Anti-CD28 Antibody and Belatacept Exert Differential Effects on Mechanisms of Renal Allograft Rejection

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 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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