Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 mice.
Constitutive reduction in the checkpoint inhibitor, CTLA-4, does not accelerate SLE in NZM 2328 mice.
复制标题
检查点抑制剂 CTLA-4 的组成性减少不会加速 NZM 2328 小鼠的 SLE。
DOI：
10.1136/lupus-2018-000313
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发表时间：
2019
影响因子：
3.9
通讯作者：
Jacob,ChaimO
中科院分区：
文献类型：
--
作者：
Stohl,William;Yu,Ning;Chalmers,SamanthaA;Putterman,Chaim;Jacob,ChaimO
背景/目的肿瘤患者中免疫检查点抑制剂（ICI）的治疗正在增加。虽然ICI触发风湿性免疫相关的不良事件，发展SLE的特点是罕见的。长期使用ICI治疗是否会促进SLE的特征仍不清楚。为了开始解决这一问题，我们产生了SLE倾向NZM 2328小鼠与终身减少CTLA-4 expression.MethodsSince CTLA-4-deficient（Ctla 4 −/−）NZM小鼠开发了一个致命的淋巴组织增生性疾病的3-6周龄，在这些小鼠中的SLE的发展不能被研究。Ctla 4 haploinsufficient NZM. Ctla 4 +/−小鼠进行了评估，在与同窝雌性NZM. Ctla 4 +/+小鼠平行。评估包括CTLA-4的表达和淋巴细胞概况，通过荧光激活细胞分选评估;血清学概况，通过ELISA评估;肾免疫病理学，通过组织学和免疫荧光评估;和临床病程，通过mortality.ResultsCTLA-4的表达在NZM. Ctla 4 +/−小鼠比在NZM. Ctla 4 +/+小鼠较低。NZM. Ctla 4 +/−小鼠的脾单核细胞、B细胞、浆细胞、CD 4+细胞、近期活化的CD 4+细胞和CD 4 +T调节（Treg）细胞增加（p≤0.042）。NZM. Ctla 4 +/−小鼠的血清学特征，肾脏免疫病理学和死亡率的程度保持insufficient.ConclusionLifelong减少CTLA-4的表达在NZM小鼠既不加速也不加重SLE。Treg细胞的扩增可能起到了保护作用。我们的观察提出了这样的希望，即如果需要，用抗CTLA-4药物长期治疗SLE患者不会对SLE疾病活动产生不利影响。
Background/objectiveTreatment with immune checkpoint inhibitors (ICIs) in oncology patients is increasing. Although ICIs trigger rheumatic immune-related adverse events, development of SLE features has been rare. Whether long-term treatment with ICIs would promote SLE features remains unknown. To begin to address this, we generated SLE-prone NZM 2328 mice with lifelong reduction in CTLA-4 expression.MethodsSince CTLA-4-deficient (Ctla4−/−) NZM mice developed a lethal lymphoproliferative disorder by 3–6 weeks of age, development of SLE in these mice could not be studied.Ctla4haploinsufficient NZM.Ctla4+/−mice were assessed in parallel with littermate female NZM.Ctla4+/+mice. Evaluations included CTLA-4 expression and lymphocyte profiles, assessed by fluorescence-activated cell sorting; serological profiles, assessed by ELISA; renal immunopathology, assessed by histology and immunofluorescence; and clinical courses, assessed by mortality.ResultsCTLA-4 expression was lower in NZM.Ctla4+/−mice than in NZM.Ctla4+/+mice. Spleen mononuclear cells, B cells, plasma cells, CD4+cells, recently activated CD4+cells and CD4+T regulatory (Treg) cells were increased in NZM.Ctla4+/−mice (p≤0.042). The serological profile, degree of renal immunopathology and mortality in NZM.Ctla4+/−mice remained unaffected.ConclusionLifelong reduction in CTLA-4 expression in NZM mice neither accelerated nor aggravated SLE. Expansion in Treg cells may have played a protective role. Our observations raise the hope that long-term treatment of patients with SLE with an anti-CTLA-4 agent, should the need arise, would not adversely affect SLE disease activity.