Targeting human plasmacytoid dendritic cells through BDCA2 prevents skin inflammation and fibrosis in a novel xenotransplant mouse model of scleroderma

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Ross, R., Corinaldesi, C., Migneco, G., Carr, I., Antanaviciute, A., Wasson, C., Carriero, A., Distler, J., Holmes, S., El-Sherbiny, Y. ORCID: 0000-0003-4791-3475, McKimmie, C. and Del Galdo, F., 2021. Targeting human plasmacytoid dendritic cells through BDCA2 prevents skin inflammation and fibrosis in a novel xenotransplant mouse model of scleroderma. Annals of the Rheumatic Diseases. ISSN 0003-4967

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Official URL: https://doi.org/10.1136/annrheumdis-2020-218439

Abstract

Objectives: Plasmacytoid dendritic cells (pDCs) have been implicated in the pathogenesis of autoimmune diseases, such as scleroderma (SSc). However, this has been derived by indirect evidence using ex vivo human samples or mouse pDC in vivo. We have developed human-specific pDC models to directly identify their role in inflammation and fibrosis, as well as attenuation of pDC function with BDCA2-targeting to determine its therapeutic application.

Methods: RNA-seq of human pDC with TLR9 agonist ODN2216 and humanised monoclonal BDCA2 antibody, CBS004. Organotypic skin rafts consisting of fibroblasts and keratinocytes were stimulated with supernatant from TLR9-stimulated pDC and with CBS004. Human pDCswere xenotransplanted into SCID mice treated with Aldara (inflammatory model), or bleomycin (fibrotic model) with CBS004 or human IgG control. Punch biopsy of skin was used to assess gene and protein expression.

Results: RNA-seq shows TLR9-induced activation of human pDC goes beyond type I interferon (IFN) secretion, which is functionally inactivated by BDCA2 targeting. Consistent with these findings, we show that BDCA2 targeting of pDC can completely suppress in vitro skin IFN-induced response. Most importantly, xenotransplantation of human pDC significantly increased in vivo skin IFN-induced response to TLR agonist and strongly enhanced fibrotic and immune response to bleomycin compared with controls. In these contexts, BDCA2 targeting suppressed human pDC- specific pathological responses.

Conclusions: Our data indicate that human pDC plays a key role in inflammation and immune-driven skin fibrosis, which can be effectively blocked by BDCA2 targeting, providing direct evidence supporting the development of attenuation of pDC function as a therapeutic application for SSc.

Item Type:

Journal article

Publication Title:

Annals of the Rheumatic Diseases

Creators:

Ross, R., Corinaldesi, C., Migneco, G., Carr, I., Antanaviciute, A., Wasson, C., Carriero, A., Distler, J., Holmes, S., El-Sherbiny, Y., McKimmie, C. and Del Galdo, F.

Publisher:

BMJ Publishing Group

Date:

4 February 2021

ISSN:

0003-4967

Identifiers: