贝拉塔克普
CD28
CD80
阿巴塔克普
免疫学
医学
移植
T细胞
肾移植
药理学
生物
癌症研究
免疫系统
抗体
细胞毒性T细胞
内科学
美罗华
CD40
体外
生物化学
肾移植
作者
Simon Ville,Nicolas Poirier,Julien Branchereau,Vianney Charpy,Sabrina Pengam,Véronique Nerrière‐Daguin,Stéphanie Le Bas‐Bernardet,Flora Coulon,Caroline Mary,Alexis Chenouard,Jérémy Hervouet,David Minault,Steven Nédellec,Karine Renaudin,Bernard Vanhove,Gilles Blancho
出处
期刊:Journal of The American Society of Nephrology
日期:2016-05-09
卷期号:27 (12): 3577-3588
被引量:56
标识
DOI:10.1681/asn.2015070774
摘要
Belatacept is a biologic that targets CD80/86 and prevents its interaction with CD28 and its alternative ligand, cytotoxic T lymphocyte antigen 4 (CTLA-4). Clinical experience in kidney transplantation has revealed a high incidence of rejection with belatacept, especially with intensive regimens, suggesting that blocking CTLA-4 is deleterious. We performed a head to head assessment of FR104 ( n =5), a selective pegylated Fab′ antibody fragment antagonist of CD28 that does not block the CTLA-4 pathway, and belatacept ( n =5) in kidney allotransplantation in baboons. The biologics were supplemented with an initial 1-month treatment with low-dose tacrolimus. In cases of acute rejection, animals also received steroids. In the belatacept group, four of five recipients developed severe, steroid–resistant acute cellular rejection, whereas FR104-treated animals did not. Assessment of regulatory T cell–specific demethylated region methylation status in 1-month biopsy samples revealed a nonsignificant trend for higher regulatory T cell frequencies in FR104-treated animals. Transcriptional analysis did not reveal significant differences in Th17 cytokines but did reveal higher levels of IL-21, the main cytokine secreted by CD4 T follicular helper (Tfh) cells, in belatacept-treated animals. In vitro , FR104 controlled the proliferative response of human preexisting Tfh cells more efficiently than belatacept. In mice, selective CD28 blockade also controlled Tfh memory cell responses to KLH stimulation more efficiently than CD80/86 blockade. Our data reveal that selective CD28 blockade and belatacept exert different effects on mechanisms of renal allograft rejection, particularly at the level of Tfh cell stimulation.
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