Treatment of Murine Lupus Using Nucleosomal T Cell Epitopes Identified by Bone Marrow-Derived Dendritic Cells
Resource
ARTHRITIS AND RHEUMATISM v.50 n.10 pp.3250-3259
Journal
ARTHRITIS AND RHEUMATISM
Journal Volume
v.50
Journal Issue
n.10
Pages
3250-3259
Date Issued
2004
Date
2004
Author(s)
SUEN, JAU-LING
CHUANG, YA-HUI
TSAI, BOR-YU
PETER M. YAU
CHIANG, BOR-LUEN
Abstract
Objective. Systemic lupus erythematosus (SLE) is characterized by the existence of a heterogeneous group of autoantibodies directed against intact nuclear structures, such as nucleosomes. The most prominent of these autoantibodies are those directed against double-stranded DNA (dsDNA ) and histones. The majority are of the IgG isotype and show affinity maturation, both of which are known hallmarks of T cell help. Much evidence suggests that the nucleosome is a major candidate autoantigen in SLE. In this study, a novel strategy was used to identify the critical CD4 + T cell autoepitopes in nucleosomes. In addition, peptide-based therapy was then performed in a lupus animal model. Methods. Bone marrow (BM)- derived dendritic cells (DCs) were used to examine the self-T cell responses against nucleosomes and to characterize the T cell epitope(s) of nucleosomes in (NZB x NZW)F-1 (BWF1) mice. Results. Several potential auto-T cell epitopes of core histone proteins (H2A, H2B, H3, and H4) were identified. Nucleosome-pulsed BM-derived DCs elicited release of interleukin-4 and interferon-gamma, representing a Th0 (i.e. , mixed Th1 and Th2) pattern of cytokine production. In addition, intradermal immunization of BWF1 mice with the H3( 111-130) peptide not only suppressed the level of anti- dsDNA and anti-single-stranded DNA IgG, but also significantly delayed the progress of glomerulonephritis in lupus- prone BWF1 mice. Conclusion. These results will help in understanding how pathogenic autoimmune responses develop in spontaneous SLE. This may potentially open the way to T cell-based immunotherapy for lupus.