat. (2026). Citation check: Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice. https://app.cochat.ai/papers/10.1172/jci60530
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- Takiishi, T., Korf, H., Van Belle, T. L., Robert, S., Grieco, F. A., Caluwaerts, S., Galleri, L., Spagnuolo, I., Steidler, L., Van Huynegem, K., Demetter, P., Wasserfall, C., Atkinson, M. A., Dotta, F., Rottiers, P., Gysemans, C., & Mathieu, C. (2012). Reversal of autoimmune diabetes by restoration of antigen-specific tolerance using genetically modified Lactococcus lactis in mice. Journal of Clinical Investigation. https://doi.org/10.1172/jci60530
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