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Vaccine-like and Prophylactic Treatments of EAE with Novel IDomain Antigen Conjugates (IDAC): Targeting Multiple Antigenic Peptides to APC
Büyüktimkin, Barlas Manikwar, Prakash Kiptoo, Paul Badawi, Ahmed H. Stewart, John M. Siahaan, Teruna J.
Büyüktimkin, Barlas
Manikwar, Prakash
Kiptoo, Paul
Badawi, Ahmed H.
Stewart, John M.
Siahaan, Teruna J.
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Abstract
The objective of this work is to utilize novel I-domain antigenic-peptide conjugates (IDAC) for
targeting antigenic peptides to antigen-presenting cells (APC) to simulate tolerance in
experimental autoimmune encephalomyelitis (EAE). IDAC-1 and IDAC-3 molecules are
conjugates between the I-domain protein and PLP-Cys and Ac-PLP-Cys-NH2 peptides,
respectively, tethered to N-terminus and Lys residues on the I-domain. The hypothesis is that the
I-domain protein binds to ICAM-1 and PLP peptide binds to MHC-II on the surface of APC; this
binding event inhibits the formation of the immunological synapse at the APC-T-cell interface to
alter T-cell differentiation from inflammatory to regulatory phenotypes. Conjugation of peptides
to the I-domain did not change the secondary structure of IDAC molecules as determined by
circular dichroism spectroscopy. The efficacies of IDAC-1 and -3 were evaluated in EAE mice by
administering i.v or s.c. injections of IDAC in a prophylactic or a vaccine-like dosing schedule.
IDAC-3 was better than IDAC-1 in suppressing and delaying the onset of EAE when delivered in
prophylactic and vaccine-like manners. IDAC-3 also suppressed subsequent relapse of the disease.
The production of IL-17 was lowered in the IDAC-33 treated mice compared to those treated with
PBS. In contrast, the production of IL-10 was increased, suggesting that there is a shift from
inflammatory to regulatory T-cell populations in IDAC-33treated mice. In conclusion, the Idomain
can effectively deliver antigenic peptides in a vaccine-like or prophylactic manner for
inducing immunotolerance in the EAE mouse model.
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Date
2013-01-07
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Publisher
American Chemical Society
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Keywords
Multiple sclerosis, EAE, Vaccine, Peptide/protein conjugates, TCR/MHC-Ag, PLP, I-domain, Multi-antigens, Th1, Th17, T-reg, APC
Citation
Büyüktimkin, B., Manikwar, P., Kiptoo, P. K., Badawi, A. H., Stewart, J. M., & Siahaan, T. J. (2013). Vaccine-like and Prophylactic Treatments of EAE with Novel I-Domain Antigen Conjugates (IDAC): Targeting Multiple Antigenic Peptides to APC. Molecular Pharmaceutics, 10(1), 297–306. http://doi.org/10.1021/mp300440x