Abstract
Rheumatoid arthritis (RA) can be initiated and driven by immune responses to multiple antigenic epitopes including those in cartilage proteoglycan (PG, aggrecan) and type II collagen. RA is driven by T helper 1 (Th1) or Th17 pro-inflammatory T cell responses. LEAPS (Ligand Epitope Antigen Presentation System) DerG peptide conjugate vaccines were prepared using epitopes from PG that elicit immune responses in RA patients: epitope PG70 (DerG-PG70, also designated CEL-4000) and the citrullinated form of another epitope (PG275Cit). The LEAPS peptides were administered alone or together in Seppic ISA51vg adjuvant to mice with PG G1 domain-induced arthritis (GIA), a mouse model of RA. Each of these LEAPS peptides and the combination modulated the inflammatory response and stopped the progression of arthritis in the GIA mouse model. Despite having a therapeutic effect, the DerG-PG275Cit vaccine did not elicit significant antibody responses, whereas DerG-PG70 (alone or with DerG-PG275Cit) induced both therapy and antibodies. Spleen T cells from GIA mice, vaccinated with the DerG LEAPS peptides, preferentially produced anti-inflammatory (IL-4 and IL-10) rather than pro-inflammatory (IFN-γ or IL-17) cytokines in culture. Similarly, cytokines secreted by CD4+ cells of unvaccinated GIA mice, differentiated in vitro to Th2 cells and treated with either or both DerG vaccine peptides, exhibited an anti-inflammatory (IL-4, IL-10) profile. These results suggest that the two peptides elicit different therapeutic immune responses by the immunomodulation of disease-promoting pro-inflammatory responses and that the combination of the two LEAPS conjugates may provide broader epitope coverage and, in some cases, greater efficacy than either conjugate alone.
Highlights
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by systemic inflammation, progressive joint deterioration, and loss of mobility
For an introductory study, mice presenting with early-phase G1 domain-induced arthritis (GIA) disease (n = 8 per group) were treated with adjuvant only (PBS in adjuvant control) or the following Ligand Epitope Antigen Presentation System (LEAPS) vaccine peptides in adjuvant: CEL-4000, DerG-PG275Cit, or the combination of Vaccines 2021, 9, x FOR PEER REVIEW
By eliciting Th2 responses, vaccination with CEL-4000 and/or DerG-PG275Cit is shifting the immunopathological, inflammatory joint disease-driving T helper 1 (Th1) response of the GIA model of RA, to a benign response to reset the immune balance in an antigen-specific manner
Summary
Rheumatoid arthritis (RA) is an autoimmune disorder characterized by systemic inflammation, progressive joint deterioration, and loss of mobility. According to the CDC, an estimated 1.5 million people in the USA had RA in 2007, with approximately 50 million worldwide having some form of arthritis [1]. Another more recent report looking at more selective populations in 2019 stated 4,600,000 cases in 2019 [2]. In 2012, three of the ten best-selling drugs in the USA were RA biologics that treated arthritis symptoms by ablation of activated immune cells or neutralization of pro-inflammatory cytokines. Autoimmune diseases can be initiated and driven by cytokines produced by T cells, B cells, macrophages, dendritic cells (DCs) and other cells in response to multiple antigenic epitopes and pro-inflammatory stimuli. Pro-inflammatory cytokines that promote or are secreted by T helper 1 (Th1) cells (IL-12, IFN-γ, TNF-α, IL-2) or Th17 cells (IL-23, IL-17, TNF-α, IL-22) often drive RA disease whereas cytokines secreted by Th2 cells (IL-4, IL-5, IL-10) and regulatory T (Treg) cells (TGF-β and IL-10) are anti-inflammatory and regulatory [4]
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