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Vaccine. 2017 Jul 13;35(32):4048-4056. doi: 10.1016/j.vaccine.2017.05.009. Epub 2017 Jun 3.

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

Author information

1
Rush University Medical Center, Department of Orthopedic Surgery, 1735 W. Harrison St., Cohn Research Building, Chicago, IL 60612, United States. Electronic address: Katalin_Mikecz@rush.edu.
2
Rush University Medical Center, Department of Orthopedic Surgery, 1735 W. Harrison St., Cohn Research Building, Chicago, IL 60612, United States. Electronic address: Tibor_Glant@rush.edu.
3
Rush University Medical Center, Department of Orthopedic Surgery, 1735 W. Harrison St., Cohn Research Building, Chicago, IL 60612, United States. Electronic address: Adrienn_Markovics@rush.edu.
4
Roseman University of Health Sciences College of Medicine, 10530 Discovery Dr., Las Vegas, NV 89135, United States. Electronic address: krosenthal@roseman.edu.
5
Rush University Medical Center, Department of Orthopedic Surgery, 1735 W. Harrison St., Cohn Research Building, Chicago, IL 60612, United States. Electronic address: kurkojulcsi@gmail.com.
6
CEL-SCI Corporation, 8229 Boone Blvd., Suite 802, Vienna, VA 22182, United States. Electronic address: rcarambula@cel-sci.com.
7
CEL-SCI Corporation, 8229 Boone Blvd., Suite 802, Vienna, VA 22182, United States. Electronic address: scress@cel-sci.com.
8
CEL-SCI Corporation, 8229 Boone Blvd., Suite 802, Vienna, VA 22182, United States. Electronic address: hstein3@gmail.com.
9
CEL-SCI Corporation, 8229 Boone Blvd., Suite 802, Vienna, VA 22182, United States. Electronic address: dzimmerman@cel-sci.com.

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.

KEYWORDS:

Autoimmunity; Cytokines; Immunotherapy; Murine models; Peptide vaccine; Rheumatoid arthritis; Therapeutic vaccine

PMID:
28583308
PMCID:
PMC5568759
DOI:
10.1016/j.vaccine.2017.05.009
[Indexed for MEDLINE]
Free PMC Article

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