TY - JOUR
T1 - Vaccination by two derg leaps conjugates incorporating distinct proteoglycan (Pg, aggrecan) epitopes provides therapy by different immune mechanisms in a mouse model of rheumatoid arthritis
AU - Zimmerman, Daniel H.
AU - Mikecz, Katalin
AU - Markovics, Adrienn
AU - Carambula, Roy E.
AU - Ciemielewski, Jason C.
AU - Toth, Daniel M.
AU - Glant, Tibor T.
AU - Rosenthal, Ken S.
N1 - Funding Information:
Acknowledgments: Research reported in this publication was supported by the National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) of USA under award number R44 AR063504-02A1 for DH Zimmerman as well as by CEL-SCI Corporation; also supported under award numbers NIH/NIAMS R01 AR064206 and R01 AR062991 for K Mikecz at Rush University Medical Center. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health, CEL-SCI Corporation or Rush University Medical Center. We also acknowledge the excellent work and report by Alison Bendele of Bolder Biopath).
Funding Information:
Funding: This research was funded by National Institute of Arthritis, Musculoskeletal and Skin Diseases (NIAMS) of the National Institutes of Health (NIH) of USA under award number R44 AR063504-02A1 for DH Zimmerman, as well as by CEL-SCI Corporation. The research was also funded under award numbers NIH/NIAMS R01 AR064206 and R01 AR062991 for K Mikecz at Rush University Medical Center.
Publisher Copyright:
© 2021 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2021/5
Y1 - 2021/5
N2 - 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.
AB - 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.
KW - Immunotherapy
KW - PG G1 domain-induced arthritis
KW - Peptide vaccine
KW - Proteoglycan (PG, aggrecan)
KW - Rheumatoid arthritis
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U2 - 10.3390/vaccines9050448
DO - 10.3390/vaccines9050448
M3 - Article
AN - SCOPUS:85105906638
SN - 2076-393X
VL - 9
JO - Vaccines
JF - Vaccines
IS - 5
M1 - 448
ER -
