Vaccinelike and Prophylactic Treatments of EAE with Novel I-Domain Antigen Conjugates (IDAC): Targeting Multiple Antigenic Peptides to APC
- Barlas Büyüktimkin
- Prakash Manikwar
- Paul K. Kiptoo
- Ahmed H. Badawi
- John M. Stewart, Jr.
- , and
- Teruna J. Siahaan
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 iv or sc injections of IDAC in a prophylactic or a vaccinelike dosing schedule. IDAC-3 was better than IDAC-1 in suppressing and delaying the onset of EAE when delivered in prophylactic and vaccinelike manners. IDAC-3 also suppressed subsequent relapse of the disease. The production of IL-17 was lowered in the IDAC-3-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-3-treated mice. In conclusion, the I-domain can effectively deliver antigenic peptides in a vaccinelike or prophylactic manner for inducing immunotolerance in the EAE mouse model.
This article is cited by 3 publications.
- Christopher Kuehl, Sharadvi Thati, Bradley Sullivan, Joshua Sestak, Michael Thompson, Teruna Siahaan, Cory Berkland. Pulmonary Administration of Soluble Antigen Arrays Is Superior to Antigen in Treatment of Experimental Autoimmune Encephalomyelitis. Journal of Pharmaceutical Sciences 2017, 106 (11) , 3293-3302. https://doi.org/10.1016/j.xphs.2017.06.008
- Barlas Büyüktimkin, John Stewart, Kayann Tabanor, Paul Kiptoo, Teruna J. Siahaan. Protein and Peptide Conjugates for Targeting Therapeutics and Diagnostics to Specific Cells. 2016, 475-502. https://doi.org/10.1002/9781118833322.ch20
- Sharadvi Thati, Christopher Kuehl, Brittany Hartwell, Joshua Sestak, Teruna Siahaan, M. Laird Forrest, Cory Berkland. Routes of Administration and Dose Optimization of Soluble Antigen Arrays in Mice with Experimental Autoimmune Encephalomyelitis. Journal of Pharmaceutical Sciences 2015, 104 (2) , 714-721. https://doi.org/10.1002/jps.24272