An epitope-specific DerG-PG70 LEAPS vaccine modulates T cell responses and suppresses arthritis progression in two related murine models of rheumatoid arthritis.

Abstract

Rheumatoid arthritis (RA) is an autoimmune joint disease maintained by aberrant immune responses involving CD4+ T helper (Th)1 and Th17 cells. In this study, we tested the therapeutic efficacy of Ligand Epitope Antigen Presentation System (LEAPS™) vaccines in two Th1 cell-driven mouse models of RA, cartilage proteoglycan (PG)-induced arthritis (PGIA) and PG G1-domain-induced arthritis (GIA). The immunodominant PG peptide PG70 was attached to a DerG or J immune cell binding peptide, and the DerG-PG70 and J-PG70 LEAPS vaccines were administered to the mice after the onset of PGIA or GIA symptoms. As indicated by significant decreases in visual and histopathological scores of arthritis, the DerG-PG70 vaccine inhibited disease progression in both PGIA and GIA, while the J-PG70 vaccine was ineffective. Splenic CD4+ cells from DerG-PG70-treated mice were diminished in Th1 and Th17 populations but enriched in Th2 and regulatory T (Treg) cells. In vitro spleen cell-secreted and serum cytokines from DerG-PG70-treated mice demonstrated a shift from a pro-inflammatory to an anti-inflammatory/regulatory profile. DerG-PG70 peptide tetramers preferentially bound to CD4+ T-cells of GIA spleen cells. We conclude that the DerG-PG70 vaccine (now designated CEL-4000) exerts its therapeutic effect by interacting with CD4+ cells, which results in an antigen-specific down-modulation of pathogenic T-cell responses in both the PGIA and GIA models of RA. Future studies will need to determine the potential of LEAPS vaccination to provide disease suppression in patients with RA.

• Authors: Katalin Mikecz, Tibor T Glant, Adrienn Markovics, Kenneth S Rosenthal, Julia Kurko, Roy E Carambula, Steve Cress, Harold L Steiner Rd, Daniel H Zimmerman
• Journal: Vaccine (Vaccine) Vol. 35 Issue 32 Pg. 4048-4056 (07 13 2017) ISSN: 1873-2518 [Electronic] Netherlands
• PMID: 28583308 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
• Copyright: Copyright © 2017 The Authors. Published by Elsevier Ltd.. All rights reserved.

Chemical References

• Aggrecans
• Epitopes
• Vaccines

Topics

• Aggrecans (genetics, immunology)
• Animals
• Arthritis, Rheumatoid (therapy)
• Disease Models, Animal
• Epitopes (genetics, immunology)
• Female
• Mice, Inbred BALB C
• T-Lymphocytes (immunology)
• Treatment Outcome
• Vaccines (therapeutic use)