Vaccinelike and prophylactic treatments of EAE with novel I-domain antigen conjugates (IDAC): targeting multiple antigenic peptides to APC.
Vaccinelike and prophylactic treatments of EAE with novel I-domain antigen conjugates (IDAC): targeting multiple antigenic peptides to APC.
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DOI：
10.1021/mp300440x
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发表时间：
2013-01-07
影响因子：
4.9
通讯作者：
Siahaan TJ
中科院分区：
文献类型：
--
作者：
Büyüktimkin B;Manikwar P;Kiptoo PK;Badawi AH;Stewart JM Jr;Siahaan TJ
这项工作的目的是利用新的i结构域抗原肽偶联物（IDAC）将抗原肽靶向抗原提呈细胞（APC）以模拟实验性自身免疫性脑脊髓炎（EAE）的耐受性。IDAC-1和IDAC-3分子是i结构域蛋白与PLP-Cys和Ac-PLP-Cys-NH2肽之间的偶联物，分别连接在i结构域的n端和Lys残基上。假设i结构域蛋白与ICAM-1结合，PLP肽与APC表面的MHC-II结合；这种结合事件抑制apc - t细胞界面上免疫突触的形成，从而改变t细胞从炎症型向调节性表型的分化。经圆二色光谱测定，肽偶联到i结构域不会改变IDAC分子的二级结构。在EAE小鼠中，通过预防性或疫苗样给药方案静脉注射或皮下注射IDAC-1和-3来评估IDAC-1和-3的疗效。以预防和疫苗样方式给药时，IDAC-3在抑制和延迟EAE发作方面优于IDAC-1。IDAC-3也抑制了随后的疾病复发。与PBS处理的小鼠相比，IDAC-33处理的小鼠IL-17的产生降低。相反，IL-10的产生增加，表明在idac -33处理的小鼠中，炎性t细胞群向调节性t细胞群转变。综上所述，在EAE小鼠模型中，i结构域可以有效地以疫苗样或预防性的方式传递抗原肽，诱导免疫耐受。
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 I-domain can effectively deliver antigenic peptides in a vaccine-like or prophylactic manner for inducing immunotolerance in the EAE mouse model.
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影响因子：
15.9
作者：
Haak, Stefan;Croxford, Andrew L.;Waisman, Ari
通讯作者：
Waisman, Ari
影响因子：
4.7
作者：
Manikwar, Prakash;Bueyuektimkin, Barlas;Siahaan, Teruna J.
通讯作者：
Siahaan, Teruna J.
影响因子：
3
作者：
Murray, Joseph S.;Oney, Sabah;Siahaan, Teruna J.
通讯作者：
Siahaan, Teruna J.
影响因子：
3.2
作者：
Seidel, MF;Keck, R;Vetter, H
通讯作者：
Vetter, H
DOI：
10.1073/pnas.0504131102
发表时间：
2005-07-05
影响因子：
11.1
作者：
Smith, CE;Eagar, TN;Miller, SD
通讯作者：
Miller, SD