Active immunization with myelin-derived altered peptide ligand reduces mechanical pain hypersensitivity following peripheral nerve injury.
Active immunization with myelin-derived altered peptide ligand reduces mechanical pain hypersensitivity following peripheral nerve injury.
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DOI：
10.1186/s12974-015-0253-4
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发表时间：
2015-02-13
影响因子：
9.3
通讯作者：
Moalem-Taylor G
中科院分区：
文献类型：
--
作者：
Perera CJ;Duffy SS;Lees JG;Kim CF;Cameron B;Apostolopoulos V;Moalem-Taylor G
T细胞与周围神经损伤引起的神经性疼痛有关。免疫原性髓鞘碱性蛋白（MBP）肽已被证明以T细胞依赖性方式启动机械异常性疼痛。拮抗性改变的肽配体（APLs）是在T细胞受体接触位点的氨基酸残基中具有取代的肽，并且可以抑制T细胞功能并调节炎症反应。在本研究中，我们研究了MBP衍生的APL免疫对周围神经损伤动物模型的疼痛行为和神经炎症的影响。在左侧坐骨神经慢性压迫性损伤（CCI）后，将刘易斯大鼠在尾根部皮下免疫接种于在完全弗氏佐剂（CFA）中的MBP（环-MBP 87 -99）或APL（环-（87-99）[A91，A96] MBP 87 -99）的弱致脑炎肽或仅CFA（对照）。通过测量机械刺激的缩爪阈值测试疼痛超敏性，通过流式细胞术分析脾和淋巴结中的调节性T细胞，并通过免疫组织化学评估免疫细胞浸润到神经系统中（CCI后10天和30天）。测定神经损伤大鼠（CCI后第10天）血清和神经组织中的细胞因子。与环-MBP 87 -99处理的和对照大鼠相比，用APL环-（87-99）[A91，A96] MBP 87 - 99免疫的大鼠在同侧后爪中具有显著降低的机械疼痛超敏性。这与APL治疗动物的受损神经中T细胞和ED 1+巨噬细胞浸润显著减少有关。CCI后第30天，APL治疗的大鼠中抗炎（M2）巨噬细胞的百分比显著上调。与对照组大鼠相比，MBP治疗组大鼠同侧腰髓小胶质细胞活化显著增加，但在用MBP衍生的APL免疫的大鼠中没有改变。此外，免疫与APL显着增加脾脏调节性T细胞。CCI后几种细胞因子显著改变，但APL治疗组和对照组大鼠之间没有观察到显著差异。这些结果表明，免疫偏离主动免疫与非致脑炎MBP衍生APL介导周围神经损伤的动物的镇痛作用。因此，T细胞免疫调节作为治疗周围神经性疼痛的可能治疗策略值得进一步研究。
T cells have been implicated in neuropathic pain that is caused by peripheral nerve injury. Immunogenic myelin basic protein (MBP) peptides have been shown to initiate mechanical allodynia in a T cell-dependent manner. Antagonistic altered peptide ligands (APLs) are peptides with substitutions in amino acid residues at T cell receptor contact sites and can inhibit T cell function and modulate inflammatory responses. In the present study, we studied the effects of immunization with MBP-derived APL on pain behavior and neuroinflammation in an animal model of peripheral nerve injury. Lewis rats were immunized subcutaneously at the base of the tail with either a weakly encephalitogenic peptide of MBP (cyclo-MBP87-99) or APL (cyclo-(87-99)[A91,A96]MBP87-99) in complete Freund’s adjuvant (CFA) or CFA only (control), following chronic constriction injury (CCI) of the left sciatic nerve. Pain hypersensitivity was tested by measurements of paw withdrawal threshold to mechanical stimuli, regulatory T cells in spleen and lymph nodes were analyzed by flow cytometry, and immune cell infiltration into the nervous system was assessed by immunohistochemistry (days 10 and 30 post-CCI). Cytokines were measured in serum and nervous tissue of nerve-injured rats (day 10 post-CCI). Rats immunized with the APL cyclo-(87-99)[A91,A96]MBP87-99 had significantly reduced mechanical pain hypersensitivity in the ipsilateral hindpaw compared to cyclo-MBP87-99-treated and control rats. This was associated with significantly decreased infiltration of T cells and ED1+ macrophages in the injured nerve of APL-treated animals. The percentage of anti-inflammatory (M2) macrophages was significantly upregulated in the APL-treated rats on day 30 post-CCI. Compared to the control rats, microglial activation in the ipsilateral lumbar spinal cord was significantly increased in the MBP-treated rats, but was not altered in the rats immunized with the MBP-derived APL. In addition, immunization with the APL significantly increased splenic regulatory T cells. Several cytokines were significantly altered after CCI, but no significant difference was observed between the APL-treated and control rats. These results suggest that immune deviation by active immunization with a non-encephalitogenic MBP-derived APL mediates an analgesic effect in animals with peripheral nerve injury. Thus, T cell immunomodulation warrants further investigation as a possible therapeutic strategy for the treatment of peripheral neuropathic pain.
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影响因子：
2.5
作者：
Ibarra, A.;Sosa, M.;Gutierrez-Ospina, G.
通讯作者：
Gutierrez-Ospina, G.
影响因子：
7.4
作者：
Barclay, Jane;Clark, Anna K.;Malcangio, Marzia
通讯作者：
Malcangio, Marzia
影响因子：
32.4
作者：
Cao, Xuefang;Cai, Sheng F.;Ley, Timothy J.
通讯作者：
Ley, Timothy J.
DOI：
10.1523/jneurosci.4569-09.2009
发表时间：
2009-11-18
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Costigan M;Moss A;Latremoliere A;Johnston C;Verma-Gandhu M;Herbert TA;Barrett L;Brenner GJ;Vardeh D;Woolf CJ;Fitzgerald M
通讯作者：
Fitzgerald M
影响因子：
15.9
作者：
Hauben, E;Agranov, E;Schwartz, M
通讯作者：
Schwartz, M