Inhibition of calpain attenuates encephalitogenicity of MBP-specific T cells.
Inhibition of calpain attenuates encephalitogenicity of MBP-specific T cells.
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DOI：
10.1111/j.1471-4159.2009.06287.x
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发表时间：
2009-09
影响因子：
4.7
通讯作者：
Banik NL
中科院分区：
文献类型：
--
作者：
Guyton MK;Brahmachari S;Das A;Samantaray S;Inoue J;Azuma M;Ray SK;Banik NL
多发性硬化症（MS）是一种T细胞介导的中枢神经系统自身免疫性疾病，具有导致残疾的免疫和神经退行性事件。将髓鞘碱性蛋白（MBP）特异性T细胞连续转移（AT）到未经处理的雌性SJL/J小鼠中导致复发-缓解（RR）形式的实验性自身免疫性脑脊髓炎（EAE）。阻断MBP特异性T细胞在AT之前被激活的机制可能有助于表征MS的免疫臂，并为治疗提供新的靶点。一种这样的靶标是钙蛋白酶，其参与T细胞的活化、免疫细胞向CNS中的迁移、轴突和髓鞘蛋白的降解以及神经元凋亡。因此，测试了抑制MBP特异性T细胞中的钙蛋白酶将减少其在RR-EAE小鼠中的致脑炎性的假设。在AT之前用钙蛋白酶抑制剂SJA 6017孵育MBP特异性T细胞显著抑制这些T细胞诱导RR-EAE临床症状的能力。这些减少与脱髓鞘、炎症、轴突损伤以及少突胶质细胞和神经元损失的减少相关。此外，钙蛋白酶：钙蛋白酶抑制素比率、tBID的产生、Bax：Bcl-2比率、钙蛋白酶和半胱氨酸蛋白酶的活性以及核小体间DNA片段化都有所减弱。因此，这些数据表明钙蛋白酶是治疗EAE和MS的有希望的靶点。
Multiple sclerosis (MS) is a T cell-mediated autoimmune disease of the CNS, possessing both immune and neurodegenerative events that lead to disability. Adoptive transfer (AT) of myelin basic protein (MBP)-specific T cells into naïve female SJL/J mice results in a relapsing-remitting (RR) form of experimental autoimmune encephalomyelitis (EAE). Blocking the mechanisms by which MBP-specific T cells are activated before AT may help characterize the immune arm of MS and offer novel targets for therapy. One such target is calpain, which is involved in activation of T cells, migration of immune cells into the CNS, degradation of axonal and myelin proteins, and neuronal apoptosis. Thus, the hypothesis that inhibiting calpain in MBP-specific T cells would diminish their encephalitogenicity in RR-EAE mice was tested. Incubating MBP-specific T cells with the calpain inhibitor SJA6017 before AT markedly suppressed the ability of these T cells to induce clinical symptoms of RR-EAE. These reductions correlated with decreases in demyelination, inflammation, axonal damage, and loss of oligodendrocytes and neurons. Also, calpain:calpastatin ratio, production of tBid, and Bax:Bcl-2 ratio, and activities of calpain and caspases, and internucleosomal DNA fragmentation were attenuated. Thus, these data suggest calpain as a promising target for treating EAE and MS.
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