Immunological characterization of de novo and recall alloantibody suppression by CTLA4Ig in a mouse model of allosensitization
Immunological characterization of de novo and recall alloantibody suppression by CTLA4Ig in a mouse model of allosensitization
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DOI：
10.1016/j.trim.2016.08.001
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发表时间：
2016-09-01
影响因子：
1.5
通讯作者：
Jordan, Stanley C.
中科院分区：
文献类型：
--
作者：
Kim, Irene;Wu, Gordon;Jordan, Stanley C.
众所周知，CTLA4Ig在移植过程中抑制同种异体T细胞的激活。然而，CTLA4Ig抑制同种异体抗体的免疫学特征和机制却知之甚少。在这里，我们使用了同种异体致敏的小鼠模型来评估CTLA4Ig(Abatacept)在从头开始和召回同种异体抗体反应过程中抑制供体特异性抗体(DSA)的效果。我们发现Abatacept抑制了对表达HLAA2的皮肤移植物的从头DSA、IgM和Ig G反应。在初次免疫期间给予阿巴特塞特也可以减少再次免疫所引起的召回免疫反应。Abatacept对DSA反应的抑制与减少生发中心激活标记GL7的表达和流式细胞仪检测到的CD4(+)PD1(+)CXCR5(+)滤泡辅助性T细胞(TFH)亚群减少有关。Abatacept抑制召回DSA的疗效是中等的。体外实验表明，阿巴塔塞普可抑制同种异体移植受者CD138(+)浆细胞分泌DSA-Ig G。另外，使用分泌IgG1的小鼠杂交瘤细胞株进行的实验表明，阿巴塔塞普与这些细胞上表达的CD80结合，随后抑制细胞增殖并减少Ig G ELISpot的形成。综上所述，CTLA4Ig是一种有效的从头DSA反应的抑制因子，同时也影响回忆反应。数据表明，Recall DSA反应的改变是由于对浆细胞的直接抑制作用。(C)2016爱思唯尔B.V.保留所有权利。
It is well known that CTLA4Ig inhibits allogenic T-cell activation in transplantation. The immunological features and mechanisms associated with alloantibody suppression by CTLA4Ig, however, are poorly understood. Here, we used a mouse model of allosensitization to evaluate the efficacy of CTLA4Ig (abatacept) in suppression of donor-specific antibody (DSA) during de novo and recall alloantibody responses. We found that abatacept inhibited de novo DSA IgM and IgG responses to HLA-A2 expressing skin grafts. Abatacept administered during primary T cell priming also reduced recall IgG responses induced by re-immunization. Suppression of de novo DSA responses by abatacept is associated with a reduction in splenic expression of the germinal center activation marker GL7 and a reduction of CD4(+)PD1(+)CXCR5(+) follicularT helper (Tfh) subset in splenic lymphocytes detected by flow cytometry. The efficacy of abatacept on recall DSA suppression is moderate. In vitro experiments demonstrated that abatacept inhibited DSA IgG secretion by CD138(+) plasma cells isolated from allograft recipients. Additional experiments using an IgG1 secreting mouse hybridoma cell line showed that abatacept binds to CD80 expressed on these cells with subsequent inhibition of cell proliferation and reduction in IgG ELISpot formation. In conclusion, CTLA4Ig is a potent suppressor of de novo DSA responses and also affects recall responses. The data suggests modification of recall DSA responses is due to a direct suppressive effect on plasma cells. (C) 2016 Elsevier B.V. All rights reserved.