Anti-Interleukin 6 Receptor Antibodies Attenuate Antibody Recall Responses in a Mouse Model of Allosensitization
Anti-Interleukin 6 Receptor Antibodies Attenuate Antibody Recall Responses in a Mouse Model of Allosensitization
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DOI：
10.1097/tp.0000000000000437
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发表时间：
2014-12-27
期刊：
影响因子：
6.2
通讯作者：
Jordan, Stanley
中科院分区：
文献类型：
--
作者：
Kim, Irene;Wu, Gordon;Jordan, Stanley
背景白细胞介素（IL）-6是辅助性T细胞17型（Th 17）和Treg细胞的调节细胞因子，并且是B/浆细胞的有效刺激物。本研究评价了用抗IL-6受体单克隆抗体（mMR 16 -1）阻断IL-6受体（IL-6 R）对同种抗体回忆反应的影响。人类白细胞抗原（HLA）的小鼠模型。使用A2致敏进行研究，以评估抗IL-6 R对同种抗体回忆反应的功效，并使用多参数流式细胞术、流式抗体结合和酶联免疫斑点（ELISpot）测定来检查IL-6 R阻断对Th 17、Treg、滤泡辅助性T细胞（Tfh）和浆细胞的影响。结果。C57 BL/6小鼠再次暴露于HLA。A2（+）皮肤同种异体移植导致供体特异性（抗HLA）激增。A2）免疫球蛋白（IG）G抗体。抗IL-6 R治疗显著降低但没有消除同种抗体应答（IgG平均荧光强度，486 T 153对比对照792 +/-193，P = 0.0076）。流式细胞术分析显示，抗IL-6 R处理导致IL-21（+）CD 4（+）（Th 17）细胞（P = 0.006 vs.对照）和CXCR 5（+）CD 4（+）Tfh细胞（P = 0.04）减少，但CD 4（+）群体中foxp 3（+）CD 4（+）（Treg）细胞增加（P = 0.04 vs.对照）。IgG ELISpot实验显示，抗IL-6 R处理小鼠的骨髓和脾细胞中的IgG斑点显着减少。在体外用抗IL-6 R处理小鼠杂交瘤（PA2.1）培养物可减少IgG斑点的形成，但对细胞增殖的影响有限。这些数据表明，抗IL-6 R治疗通过调节许多免疫调节和效应细胞，包括Th 17、Tfh、Treg，以及重要的是骨髓中的长寿浆细胞，来减弱同种抗体回忆反应。
Background. Interleukin (IL)-6 is a regulatory cytokine for T helper type 17 (Th17) and Treg cells and a potent stimulus for B/plasma cells. The current study evaluated the effect of IL-6 receptor (IL-6R) blockade with an anti-IL-6R monoclonal (mMR16-1) in alloantibody recall responses.Methods. A mouse model of human leukocyte antigen (HLA). A2 sensitization was used for studies to evaluate the efficacy of anti-IL-6R on alloantibody recall responses and to examine the impact of IL-6R blockade on Th17, Treg, follicular T helper (Tfh) and plasma cells using multiparameter flow cytometry, flow antibody binding, and enzyme-linked immunospot (ELISpot) assay.Results. Re-exposure of C57BL/6 mice to HLA. A2(+) skin allografts resulted in a surge of donor-specific (anti-HLA. A2) immunoglobulin (Ig) G antibodies. Anti-IL-6R treatment significantly decreased but did not eliminate alloantibody responses (IgG mean fluorescence intensity, 486 T 153 vs. control 792 +/- 193, P = 0.0076). Flow cytometry analysis showed that anti-IL-6R treatment resulted in reduction of IL-21(+)CD4(+) (Th17) cells (P = 0.006 vs. control) and CXCR5(+) CD4(+) Tfh cells (P = 0.04), but increased foxp3(+) CD4(+) (Treg) cells in the CD4(+) population (P = 0.04 vs. control). The IgG ELISpot experiments showed a significant reduction of IgG spots in the bone marrow and the spleen cells from the anti-IL-6R-treated mice. In vitro treatment of mouse hybridoma (PA2.1) cultures with anti-IL-6R decreased IgG spot formation but had limited effect on cell proliferation.Conclusion. The data indicate that anti-IL-6R therapy attenuates alloantibody recall responses by modulating a number of immune regulatory and effector cells, including Th17, Tfh, Treg, and importantly, the long-lived plasma cells in the bone marrow.