Header

UZH-Logo

Maintenance Infos

Transcriptional targeting of DCs with lentiviral vectors induces antigen-specific tolerance in a mouse model of multiple sclerosis


de Andrade Pereira, Bruna; Fraefel, C; Hilbe, M; Ackermann, M; Dresch, C (2013). Transcriptional targeting of DCs with lentiviral vectors induces antigen-specific tolerance in a mouse model of multiple sclerosis. Gene Therapy, 20(5):556-566.

Abstract

The aim of this work was to induce permanent tolerance toward self-antigens involved in autoimmune diseases, such as multiple sclerosis (MS). We hypothesized that the stable auto-antigen presentation by dendritic cells (DCs) would tolerize auto-reactive T cells and, therefore, prevent disease development in a mouse model of experimental autoimmune encephalomyelitis (EAE), which closely resembles MS. Specifically, our strategy included the ex vivo modification of hematopoietic stem cells (HSCs) with self-inactivating (SIN) lentivirus vectors that transcriptionally target the expression of myelin antigens to DCs. As SIN lentivirus vectors support the genomic integration of transgene sequences in HSC, the transduced and transplanted HSC may provide a constant supply of antigen expressing steady-state DCs. Here, we demonstrate that targeting myelin oligodendrocyte glycoprotein (MOG) expression to DCs indeed resulted in complete and stable protection from EAE. No histological signs of EAE, such as demyelination, axonal damage, or infiltration of leukocytes in brain, spinal cord and optical nerve, were observed in tolerized mice. Tolerance induction was concomitant with the efficient deletion of MOG-specific T cells and the generation of Foxp3(+) regulatory T cells and, most importantly, directed toward a specific self-antigen while T-cell reactivity to unrelated foreign antigens was fully preserved.

Abstract

The aim of this work was to induce permanent tolerance toward self-antigens involved in autoimmune diseases, such as multiple sclerosis (MS). We hypothesized that the stable auto-antigen presentation by dendritic cells (DCs) would tolerize auto-reactive T cells and, therefore, prevent disease development in a mouse model of experimental autoimmune encephalomyelitis (EAE), which closely resembles MS. Specifically, our strategy included the ex vivo modification of hematopoietic stem cells (HSCs) with self-inactivating (SIN) lentivirus vectors that transcriptionally target the expression of myelin antigens to DCs. As SIN lentivirus vectors support the genomic integration of transgene sequences in HSC, the transduced and transplanted HSC may provide a constant supply of antigen expressing steady-state DCs. Here, we demonstrate that targeting myelin oligodendrocyte glycoprotein (MOG) expression to DCs indeed resulted in complete and stable protection from EAE. No histological signs of EAE, such as demyelination, axonal damage, or infiltration of leukocytes in brain, spinal cord and optical nerve, were observed in tolerized mice. Tolerance induction was concomitant with the efficient deletion of MOG-specific T cells and the generation of Foxp3(+) regulatory T cells and, most importantly, directed toward a specific self-antigen while T-cell reactivity to unrelated foreign antigens was fully preserved.

Statistics

Citations

4 citations in Web of Science®
4 citations in Scopus®
Google Scholar™

Altmetrics

Downloads

3 downloads since deposited on 17 Sep 2012
1 download since 12 months
Detailed statistics

Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:05 Vetsuisse Faculty > Institute of Veterinary Pathology
05 Vetsuisse Faculty > Institute of Virology
Dewey Decimal Classification:570 Life sciences; biology
Language:English
Date:2013
Deposited On:17 Sep 2012 12:20
Last Modified:05 Apr 2016 15:57
Publisher:Nature Publishing Group
ISSN:0969-7128
Publisher DOI:https://doi.org/10.1038/gt.2012.73
PubMed ID:22951454

Download

Preview Icon on Download
Filetype: PDF - Registered users only
Size: 1MB
View at publisher

Article Networks

TrendTerms

TrendTerms displays relevant terms of the abstract of this publication and related documents on a map. The terms and their relations were extracted from ZORA using word statistics. Their timelines are taken from ZORA as well. The bubble size of a term is proportional to the number of documents where the term occurs. Red, orange, yellow and green colors are used for terms that occur in the current document; red indicates high interlinkedness of a term with other terms, orange, yellow and green decreasing interlinkedness. Blue is used for terms that have a relation with the terms in this document, but occur in other documents.
You can navigate and zoom the map. Mouse-hovering a term displays its timeline, clicking it yields the associated documents.

Author Collaborations