Laquinimod Delays and Suppresses Nephritis in Lupus-Prone Mice and Affects Both Myeloid and Lymphoid Immune Cells
Laquinimod Delays and Suppresses Nephritis in Lupus-Prone Mice and Affects Both Myeloid and Lymphoid Immune Cells
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DOI：
10.1002/art.38259
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发表时间：
2014-03-01
影响因子：
13.3
通讯作者：
Skaggs, Brian J.
中科院分区：
文献类型：
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作者：
Lourenco, Elaine V.;Wong, Maida;Skaggs, Brian J.
目标。狼疮性肾炎依赖于自身抗体的沉积和多种免疫细胞类型的激活，这些细胞类型促进了肾脏炎症，包括淋巴细胞和单核/巨噬细胞。拉奎莫特目前正在治疗多发性硬化症和狼疮性肾炎的临床试验中，它减少了实验性自身免疫性脑脊髓炎患者炎性细胞向脊髓的渗透。系统性红斑狼疮(SLE)肾炎时活化的单核/巨噬细胞渗入肾脏。我们开展了这项研究，以确定在SLE肾炎中使用拉奎莫特来减少单核/巨噬细胞驱动的组织损伤以及改变淋巴细胞是否比目前主要影响淋巴细胞的治疗方法，如霉酚酸酯(MMF)有更大的疗效。为了测试拉奎莫特的疗效，我们使用了(NZB X NZW)F1小鼠SLE模型，在该模型中，疾病表现为肾炎。进行预防和治疗研究，以确定拉奎莫特是否可以预防或延缓肾炎，通过蛋白尿、血清肌酐、存活率和肾脏病理来衡量。采用流式细胞术对小鼠脾、肾白细胞计数及抑制实验进行分析。拉奎莫特预防或延迟狼疮症状的效果与MMF相当或更好。拉奎莫特治疗与单核/巨噬细胞、树突状细胞和淋巴细胞的数量减少以及脾和肾脏中髓系来源的抑制细胞的诱导有关。拉奎莫特抑制巨噬细胞分泌的肿瘤坏死因子α，并诱导产生白细胞介素10(IL-10)。此外，拉奎莫特还抑制淋巴细胞产生干扰素-γ和IL-17，下调抗原提呈细胞活化/共刺激标志物的表达。拉奎莫特对髓系和淋巴系细胞的作用可能有助于改善(NZB X NZW)F1小鼠的存活、蛋白尿和肾炎。拉奎莫特作为狼疮性肾炎的治疗药物具有广阔的发展前景。
Objective. Lupus nephritis depends on autoantibody deposition and activation of multiple immune cell types that promote kidney inflammation, including lymphocytes and monocyte/macrophages. Laquinimod, currently in clinical trials for multiple sclerosis and lupus nephritis, reduces infiltration of inflammatory cells into the spinal cord in experimental autoimmune encephalomyelitis. Activated monocyte/macrophages infiltrate the kidneys during nephritis in systemic lupus erythematosus (SLE). We undertook this study to determine whether using laquinimod to reduce monocyte/macrophage-driven tissue damage as well as to alter lymphocytes in SLE nephritis could have greater therapeutic benefit than current treatments that primarily affect lymphocytes, such as mycophenolate mofetil (MMF).Methods. To test laquinimod efficacy, we used the (NZB x NZW) F1 mouse model of SLE, in which disease manifests as nephritis. Preventive and therapeutic studies were performed to determine whether laquinimod could prevent or delay nephritis, as measured by proteinuria, serum creatinine, survival, and renal pathology. Spleen and kidney leukocyte populations and suppression assays were analyzed by flow cytometry.Results. Laquinimod prevented or delayed lupus manifestations at levels equal to or better than MMF. Laquinimod treatment was associated with reduced numbers of monocyte/macrophages, dendritic cells, and lymphocytes, as well as with induction of myeloid-derived suppressor cells in spleens and kidneys. Laquinimod suppressed macrophage-secreted tumor necrosis factor alpha and induced production of interleukin-10 (IL-10). In addition, laquinimod suppressed interferon-gamma and IL-17 production by lymphocytes and down-regulated expression of activation/costimulatory markers on antigen-presenting cells.Conclusion. The effects of laquinimod on myeloid and lymphoid cells may contribute to improvements in (NZB x NZW) F1 mouse survival, proteinuria, and glomerulonephritis. Future development of laquinimod as a therapeutic agent for lupus nephritis is promising.