Background/Purpose: B cell depletion or modulation is emerging as a major treatment modality for autoimmune diseases. However, the current treatments to accomplish this non-specifically target pathogenic as well as normal B cells. We previously demonstrated that the heavy chain variable regions of anti-DNA antibodies contain epitopes that can bind MHC class I molecules. Vaccination of lupus-prone mice with plasmid DNA vectors carrying minigenes that encode such epitopes induced CD8+ cytotoxic T lymphocytes (CTL) that killed anti-DNA antibody-producing B cells, reduced serum anti-DNA antibody levels, retarded the development of nephritis, and improved survival (Fan G and Singh RR, J Exp Med 2002). Treatment with peptides alone did not induce such CD8+ T-cells, as we and others have reported impaired CD8+ regulatory and CTL responses in mice and humans (Singh RR, et al, J Immunol 2002; Stohl W, et al, Lupus 1999). Here, we asked if we could overcome such impairment using synthetic oligodeoxynuleotides containing unmethylated cytidine-phosphate-guanosine dinucletides (CpG-ODN) that can enhance innate and adaptive immunity, and whether autoantibody V region epitopes delivered as conjugates with CpG-ODN elicit CTLs that will selectively ablate autoreactive B cells and ameliorate autoimmune disease.

Methods: We compared cytokine responses to CpG-ODN in normal and lupus-prone BWF1 mice, screened and verified BWF1-derived anti-dsDNA antibody VH regions for MHC class I binding epitopes, constructed conjugates of these epitopes with CpG-ODN or a control ODN, immunized BWF1 mice with these conjugates, and assessed CTL responses against anti-dsDNA hybridoma B cells and B cells from nephritic BWF1 mice. We then treated BWF1 mice with selected conjugates and monitored animals for serum anti-dsDNA antibody levels, proteinuria, and survival.

Results: CpG-ODN-induced cytokine responses were lower in BWF1 mice as compared to MHC-matched healthy control animals. BWF1 mice also elicited weak CD8+ T cell responses to immunization with synthetic peptides representing MHC class I binding epitopes from anti-dsDNA VH regions. Immunization with CpG-ODN conjugated to MHC class I-binding, anti-DNA Ab V_H-derived epitopes corrected this impairment in peptide-specific CTL responses in BWF1 mice. Treatment with these conjugates induced strong peptide-specific CTL responses that killed anti-dsDNA hybridoma B cells that carry these epitopes and B cells from diseased lupus-prone mice but not B cells from normal mice, reduced anti-DNA Ab production, retarded the development of lupus nephritis, and improved survival.

Conclusion: CpG-peptides conjugates can be used to elicit a robust CTL response in lupus mice. Immunization with these conjugates carrying autoantibody VH region epitopes can be used to selectively ablate autoreactive B cells. These observations have important implications for developing selective B cell depletion treatments.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/mhc-class-i-epitopes-derived-from-autoantibody-variable-regions-conjugated-to-synthetic-oligodeoxynuleotides-induce-cytotoxic-t-cells-that-deplete-autoreactive-b-cells-and-ameliorate-murine-lupus/