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Inhibition of macropinocytosis blocks antigen presentation of type II collagen in vitro and in vivo in HLA-DR1 transgenic mice

Lookup NU author(s): Dr Alexei von Delwig, Professor Catharien Hilkens, Professor John IsaacsORCiD, Dr Helen Robertson, Professor John Robinson

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Abstract

ABSTRACT : Professional antigen-presenting cells, such as dendritic cells, macrophages and B cells have been implicated in the pathogenesis of rheumatoid arthritis, constituting a possible target for antigen-specific immunotherapy. We addressed the possibility of blocking antigen presentation of the type II collagen (CII)-derived immunodominant arthritogenic epitope CII259-273 to specific CD4 T cells by inhibition of antigen uptake in HLA-DR1-transgenic mice in vitro and in vivo. Electron microscopy, confocal microscopy, subcellular fractionation and antigen presentation assays were used to establish the mechanisms of uptake, intracellular localization and antigen presentation of CII by dendritic cells and macrophages. We show that CII accumulated in membrane fractions of intermediate density corresponding to late endosomes. Treatment of dendritic cells and macrophages with cytochalasin D or amiloride prevented the intracellular appearance of CII and blocked antigen presentation of CII259-273 to HLA-DR1-restricted T cell hybridomas. The data suggest that CII was taken up by dendritic cells and macrophages predominantly via macropinocytosis. Administration of amiloride in vivo prevented activation of CII-specific polyclonal T cells in the draining popliteal lymph nodes. This study suggests that selective targeting of CII internalization in professional antigen-presenting cells prevents activation of autoimmune T cells, constituting a novel therapeutic strategy for the immunotherapy of rheumatoid arthritis.


Publication metadata

Author(s): von Delwig A, Hilkens CM, Altmann DM, Holmdahl R, Isaacs JD, Harding CV, Robertson H, McKie N, Robinson JH

Publication type: Article

Publication status: Published

Journal: Arthritis Research & Therapy

Year: 2006

Volume: 8

Issue: 4

ISSN (print): 1478-6354

ISSN (electronic): 1478-6362

Publisher: BioMed Central Ltd.

URL: http://dx.doi.org/10.1186/ar1964

DOI: 10.1186/ar1964

Notes: 1478-6362 (Electronic) Journal article


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