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.
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