Title: Perinatal tolerance to proinsulin is sufficient to prevent autoimmune diabetes
Authors: Jhala, G
Chee, J
Trivedi, PM
Selck, C
Gurzov, EN
Graham, KL
Thomas, HE
Kay, TWH
Krishnamurthy, B
Issue Year: 2016
Series JCI Insight:
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-gamma when challenged. This long-lasting effect from a brief period of treatment suggests that autoreactive T cells are not produced subsequently. We tracked IGRP(206-214)-specific CD8(+) T cells in NOD mice expressing IGRP in APCs. When IGRP was expressed only until weaning, IGRP(206-214)-specific CD8(+) 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.
URI: https://publications.svi.edu.au/publications/6586
Other Identifiers 10.1172/jci.insight.86065
Publication type Article