Session Type: Abstract Submissions (ACR)
Pathogenesis of systemic sclerosis (SSc) remains unclear. Alterations in adaptive and innate immune responses, with increased T-cells that produce type 2 cytokines and impaired responsiveness to Toll-like receptors, have been reported in patients with SSc. Dendritic cells (DC) that participate in both innate and adaptive immunity are increasingly being investigated in the pathogenesis and immune intervention in various autoimmune diseases and other immune-mediated conditions. Little is known about the alterations and role of DC in SSc. Our goal in this study is to investigate alterations of DC subsets and their roles in the pathogenesis of SSc.
In order to investigate the time kinetics of DC alterations in the affected and lymphoid organs and to manipulate DCs in vivo, we used the bleomycin-induced mouse model where the exact timing of pathogenic insult is known. Although, the bleomycin or any of the currently available animal models do not reproduce all aspects of human SSc, bleomycin-induced dermal and pulmonary fibrosis mimics human SSc in many ways. C57BL/6 mice were injected with bleomycin or PBS for 2 weeks, and cells isolated from lung tissue or lavage, skin, lymph nodes, spleen and bone marrow were analyzed for various immune cell types including DC subsets namely myeloid DC (mDC) and plasmacytoid DC (PDC). To directly determine the role of pDC, these cells were depleted using an anti-PDCA1 antibody (Miltenyi Biotec) or an IgG isotype control antibody. Animals were euthanized 2 weeks after treatment. Disease was assessed by clinical and histological scoring.
Both DC subsets were increased in the lungs of bleomycin-injected mice, with a more profound increase in pDCs that were significantly elevated in the lungs (p<0.008), skin (p<0.04), and their associated draining lymph nodes in bleomycin-injected mice compared to PBS controls. Neither DC susbets differed in the spleen of bleomycin-injected mice when compared to controls. Treatment with anti-PDCA1 antibody significantly reduced pDC numbers in the spleen and lung by two-fold as compared to animals injected with an isotype control antibody. pDC-depleted mice had a significant improvement in combined clinical disease severity score (p<0.001) and histopathology (p<0.009), along with a reduction in cellular infiltrates comprising of B-cells, T-cells, NK and NK-T cell as compared to control mice. qPCR array analysis of lung tissue for molecules potentially involved in DC function and recruitment thus far shows alterations in chemokines Ccl2 and Ccl19, and in macrophage migration inhibiting factor namely Cd74, which have been implicated in fibrosis development.
A more profound accumulation of pDCs, as compared to the other major DC subset, in the affected organs and their draining lymph nodes, but less so in the lymphoid organs, of bleomycin-injected mice suggests a possible role of pDC in SSc process. Indeed, antibody depletion of pDC reduces skin and lung fibrosis in the bleomycin model. A significant reduction in several immune cell types in pDC-depleted mice suggests a major pathogenic role of pDC in inflammatory/fibrosis process.
D. E. Furst,
Abbott, Actelion, Amgen, BMS, Janssen, Gilead, GSK, NIH, Novartis, Pfizer, Roche/Genentech, UCB,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/the-impact-of-plasmacytoid-dendiritc-cells-pdcs-on-fibrosis-in-bleomycin-induced-murine-model-of-systemic-sclerosis-ssc/