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Materno-Fetal transfer of preproinsulin through the neonatal FC receptor prevents autoimmune diabetes

Culina, Slobodan, Gupta, Nimesh, Boisgard, Raphael, Afonso, Georgia, Gagnerault, Marie-Claude, Dimitrov, Jordan, Østerbye, Thomas, Justesen, Sune, Luce, Sandrine, Attias, Mikhaël, Kyewski, Bruno, Buus, Søren, Wong, Florence Susan, Lacroix-Desmazes, Sebastien and Mallone, Roberto 2015. Materno-Fetal transfer of preproinsulin through the neonatal FC receptor prevents autoimmune diabetes. Diabetes 64 (10) , pp. 3532-3542. 10.2337/db15-0024

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Abstract

The first signs of autoimmune activation leading to β-cell destruction in type 1 diabetes (T1D) appear during the first months of life. Thus, the perinatal period offers a suitable time window for disease prevention. Moreover, thymic selection of autoreactive T cells is most active during this period, providing a therapeutic opportunity not exploited to date. We therefore devised a strategy by which the T1D-triggering antigen preproinsulin fused with the immunoglobulin (Ig)G Fc fragment (PPI-Fc) is delivered to fetuses through the neonatal Fc receptor (FcRn) pathway, which physiologically transfers maternal IgGs through the placenta. PPI-Fc administered to pregnant PPIB15–23 T-cell receptor–transgenic mice efficiently accumulated in fetuses through the placental FcRn and protected them from subsequent diabetes development. Protection relied on ferrying of PPI-Fc to the thymus by migratory dendritic cells and resulted in a rise in thymic-derived CD4+ regulatory T cells expressing transforming growth factor-β and in increased effector CD8+ T cells displaying impaired cytotoxicity. Moreover, polyclonal splenocytes from nonobese diabetic (NOD) mice transplacentally treated with PPI-Fc were less diabetogenic upon transfer into NOD.scid recipients. Transplacental antigen vaccination provides a novel strategy for early T1D prevention and, further, is applicable to other immune-mediated conditions.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
Publisher: American Diabetes Association
ISSN: 0012-1797
Date of Acceptance: 15 April 2015
Last Modified: 13 Jun 2019 12:32
URI: http://orca.cf.ac.uk/id/eprint/88147

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