| RRC ID |
44823
|
| 著者 |
Cox JH, Hussell S, Søndergaard H, Roepstorff K, Bui JV, Deer JR, Zhang J, Li ZG, Lamberth K, Kvist PH, Padkjær S, Haase C, Zahn S, Odegard VH.
|
| タイトル |
Antibody-mediated targeting of the Orai1 calcium channel inhibits T cell function.
|
| ジャーナル |
PLoS One
|
| Abstract |
Despite the attractiveness of ion channels as therapeutic targets, there are no examples of monoclonal antibodies directed against ion channels in clinical development. Antibody-mediated inhibition of ion channels could offer a directed, specific therapeutic approach. To investigate the potential of inhibiting ion channel function with an antibody, we focused on Orai1, the pore subunit of the calcium channel responsible for store-operated calcium entry (SOCE) in T cells. Effector T cells are key drivers of autoimmune disease pathogenesis and calcium signaling is essential for T cell activation, proliferation, and cytokine production. We show here the generation of a specific anti-human Orai1 monoclonal antibody (mAb) against an extracellular loop of the plasma membrane-spanning protein. The anti-Orai1 mAb binds native Orai1 on lymphocytes and leads to cellular internalization of the channel. As a result, T cell proliferation, and cytokine production is inhibited in vitro. In vivo, anti-Orai1 mAb is efficacious in a human T cell-mediated graft-versus host disease (GvHD) mouse model. This study demonstrates the feasibility of antibody-mediated inhibition of Orai1 function and, more broadly, reveals the possibility of targeting ion channels with biologics for the treatment of autoimmunity and other diseases.
|
| 巻・号 |
8(12)
|
| ページ |
e82944
|
| 公開日 |
2013-1-1
|
| DOI |
10.1371/journal.pone.0082944
|
| PII |
PONE-D-13-37115
|
| PMID |
24376610
|
| PMC |
PMC3871607
|
| MeSH |
Amino Acid Sequence
Animals
Antibodies, Monoclonal / biosynthesis
Antibodies, Monoclonal / isolation & purification
Antibodies, Monoclonal / pharmacology*
Calcium / metabolism
Calcium Channel Blockers / isolation & purification
Calcium Channel Blockers / metabolism
Calcium Channel Blockers / pharmacology*
Calcium Channels / genetics*
Calcium Channels / immunology
Disease Models, Animal
Female
Gene Expression
Graft vs Host Disease / immunology
Graft vs Host Disease / metabolism
Graft vs Host Disease / pathology
Graft vs Host Disease / prevention & control*
Humans
Hybridomas / immunology
Ion Transport
Jurkat Cells
Leukocytes, Mononuclear / cytology
Leukocytes, Mononuclear / drug effects*
Leukocytes, Mononuclear / immunology
Mice
Molecular Sequence Data
ORAI1 Protein
Primary Cell Culture
|
| IF |
2.74
|
| 引用数 |
22
|
|
WOS 分野
|
BIOCHEMISTRY & MOLECULAR BIOLOGY
|
| リソース情報 |
| ヒト・動物細胞 |
Ba/F3(RCB0805) |
