Treatment of murine lupus using nucleosomal T cell epitopes identified by bone marrow–derived dendritic cells

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 × NZW)F₁ (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‐γ, 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.