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Perinatal tolerance to proinsulin is sufficient to prevent autoimmune diabetes.
- Source :
-
JCI insight [JCI Insight] 2016 Jul 07; Vol. 1 (10), pp. e86065. Date of Electronic Publication: 2016 Jul 07. - Publication Year :
- 2016
-
Abstract
- High-affinity self-reactive thymocytes are purged in the thymus, and residual self-reactive T cells, which are detectable in healthy subjects, are controlled by peripheral tolerance mechanisms. Breakdown in these mechanisms results in autoimmune disease, but antigen-specific therapy to augment natural mechanisms can prevent this. We aimed to determine when antigen-specific therapy is most effective. Islet autoantigens, proinsulin (PI), and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) were expressed in the antigen-presenting cells (APCs) of autoimmune diabetes-prone nonobese diabetic (NOD) mice in a temporally controlled manner. PI expression from gestation until weaning was sufficient to completely protect NOD mice from diabetes, insulitis, and development of insulin autoantibodies. Insulin-specific T cells were significantly diminished, were naive, and did not express IFN-γ when challenged. This long-lasting effect from a brief period of treatment suggests that autoreactive T cells are not produced subsequently. We tracked IGRP <subscript>206-214</subscript> -specific CD8 <superscript>+</superscript> T cells in NOD mice expressing IGRP in APCs. When IGRP was expressed only until weaning, IGRP <subscript>206-214</subscript> -specific CD8 <superscript>+</superscript> T cells were not detected later in life. Thus, anti-islet autoimmunity is determined during early life, and autoreactive T cells are not generated in later life. Bolstering tolerance to islet antigens in the perinatal period is sufficient to impart lasting protection from diabetes.
- Subjects :
- Animals
Antigen-Presenting Cells cytology
Autoantigens
CD8-Positive T-Lymphocytes cytology
Glucose-6-Phosphatase metabolism
Immune Tolerance
Mice
Mice, Inbred C57BL
Mice, Inbred NOD
Mice, Transgenic
Diabetes Mellitus, Type 1 drug therapy
Diabetes Mellitus, Type 1 prevention & control
Proinsulin therapeutic use
Subjects
Details
- Language :
- English
- ISSN :
- 2379-3708
- Volume :
- 1
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- JCI insight
- Publication Type :
- Academic Journal
- Accession number :
- 27699217
- Full Text :
- https://doi.org/10.1172/jci.insight.86065