Oral Fc-Coupled Preproinsulin Achieves Systemic and Thymic Delivery Through the Neonatal Fc Receptor and Partially Delays Autoimmune Diabetes
Tolerogenic vaccinations using beta-cell antigens are attractive for type 1 diabetes prevention, but clinical trials have been disappointing. This is probably due to the late timing of intervention, when multiple auto-antibodies are already present. We therefore devised a strategy to introduce the i...
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doaj-619bdaacd0404e728169c25e5d8a2f222021-08-10T04:29:52ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-08-011210.3389/fimmu.2021.616215616215Oral Fc-Coupled Preproinsulin Achieves Systemic and Thymic Delivery Through the Neonatal Fc Receptor and Partially Delays Autoimmune DiabetesNoémie Corcos0Slobodan Culina1Claire Deligne2Cassandra Lavaud3Sylvaine You4Roberto Mallone5Roberto Mallone6Université de Paris, Institut Cochin, CNRS, INSERM, Paris, FranceUniversité de Paris, Institut Cochin, CNRS, INSERM, Paris, FranceUniversité de Paris, Institut Cochin, CNRS, INSERM, Paris, FranceUniversité de Paris, Institut Cochin, CNRS, INSERM, Paris, FranceUniversité de Paris, Institut Cochin, CNRS, INSERM, Paris, FranceUniversité de Paris, Institut Cochin, CNRS, INSERM, Paris, FranceAssistance Publique Hôpitaux de Paris, Hôpitaux Universitaires de Paris Centre-Université de Paris, Cochin Hospital, Service de Diabétologie et Immunologie Clinique, Paris, FranceTolerogenic vaccinations using beta-cell antigens are attractive for type 1 diabetes prevention, but clinical trials have been disappointing. This is probably due to the late timing of intervention, when multiple auto-antibodies are already present. We therefore devised a strategy to introduce the initiating antigen preproinsulin (PPI) during neonatal life, when autoimmunity is still silent and central tolerance mechanisms, which remain therapeutically unexploited, are more active. This strategy employs an oral administration of PPI-Fc, i.e. PPI fused with an IgG Fc to bind the intestinal neonatal Fc receptor (FcRn) that physiologically delivers maternal antibodies to the offspring during breastfeeding. Neonatal oral PPI-Fc vaccination did not prevent diabetes development in PPI T-cell receptor-transgenic G9C8.NOD mice. However, PPI-Fc was efficiently transferred through the intestinal epithelium in an Fc- and FcRn-dependent manner, was taken up by antigen presenting cells, and reached the spleen and thymus. Although not statistically significant, neonatal oral PPI-Fc vaccination delayed diabetes onset in polyclonal Ins2-/-.NOD mice that spontaneously develop accelerated diabetes. Thus, this strategy shows promise in terms of systemic and thymic antigen delivery via the intestinal FcRn pathway, but the current PPI-Fc formulation/regimen requires further improvements to achieve diabetes prevention.https://www.frontiersin.org/articles/10.3389/fimmu.2021.616215/fullautoimmunityimmune toleranceneonatal Fc receptor (FcRn)type 1 diabetespreproinsulinT cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Noémie Corcos Slobodan Culina Claire Deligne Cassandra Lavaud Sylvaine You Roberto Mallone Roberto Mallone |
spellingShingle |
Noémie Corcos Slobodan Culina Claire Deligne Cassandra Lavaud Sylvaine You Roberto Mallone Roberto Mallone Oral Fc-Coupled Preproinsulin Achieves Systemic and Thymic Delivery Through the Neonatal Fc Receptor and Partially Delays Autoimmune Diabetes Frontiers in Immunology autoimmunity immune tolerance neonatal Fc receptor (FcRn) type 1 diabetes preproinsulin T cells |
author_facet |
Noémie Corcos Slobodan Culina Claire Deligne Cassandra Lavaud Sylvaine You Roberto Mallone Roberto Mallone |
author_sort |
Noémie Corcos |
title |
Oral Fc-Coupled Preproinsulin Achieves Systemic and Thymic Delivery Through the Neonatal Fc Receptor and Partially Delays Autoimmune Diabetes |
title_short |
Oral Fc-Coupled Preproinsulin Achieves Systemic and Thymic Delivery Through the Neonatal Fc Receptor and Partially Delays Autoimmune Diabetes |
title_full |
Oral Fc-Coupled Preproinsulin Achieves Systemic and Thymic Delivery Through the Neonatal Fc Receptor and Partially Delays Autoimmune Diabetes |
title_fullStr |
Oral Fc-Coupled Preproinsulin Achieves Systemic and Thymic Delivery Through the Neonatal Fc Receptor and Partially Delays Autoimmune Diabetes |
title_full_unstemmed |
Oral Fc-Coupled Preproinsulin Achieves Systemic and Thymic Delivery Through the Neonatal Fc Receptor and Partially Delays Autoimmune Diabetes |
title_sort |
oral fc-coupled preproinsulin achieves systemic and thymic delivery through the neonatal fc receptor and partially delays autoimmune diabetes |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Immunology |
issn |
1664-3224 |
publishDate |
2021-08-01 |
description |
Tolerogenic vaccinations using beta-cell antigens are attractive for type 1 diabetes prevention, but clinical trials have been disappointing. This is probably due to the late timing of intervention, when multiple auto-antibodies are already present. We therefore devised a strategy to introduce the initiating antigen preproinsulin (PPI) during neonatal life, when autoimmunity is still silent and central tolerance mechanisms, which remain therapeutically unexploited, are more active. This strategy employs an oral administration of PPI-Fc, i.e. PPI fused with an IgG Fc to bind the intestinal neonatal Fc receptor (FcRn) that physiologically delivers maternal antibodies to the offspring during breastfeeding. Neonatal oral PPI-Fc vaccination did not prevent diabetes development in PPI T-cell receptor-transgenic G9C8.NOD mice. However, PPI-Fc was efficiently transferred through the intestinal epithelium in an Fc- and FcRn-dependent manner, was taken up by antigen presenting cells, and reached the spleen and thymus. Although not statistically significant, neonatal oral PPI-Fc vaccination delayed diabetes onset in polyclonal Ins2-/-.NOD mice that spontaneously develop accelerated diabetes. Thus, this strategy shows promise in terms of systemic and thymic antigen delivery via the intestinal FcRn pathway, but the current PPI-Fc formulation/regimen requires further improvements to achieve diabetes prevention. |
topic |
autoimmunity immune tolerance neonatal Fc receptor (FcRn) type 1 diabetes preproinsulin T cells |
url |
https://www.frontiersin.org/articles/10.3389/fimmu.2021.616215/full |
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