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APRIL/BLyS 缺陷型大鼠可预防啮齿类动物肾移植模型中供体特异性抗体（DSA）的产生和细胞增殖。

APRIL/BLyS deficient rats prevent donor specific antibody (DSA) production and cell proliferation in rodent kidney transplant model.

机构信息

Department of Surgery, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

Division of Nephrology, Department of Medicine, University of Wisconsin-Madison, Madison, Wisconsin, United States of America.

出版信息

PLoS One. 2022 Oct 13;17(10):e0275564. doi: 10.1371/journal.pone.0275564. eCollection 2022.

DOI:10.1371/journal.pone.0275564
PMID:36227902
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9562156/
Abstract

APRIL (A proliferation inducing ligand) and BLyS (B Lymphocyte Stimulator) are two critical survival factors for B lymphocytes and plasma cells, the main source of alloantibody. We sought to characterize the specific effects of these cytokines in a kidney transplant model of antibody mediated rejection (AMR). We engineered APRIL-/- and BLyS-/- Lewis rats using CRISPR/Cas9. APRIL-/- and BLyS-/- rats were sensitized with Brown Norway (BN) blood (complete MHC mismatch). Twenty-one days following sensitization, animals were harvested and collected tissues were analyzed using flow cytometry, ELISPOT, and immunohistochemistry. Flow cross match and a 3 day mixed lymphocyte reaction (MLR) was performed to assess donor specific antibody (DSA) production and T-cell proliferation, respectively. Sensitized dual knock out Lewis rats (APRIL-/-/BLyS-/-) underwent kidney transplantation and were sacrificed on day 7 post-transplant. Sensitized BLyS-/- had significant decreases in DSA and cell proliferation compared to WT and APRIL-/- (p<0.02). Additionally, BLyS-/- rats had a significant reduction in IgG secreting cells in splenic marginal zone B lymphocytes, and in cell proliferation when challenged with alloantigen compared to WT and APRIL-/-. Transplanted APRIL-/-/BLyS-/- rodents had significantly less DSA and antibody secreting cells compared to WT (p<0.05); however, this did not translate into a significant difference in AMR seen between groups. In summary, our studies suggest that APRIL and BLyS play a greater role in DSA generation rather than AMR, highlighting the role of cellular pathways that regulate AMR.

摘要

四月增殖诱导配体（APRIL）和 B 淋巴细胞刺激因子（BLyS）是 B 淋巴细胞和浆细胞的两个关键存活因子，是同种抗体的主要来源。我们试图在抗体介导的排斥反应（AMR）的肾移植模型中描述这些细胞因子的特定作用。我们使用 CRISPR/Cas9 工程改造 APRIL-/-和 BLyS-/-Lewis 大鼠。APRIL-/-和 BLyS-/-大鼠用 Brown Norway（BN）血液（完全 MHC 不匹配）致敏。致敏 21 天后，采集动物并收集组织，使用流式细胞术、ELISPOT 和免疫组织化学进行分析。进行流式细胞交叉匹配和 3 天混合淋巴细胞反应（MLR），分别评估供体特异性抗体（DSA）产生和 T 细胞增殖。致敏的双重敲除 Lewis 大鼠（APRIL-/-/BLyS-/-）接受肾移植，并在移植后第 7 天处死。与 WT 和 APRIL-/-相比，致敏的 BLyS-/-大鼠的 DSA 和细胞增殖显著降低（p<0.02）。此外，与 WT 和 APRIL-/-相比，BLyS-/-大鼠脾边缘区 B 淋巴细胞中 IgG 分泌细胞和同种抗原刺激时的细胞增殖显著减少。与 WT 相比，移植的 APRIL-/-/BLyS-/-啮齿动物的 DSA 和抗体分泌细胞显著减少（p<0.05）；然而，这并没有转化为各组之间 AMR 差异的显著性。总之，我们的研究表明，APRIL 和 BLyS 在 DSA 产生中起更大作用，而不是 AMR，突出了调节 AMR 的细胞途径的作用。

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本文引用的文献

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Plasma cell targeting to prevent antibody-mediated rejection.针对浆细胞以预防抗体介导的排斥反应。
Am J Transplant. 2020 Jun;20 Suppl 4:33-41. doi: 10.1111/ajt.15889.
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OPTN/SRTR 2018 Annual Data Report: Kidney.OPTN/SRTR 2018 年度数据报告：肾脏。
Am J Transplant. 2020 Jan;20 Suppl s1:20-130. doi: 10.1111/ajt.15672.
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Desensitization and treatment with APRIL/BLyS blockade in rodent kidney transplant model.在啮齿动物肾移植模型中进行脱敏和 APRIL/BLyS 阻断治疗。
PLoS One. 2019 Feb 8;14(2):e0211865. doi: 10.1371/journal.pone.0211865. eCollection 2019.
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A 2018 Reference Guide to the Banff Classification of Renal Allograft Pathology.2018 年肾移植病理的班夫分类参考指南。
Transplantation. 2018 Nov;102(11):1795-1814. doi: 10.1097/TP.0000000000002366.
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Belimumab in kidney transplantation: an experimental medicine, randomised, placebo-controlled phase 2 trial.贝利尤单抗治疗肾移植：一项实验医学、随机、安慰剂对照的 2 期临床试验。
Lancet. 2018 Jun 30;391(10140):2619-2630. doi: 10.1016/S0140-6736(18)30984-X. Epub 2018 Jun 14.
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Complete B Cell Deficiency Reduces Allograft Inflammation and Intragraft Macrophages in a Rat Kidney Transplant Model.完全 B 细胞缺陷可减少大鼠肾移植模型中的移植物炎症和移植物内巨噬细胞。
Transplantation. 2018 Mar;102(3):396-405. doi: 10.1097/TP.0000000000002010.
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Regulatory T cells in multiple sclerosis and myasthenia gravis.多发性硬化症和重症肌无力中的调节性T细胞。
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Neutralizing BAFF/APRIL with atacicept prevents early DSA formation and AMR development in T cell depletion induced nonhuman primate AMR model.用阿他西普中和BAFF/APRIL可预防T细胞耗竭诱导的非人灵长类动物急性排斥反应模型中早期供者特异性抗体的形成和急性排斥反应的发生。
Am J Transplant. 2015 Mar;15(3):815-22. doi: 10.1111/ajt.13045. Epub 2015 Feb 12.
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