人类巨噬细胞迁移抑制因子增强了在过敏性哮喘临床相关模型中间充质干细胞的疗效
2023/10/25
摘要
目前的哮喘治疗侧重于减轻症状，但未能恢复现有的结构损伤。间充质干细胞（MSC）的治疗可以改善气道炎症并逆转气道重塑。然而，患者疾病微环境的差异似乎会影响MSC的治疗效果。人类巨噬细胞迁移抑制因子（hMIF）基因位于794位的多态性CATT四核苷酸重复已与哮喘的易感性和严重程度增加有关。我们在高和低hMIF环境中以及使用人源MIF小鼠预先许可MSC的情况下，研究了人类MSC在临床相关的过敏性哮喘家尘螨模型中的疗效。MSC显著减轻了高表达CATT7小鼠的气道炎症和气道重塑，但未在CATT5或野生型小鼠中产生相同效果。疗效差异与CATT7小鼠肺部MSC滞留的增加相关。MIF许可在以前无效的剂量下增强了MSC的抗炎效果。从机制上看，MIF与MSC上表达的CD74结合导致COX-2表达上调。在MSC给药之前阻断CD74或COX-2功能会减弱体内MIF许可MSC的疗效。这些发现表明，在具有高MIF基因型（CATT6/7/8）的严重哮喘患者中，MSC的给药可能更有效。
Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma
Ian J Hawthorne, Hazel Dunbar, Courteney Tunstead, Tamara Schorpp, Daniel J Weiss, Sara Rolandsson Enes, Claudia C Dos Santos, Michelle E Armstrong, Seamas C Donnelly, Karen English
Abstract
Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodelling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. Polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility and severity of asthma. We investigated the efficacy of human MSCs in high vs low hMIF environments and the impact of MIF pre-licensing of MSCs using humanised MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodelling in high MIF expressing CATT7mice, but not in CATT5or wildtype littermates. Differences in efficacy correlated with increased MSC retention in the lungs of CATT7mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of COX-2 expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT6/7/8).
目前的哮喘治疗侧重于减轻症状，但未能恢复现有的结构损伤。间充质干细胞（MSC）的治疗可以改善气道炎症并逆转气道重塑。然而，患者疾病微环境的差异似乎会影响MSC的治疗效果。人类巨噬细胞迁移抑制因子（hMIF）基因位于794位的多态性CATT四核苷酸重复已与哮喘的易感性和严重程度增加有关。我们在高和低hMIF环境中以及使用人源MIF小鼠预先许可MSC的情况下，研究了人类MSC在临床相关的过敏性哮喘家尘螨模型中的疗效。MSC显著减轻了高表达CATT7小鼠的气道炎症和气道重塑，但未在CATT5或野生型小鼠中产生相同效果。疗效差异与CATT7小鼠肺部MSC滞留的增加相关。MIF许可在以前无效的剂量下增强了MSC的抗炎效果。从机制上看，MIF与MSC上表达的CD74结合导致COX-2表达上调。在MSC给药之前阻断CD74或COX-2功能会减弱体内MIF许可MSC的疗效。这些发现表明，在具有高MIF基因型（CATT6/7/8）的严重哮喘患者中，MSC的给药可能更有效。
(中日友好医院呼吸与危重症医学科 顾宪民 摘译 林江涛 审校)
(Mol Ther.2023 Sep 20;S1525-0016(23)00500-2.doi: 10.1016/j.ymthe.2023.09.013.)
(Mol Ther.2023 Sep 20;S1525-0016(23)00500-2.doi: 10.1016/j.ymthe.2023.09.013.)
Human macrophage migration inhibitory factor potentiates mesenchymal stromal cell efficacy in a clinically relevant model of allergic asthma
Ian J Hawthorne, Hazel Dunbar, Courteney Tunstead, Tamara Schorpp, Daniel J Weiss, Sara Rolandsson Enes, Claudia C Dos Santos, Michelle E Armstrong, Seamas C Donnelly, Karen English
Abstract
Current asthma therapies focus on reducing symptoms but fail to restore existing structural damage. Mesenchymal stromal cell (MSC) administration can ameliorate airway inflammation and reverse airway remodelling. However, differences in patient disease microenvironments seem to influence MSC therapeutic effects. Polymorphic CATT tetranucleotide repeat at position 794 of the human macrophage migration inhibitory factor (hMIF) gene has been associated with increased susceptibility and severity of asthma. We investigated the efficacy of human MSCs in high vs low hMIF environments and the impact of MIF pre-licensing of MSCs using humanised MIF mice in a clinically relevant house dust mite (HDM) model of allergic asthma. MSCs significantly attenuated airway inflammation and airway remodelling in high MIF expressing CATT7mice, but not in CATT5or wildtype littermates. Differences in efficacy correlated with increased MSC retention in the lungs of CATT7mice. MIF licensing potentiated MSC anti-inflammatory effects at a previously ineffective dose. Mechanistically, MIF binding to CD74 expressed on MSCs leads to upregulation of COX-2 expression. Blockade of CD74 or COX-2 function in MSCs prior to administration attenuated the efficacy of MIF-licensed MSCs in vivo. These findings suggest that MSC administration may be more efficacious in severe asthma patients with high MIF genotypes (CATT6/7/8).
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