We induced very low-dose tolerance by injecting lupus prone (SWR × NZB)F1 (SNF1) mice with 1 μg nucleosomal histone peptide autoepitopes s.c. every 2 wk. The subnanomolar peptide therapy diminished autoantibody levels and prolonged life span by delaying nephritis, especially by reducing inflammatory cell reaction and infiltration in kidneys. H4 71-94 was the most effective autoepitope. Low-dose tolerance therapy induced CD8+, as well as CD4+CD25+ regulatory T (Treg) cell subsets containing autoantigen-specific cells. These adaptive Treg cells suppressed IFN-γ responses of pathogenic lupus T cells to nucleosomal epitopes at up to a 1:100 ratio and reduced autoantibody production up to 90-100% by inhibiting nucleosome-stimulated T cell help to nuclear autoantigen-specific B cells. Both CD4+CD25 + and CD8+ Treg cells produced and required TGF-β1 for immunosuppression, and were effective in suppressing lupus autoimmunity upon adoptive transfer in vivo. The CD4+CD25+ T cells were partially cell contact dependent, but CD8+ T cells were contact independent. Thus, low-dose tolerance with highly conserved histone autoepitopes repairs a regulatory defect in systemic lupus erythematosus by generating long-lasting, TGF-β-producing Treg cells, without causing allergic/anaphylactic reactions or generalized immunosuppression.
ASJC Scopus subject areas
- Immunology and Allergy