Probing the peripheral immune response in mouse models of oxaliplatin-induced peripheral neuropathy highlights their limited translatability.
Probing the peripheral immune response in mouse models of oxaliplatin-induced peripheral neuropathy highlights their limited translatability.
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DOI：
10.12688/wellcomeopenres.16635.2
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发表时间：
2021
影响因子：
--
通讯作者：
Denk F
中科院分区：
文献类型：
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作者：
Hore ZL;Villa-Hernandez S;Denk F
背景：化疗诱导的周围神经病变（CIPN）是包括奥沙利铂在内的多种化疗药物的致残性副作用。它在癌症患者中非常普遍，导致感觉异常和疼痛。不幸的是，由于对潜在的机制仍然知之甚少，缺乏有效的治疗方法。神经免疫相互作用已被强调为CIPN发展和维持的潜在贡献者，然而，奥沙利铂诱导的周围神经病变（OIPN）是否如此尚未完全确定。 研究方法：在本研究中，我们使用流式细胞术检查单次和重复奥沙利铂给药后雄性C57 BL/6小鼠的外周免疫应答。在暴露于重复给药的动物中，我们还进行了机械和热行为试验，以研究奥沙利铂如何改变表型，并对骨髓源性巨噬细胞进行了RT-qPCR实验，以进一步检查奥沙利铂对免疫细胞的影响。 结果如下：与其他报告相反，我们未能观察到背根神经节、坐骨神经或腹股沟淋巴结中总体白细胞、淋巴细胞或髓样细胞数量的实质性变化。然而，我们确实注意到重复给药后几个髓系亚群中的微妙的组织依赖性变化。这些包括坐骨神经中MHCII抗原呈递细胞的显著减少和腹股沟淋巴结中浸润细胞类型的增加。虽然奥沙利铂重复给药具有全身效应，但我们无法检测到对冷刺激或机械刺激的疼痛样行为表型。因此，我们无法评论观察到的骨髓变化是否与OIPN相关。 结论：我们的讨论将这些结果置于更广泛的领域背景下，倡导更高的报告透明度，实验设计的一致性以及引入更多临床相关模型。只有通过共同努力，我们才有希望增加我们对CIPN潜在机制的理解，包括任何免疫贡献。
Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a disabling side effect of various chemotherapeutic agents, including oxaliplatin. It is highly prevalent amongst cancer patients, causing sensory abnormalities and pain. Unfortunately, as the underlying mechanisms remain poorly understood, effective therapeutics are lacking. Neuro-immune interactions have been highlighted as potential contributors to the development and maintenance of CIPN, however, whether this is the case in oxaliplatin-induced peripheral neuropathy (OIPN) is yet to be fully established. Methods: In this study we used flow cytometry to examine the peripheral immune response of male C57BL/6 mice following both single and repeated oxaliplatin administration. In animals exposed to repeated dosing, we also undertook mechanical and thermal behavioural assays to investigate how oxaliplatin alters phenotype, and conducted RT-qPCR experiments on bone marrow derived macrophages in order to further inspect the effects of oxaliplatin on immune cells. Results: In contrast to other reports, we failed to observe substantial changes in overall leukocyte, lymphocyte or myeloid cell numbers in dorsal root ganglia, sciatic nerves or inguinal lymph nodes. We did however note subtle, tissue-dependant alterations in several myeloid subpopulations following repeated dosing. These included a significant reduction in MHCII antigen presenting cells in the sciatic nerve and an increase in infiltrating cell types into the inguinal lymph nodes. Though repeated oxaliplatin administration had a systemic effect, we were unable to detect a pain-like behavioural phenotype in response to either cold or mechanical stimuli. Consequently, we cannot comment on whether the observed myeloid changes are associated with OIPN. Conclusions: Our discussion puts these results into the wider context of the field, advocating for greater transparency in reporting, alignment in experimental design and the introduction of more clinically relevant models. Only through joint concerted effort can we hope to increase our understanding of the underlying mechanisms of CIPN, including any immune contributions.