| Item type |
文献 / Documents(1) |
| 公開日 |
2020-11-19 |
| アクセス権 |
|
|
アクセス権 |
open access |
| 資源タイプ |
|
|
資源タイプ識別子 |
http://purl.org/coar/resource_type/c_6501 |
|
資源タイプ |
journal article |
| 出版社版DOI |
|
|
|
識別子タイプ |
DOI |
|
|
関連識別子 |
https://doi.org/10.3389/fimmu.2018.02534 |
|
|
言語 |
ja |
|
|
関連名称 |
10.3389/fimmu.2018.02534 |
| 出版タイプ |
|
|
出版タイプ |
VoR |
|
出版タイプResource |
http://purl.org/coar/version/c_970fb48d4fbd8a85 |
| タイトル |
|
|
タイトル |
Anti-drug Antibodies Against a Novel Humanized Anti-CD20 Antibody Impair Its Therapeutic Effect on Primary Biliary Cholangitis in Human CD20- and FcγR-Expressing Mice |
|
言語 |
en |
| タイトル別表記 |
|
|
その他のタイトル |
Anti-hCD20 Antibody Ameliorates Murine PBC |
|
言語 |
en |
| 著者 |
モリトキ, ユウキ
常山, 幸一
ナカムラ, ユカ
キクチ, ケンタロウ
シオタ, アキラ
オオスギ, ヨシユキ
Lian, Zhe-Xiong
Zhang, Weici
Yang, Guo-Xiang
ウエキ, シゲハル
タケダ, マサヒデ
オモカワ, アユミ
サガ, トモオ
サガ, アキコ
ワタナベ, ダイスケ
ミウラ, マサヒト
ウエノ, ヨシユキ
Leung, Patrick S. C.
タナカ, アツシ
Gershwin, M. Eric
ヒロカワ, マコト
|
| 抄録 |
|
|
内容記述タイプ |
Abstract |
|
内容記述 |
There is considerable interest in expanding B cell-targeted therapies in human autoimmune diseases. However, clinical trials in human primary biliary cholangitis (PBC) using a chimeric antibody against human CD20 (hCD20) have showed limited efficacy. Two potential explanations for these disappointing results are the appearance of anti-drug antibodies (ADAs) and the high frequency of patients with moderate PBC or patients who had failed ursodeoxycholic acid treatment. Here, we studied a novel humanized IgG1 antibody against hCD20 and explored its efficacy in early stage PBC using a well-defined murine model. We developed a unique murine model consisting of dnTGF-bRII mice expressing hCD20 and human Fcg receptors (hFcγRs). Beginning at 4–6 weeks of age, equivalent to stage I/II human PBC, female mice were given weekly injections of an anti-hCD20 antibody (TKM-011) or vehicle control, and monitored for liver histology as well as a broad panel of immunological readouts. After 16 weeks’ treatment, we observed a significant reduction in portal inflammation, a decrease in liver-infiltrating mononuclear cells as well as a reduction in liver CD8+ T cells. Importantly, direct correlations between numbers of liver non-B cells and B cells (r = 0.7426, p = 0.0006) and between numbers of liver memory CD8+ T cells and B cells (r = 0.6423, p = 0.0054) were apparent. Accompanying these changes was a dramatic reduction in anti-mitochondrial antibodies (AMAs), interleukin (IL)-12p40 and IL-5, and elevated levels of the anti-inflammatory chemokine CXCL1/KC. In mice that developed ADAs, clinical improvements were less pronounced. Sustained treatment with B cell-targeted therapies may broadly inhibit effector pathways in PBC, but may need to be administered early in the natural history of PBC. |
|
言語 |
en |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
anti-drug antibodies (ADAs) |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
anti-mitochondrial antibodies (AMAs) |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
B cell depletion therapy |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
human anti-chimeric antibodies (HACAs) |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
humanized anti-human CD20 antibody |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
mouse anti-human antibodies (MAHAs) |
| キーワード |
|
|
言語 |
en |
|
主題Scheme |
Other |
|
主題 |
primary biliary cholangitis (PBC) |
| 書誌情報 |
en : Frontiers in Immunology
巻 9,
p. 2534,
発行日 2018-11-02
|
| 収録物ID |
|
|
収録物識別子タイプ |
ISSN |
|
収録物識別子 |
16643224 |
| 出版者 |
|
|
出版者 |
Frontiers Media S.A. |
|
言語 |
en |
| 権利情報 |
|
|
言語 |
en |
|
権利情報 |
Copyright © 2018 Moritoki, Tsuneyama, Nakamura, Kikuchi, Shiota, Ohsugi, Lian, Zhang, Yang, Ueki, Takeda, Omokawa, Saga, Saga,Watanabe, Miura, Ueno, Leung, Tanaka, Gershwin andHirokawa. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| EID |
|
|
識別子 |
349431 |
|
識別子タイプ |
URI |
| 言語 |
|
|
言語 |
eng |
fimmu_9_2534.pdf (6.16 MB)
.png)
