移植医学：发现了对ATG免疫抑制机制的新见解

诸平

(Vienna, 04-04-2023) A team of researchers at MedUni Vienna has newly appraised the immunosuppressive effect of antithymocyte globulin (ATG) and identified a previously unknown mode of action. The new findings on ATG, which are used for induction therapy prior to organ transplantations and for the treatment of T-cell mediated rejection reactions, provide a new approach for further improvements in transplantation medicine. The results of the study were recently published in Cells.

据奥地利维也纳医科大学(Medical University of Vienna简称MedUni Vienna, Vienna, Austria)2023年4月4日报道，MedUni Vienna的一组研究人员最近评估了抗胸腺细胞球蛋白 (antithymocyte globulin简称ATG) 的免疫抑制作用，并确定了一种以前未知的作用方式。ATG的新发现可用于器官移植前的诱导治疗和T细胞介导的排斥反应（T-cell mediated rejection reactions）的治疗，为进一步改进移植医学提供了新途径（Transplantation medicine: Novel insights into immunosuppressive mechanism of ATG identified）。该研究结果于2023年1月20日已经在《细胞》（Cells）杂志网站发表——Dragan Copic, Martin Direder, Katharina Klas, Daniel Bormann, Maria Laggner, Hendrik Jan Ankersmit, Michael Mildner. Antithymocyte Globulin Inhibits CD⁸⁺ T Cell Effector Functions via the Paracrine Induction of PDL-1 on Monocytes. Cells, Published: 20 January 2023, 12(3), 382. DOI: 10.3390/cells12030382. https://doi.org/10.3390/cells12030382

ATG是移植医学中重要的治疗成分。ATG的作用由多种机制的复杂相互作用介导，包括直接抑制和耗竭T细胞、诱导调节性T细胞和调节树突状细胞（dendritic cells）。由第一作者、内科III——肾脏病学和透析科（Department of Internal Medicine III, Division of Nephrology and Dialysis）的德拉甘·科皮克（Dragan Copic）和两位研究负责人胸外科的亨德里克·扬·安克斯米特（Hendrik Jan Ankersmit）和皮肤科的迈克尔·米尔德拉（Michael Mildner）领导的研究小组，在MedUni Vienna通过更详细地检查血细胞，研究了ATG在旁分泌因子（paracrine factors）释放中的作用。

扩展对ATG的理解（Expanded understanding of ATG）

ATG的免疫抑制作用通常归因于其T细胞消耗特性。然而，来自不同研究小组的证据指出了其他作用模式，这些模式直接作用于特定的T淋巴细胞亚群，或通过旁分泌因子的释放间接作用。在当前的临床前研究中，MedUni Vienna团队能够证明ATG引发单核细胞基因特征的显著变化，具体由T细胞释放的干扰素-γ（interferon-γ简称IFN-γ）介导。这导致单核细胞中PD-L1的表面表达增加，这在功能上削弱了体外激活的CD⁸⁺ T细胞的增殖能力和颗粒酶B（Granzyme B）的释放。德拉甘·科皮克解释说:“此外，在ATG治疗数天后，单核细胞上仍能检测到PD-L1的表达，这一事实也表明ATG可能具有持续的免疫抑制作用机制。”ATG介导的PD-L1在单核细胞上表达的首次描述扩展了对ATG及其作用模式的现有理解，并为在患者相关环境中进一步研究提供了一个新的起点。

本研究得到了维也纳商业机构资助{Vienna Business Agency Grant No. 852748 (HJA), No. 862068 (HJA)}，也得到了奥地利研究促进机构资助{The Austrian Research Promotion Agency Grant No. 2343727 (HJA)}资助。

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Abstract

Background: Antithymocyte globulins (ATG) are T cell-depleting antibodies used in solid organ transplantation for induction therapy in sensitized patients with a high risk of graft rejection. Previously described effects besides the depletion of T cells have suggested additional modes of action and identified further cellular targets. Methods: We examined the transcriptional changes arising in immune cells from human blood after ex vivo stimulation with ATG at the single-cell level to uncover additional mechanisms by which ATG regulates T cell activity and effector functions. Findings: Analysis of the paracrine factors present in the plasma of ATG-treated whole blood revealed high levels of chemokines and cytokines, including interferon-γ (IFN-γ). Furthermore, we identified an increase in the surface expression of the programmed death ligand 1 (PDL-1) on monocytes mediated by the released paracrine factors. In addition, we showed that this induction is dependent on the activation of JAK/STAT signaling via the binding of IFN-γ to interferon-γ receptor 1 (IFN-γR1). Lastly, we demonstrated that the modulation of the immune regulatory axis of programmed cell death protein 1 (PD1) on activated CD8⁺ T cells with PDL-1 found on monocytes mediated by ATG potently inhibits effector functions including the proliferation and granzyme B release of activated T cells. Interpretation: Together, our findings represent a novel mode of action by which ATG exerts its immunosuppressive effects.