纳呋拉芬和芬戈莫德联用治疗免疫驱动的脱髓鞘疾病可增强疗效并实现互补

IF 4.6 2区 医学 Q2 IMMUNOLOGY Clinical & Translational Immunology Pub Date : 2023-12-12 DOI:10.1002/cti2.1480
Katharina Robichon, Rabia Bibi, Mackenzie Kiernan, Lisa Denny, Thomas E Prisinzano, Bronwyn M Kivell, Anne Camille La Flamme
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引用次数: 0

摘要

目标 多发性硬化症(MS)是一种以炎症和髓鞘损伤为特征的神经退行性疾病。虽然目前所有的改变病情疗法(DMTs)都能有效减少复发,但它们并不能延缓疾病的进展,而且几乎没有证据表明这些疗法能够修复或再髓鞘化受损的轴突。最近的证据表明,激活卡巴阿片受体(KORs)对多发性硬化症的进展有好处,本研究调查了KOR激动剂与目前两种DMTs联合治疗的效果。 方法 使用免疫驱动的多发性硬化脱髓鞘的成熟小鼠模型--实验性自身免疫性脑脊髓炎,分析 KOR 激动剂与 DMTs 芬戈莫德或富马酸二甲酯联用对疾病进展、免疫细胞浸润和活化以及髓鞘化的影响。 结果 芬戈莫德与 KOR 激动剂纳呋拉芬联用,能显著提高每种单药的疗效,具体表现为小鼠恢复能力增强,复发次数减少。这些有益效果与中枢神经系统免疫细胞浸润的减少以及外周免疫细胞的改变有关,包括自反应性 CD4+ T 细胞细胞因子产生的减少以及联合治疗动物脊髓髓鞘化的增加。相比之下,虽然富马酸二甲酯与纳呋拉芬联合使用不会对纳呋拉芬的疗效产生不利影响,但联合使用也不会显著增强这些疗效。 结论 本研究表明,KOR 激动剂可与芬戈莫德和富马酸二甲酯联用,纳呋拉芬-芬戈莫德联用可提高疗效。
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Enhanced and complementary benefits of a nalfurafine and fingolimod combination to treat immune-driven demyelination

Objectives

Multiple sclerosis (MS) is a neurodegenerative disease characterised by inflammation and damage to myelin sheaths. While all current disease-modifying treatments (DMTs) are very effective at reducing relapses, they do not slow the progression of the disease, and there is little evidence that these treatments are able to repair or remyelinate damaged axons. Recent evidence suggests that activating kappa opioid receptors (KORs) has a beneficial effect on the progression of MS, and this study investigates the effects of KOR agonists treatment in combination with two current DMTs.

Methods

Using the well-established murine model for immune-driven demyelination of MS, experimental autoimmune encephalomyelitis, the effect of KOR agonists in combination with DMTs fingolimod or dimethyl fumarate on disease progression, immune cell infiltration and activation as well as myelination were analysed.

Results

Fingolimod in combination with the KOR agonist, nalfurafine, significantly increased each individual beneficial effect as measured by increased recovery of mice and reduced relapses. These beneficial effects correlated with a reduction in immune cell infiltration into the CNS as well as peripheral immune cell alterations including a reduction in autoreactive CD4+ T-cell cytokine production as well as increased myelination in the spinal cords of co-treated animals. In contrast, while the use of dimethyl fumarate in combination with nalfurafine did not adversely affect the benefits of nalfurafine, the combination did not significantly enhance those benefits.

Conclusion

This study indicates that KOR agonists can be used in combination with fingolimod and dimethyl fumarate with the nalfurafine–fingolimod combination providing enhanced benefits.

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来源期刊
Clinical & Translational Immunology
Clinical & Translational Immunology Medicine-Immunology and Allergy
CiteScore
12.00
自引率
1.70%
发文量
77
审稿时长
13 weeks
期刊介绍: Clinical & Translational Immunology is an open access, fully peer-reviewed journal devoted to publishing cutting-edge advances in biomedical research for scientists and physicians. The Journal covers fields including cancer biology, cardiovascular research, gene therapy, immunology, vaccine development and disease pathogenesis and therapy at the earliest phases of investigation.
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