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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.

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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:07 Dec 2017 15:00
Publisher:Nature Publishing Group
ISSN:0969-7128
Publisher DOI:https://doi.org/10.1038/gt.2012.73
PubMed ID:22951454

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