Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis.
Why CCR2 and CCR5 blockade failed and why CCR1 blockade might still be effective in the treatment of rheumatoid arthritis.
复制标题
DOI：
10.1371/journal.pone.0021772
复制
发表时间：
2011
期刊：
影响因子：
3.7
通讯作者：
Tak PP
中科院分区：
文献类型：
--
作者：
Lebre MC;Vergunst CE;Choi IY;Aarrass S;Oliveira AS;Wyant T;Horuk R;Reedquist KA;Tak PP
本研究的目的是提供更多的洞察力的问题，为什么CCR 1，CCR 2和CCR 5的封锁可能已经失败的类风湿关节炎（RA）患者的临床试验，使用体外单核细胞迁移系统模型。从外周血中分离来自健康供体（HD; n = 8）或来自RA患者（对于CCR 2和CCR 5抗体n = 8;对于CCR 1阻断n =13）的单核细胞，并与不同浓度的抗CCR 1、抗CCR 2或抗CCR 5阻断抗体（或培养基或同种型对照）预孵育。 此外，还测试了小分子CCR 1拮抗剂（BX 471）。趋化性由CCL 2/MCP-1（CCR 2配体）、CCL 5/RANTES（CCR 1和CCR 5配体）或5种RA滑液（SF）的混合物诱导，并将细胞反应与单独培养基存在下的趋化性进行比较。与同种型对照相比，抗CCR 2抗体处理阻断了CCL 2/MCP-1诱导的HD和RA单核细胞的趋化性。类似地，抗CCR 5抗体处理阻断了CCL 5/RANTES诱导的RA单核细胞的趋化性。虽然CCR 2和CCR 5阻断抗体都无法抑制SF诱导的单核细胞趋化性，但即使两种受体同时被阻断，抗CCR 1抗体和CCR 1拮抗剂也能够抑制SF诱导的单核细胞趋化性。RA滑膜区室含有CCR 1、CCR 2和CCR 5的几种配体以及参与单核细胞募集到炎症部位的其他趋化因子和受体。结果表明，CCR 2和CCR 5是不关键的单核细胞向RA滑膜室的迁移。相反，阻断CCR 1可能是有效的。可以想象，CCR 1阻断在临床试验中失败，不是因为CCR 1不是一个好的靶点，而是因为在任何时候都需要非常高水平的受体占有率来抑制体内单核细胞迁移。
The aim of this study was to provide more insight into the question as to why blockade of CCR1, CCR2, and CCR5 may have failed in clinical trials in rheumatoid arthritis (RA) patients, using an in vitro monocyte migration system model. Monocytes from healthy donors (HD; n = 8) or from RA patients (for CCR2 and CCR5 antibody n = 8; for CCR1 blockade n = 13) were isolated from peripheral blood and pre-incubated with different concentrations of either anti-CCR1, anti-CCR2, or anti-CCR5 blocking antibodies (or medium or isotype controls). In addition, a small molecule CCR1 antagonist (BX471) was tested. Chemotaxis was induced by CCL2/MCP-1 (CCR2 ligand), CCL5/RANTES (CCR1 and CCR5 ligand), or by a mix of 5 RA synovial fluids (SFs), and cellular responses compared to chemotaxis in the presence of medium alone. Anti-CCR2 antibody treatment blocked CCL2/MCP-1-induced chemotaxis of both HD and RA monocytes compared to isotype control. Similarly, anti-CCR5 antibody treatment blocked CCL5/RANTES-induced chemotaxis of RA monocytes. While neither CCR2 nor CCR5 blocking antibodies were able to inhibit SF-induced monocyte chemotaxis, even when both receptors were blocked simultaneously, both anti-CCR1 antibodies and the CCR1 antagonist were able to inhibit SF-induced monocyte chemotaxis. The RA synovial compartment contains several ligands for CCR1, CCR2, and CCR5 as well as other chemokines and receptors involved in monocyte recruitment to the site of inflammation. The results suggest that CCR2 and CCR5 are not critical for the migration of monocytes towards the synovial compartment in RA. In contrast, blockade of CCR1 may be effective. Conceivably, CCR1 blockade failed in clinical trials, not because CCR1 is not a good target, but because very high levels of receptor occupancy at all times may be needed to inhibit monocyte migration in vivo.
登录
查看更多内容
影响因子：
2.1
作者：
Jiao, Z.;Wang, W.;Wang, Y.
通讯作者：
Wang, Y.
影响因子：
--
作者：
Haringman, Jasper J.;Gerlag, Danielle M.;Tak, Paul P.
通讯作者：
Tak, Paul P.
影响因子：
4.9
作者：
Haringman JJ;Tak PP
通讯作者：
Tak PP
影响因子：
4.4
作者：
PlaterZyberk, C;Hoogewerf, AJ;Wells, TNC
通讯作者：
Wells, TNC
影响因子：
4.6
作者：
AlMughales, J;Blyth, TH;Wilkinson, PC
通讯作者：
Wilkinson, PC