Vaccinelike and Prophylactic Treatments of EAE with Novel I-Domain Antigen Conjugates (IDAC): Targeting Multiple Antigenic Peptides to APC
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- 作者：Barlas B眉y眉ktimkin ; Prakash Manikwar ; Paul K. Kiptoo ; Ahmed H. Badawi ; John M. Stewart ; Jr. ; Teruna J. Siahaan
- 刊名：Molecular Pharmaceutics
- 出版年：2013
- 出版时间：January 7, 2013
- 年：2013
- 卷：10
- 期：1
- 页码：297-306
- 全文大小：541K
- 年卷期：v.10,no.1(January 7, 2013)
- ISSN：1543-8392
文摘
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鈥揟-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.