A novel vascular targeting strategy for brain-derived endothelial cells using a TCR mimic antibody.
A novel vascular targeting strategy for brain-derived endothelial cells using a TCR mimic antibody.
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DOI：
10.1002/jcp.22256
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发表时间：
2010-11
影响因子：
5.6
通讯作者：
Bickel, Ulrich
中科院分区：
文献类型：
--
作者：
Bhattacharya, Raktima;Xu, Yan;Rahman, Md. Ashequr;Couraud, Pierre-Olivier;Romero, Ignacio A.;Weksler, Babette B.;Weidanz, Jon A.;Bickel, Ulrich
Organ-specific vascular targeting, for example to the blood-brain barrier, requires the identification of unique molecular addresses on a subset of endothelial cells. The present study describes a crucial step towards tapping the exquisite specificity of the peptide/HLA class I system for this goal. We utilized a novel T-cell receptor (TCR) mimic antibody of high affinity and specificity, which is restricted by HLA-A2 and has been generated to recognize a peptide epitope derived from p68 RNA helicase (YLLPAIVHI). The parent protein is highly expressed by brain endothelial cells. Flow cytometry and confocal imaging showed that the antibody binds to HLA-A2 positive human brain derived endothelial cells, both immortalized hCMEC/D3 cells and primary cells. The TCR mimic antibody undergoes internalization into vesicles, where significant colocalization occurs with the early endosomal marker EEA-1, but barely with caveolin-1. To our knowledge internalization of neither MHC class I protein nor TCR mimics by brain endothelial cells has been previously observed. Knockdown of p68 protein expression by siRNA reduced the presentation of YLLPAIVHI-peptide/HLA-A2 complexes on the cell membrane by half as measured by flow cytometry 48h later. We also found that brain endothelial cells isolated from HLA-A2 transgenic mouse strains express the A2 transgene, and brain endothelial cells of one of these strains also present YLLPAIVHI-peptide/HLA-A2, making these mouse strains suitable models for studying TCR mimic antibodies in vivo. In conclusion, these data strongly support the notion that TCR mimic antibodies could be a new class of therapeutic targeting agents in a wide variety of diseases.
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