Functional blocking monoclonal antibodies against IL-12p40 homodimer inhibit adoptive transfer of experimental allergic encephalomyelitis.
Functional blocking monoclonal antibodies against IL-12p40 homodimer inhibit adoptive transfer of experimental allergic encephalomyelitis.
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DOI：
10.4049/jimmunol.0801734
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发表时间：
2009-04-15
期刊：
影响因子：
--
通讯作者：
Pahan K
中科院分区：
文献类型：
--
作者：
Mondal S;Roy A;Pahan K
IL-12 p70（p40：p35）和IL-23（p40：p19）是生物活性细胞因子，它们在多发性硬化的动物模型实验性变态反应性脑脊髓炎（EAE）中的作用正变得越来越清楚。另一方面，IL-12 p40同源二聚体（p402）被认为是一种无活性或抑制性分子，其功能知之甚少。为了促进对p402的研究，我们最近制备了抗小鼠p402的中和mAb。本研究证明了p402 mAb在治疗雌性SJL/J小鼠复发-缓解型EAE疾病过程中的有效性。p402单克隆抗体改善了受体小鼠EAE的临床症状和疾病进展，并抑制了供体小鼠致脑炎性T细胞的产生。组织学和血脑屏障（BBB）和血脊髓屏障（BSB）通透性研究表明，p402 mAb能有效抑制EAE小鼠脑和脊髓内单个核细胞的浸润，改善BBB和BSB的完整性。因此，p402 mAb还抑制了促炎分子的表达，使髓鞘基因的表达正常化，并阻断了EAE小鼠CNS中的脱髓鞘。另一方面，重组小鼠p402增加了单个核细胞向CNS的浸润，增强了通过BBB和BSB的通透性，刺激了CNS促炎分子的表达，加重了EAE的疾病进程。总之，我们的研究结果表明，p402参与发病机制的EAE和p402的中和可能是有益的多发性硬化症患者。
IL-12p70 (p40:p35) and IL-23 (p40:p19) are bioactive cytokines and their role in experimental allergic encephalomyelitis (EAE), an animal model for multiple sclerosis, are becoming clear. On the other hand, the IL-12p40 homodimer (p402) was considered as an inactive or inhibitory molecule and its functions are poorly understood. To facilitate the studies on p402, we have recently generated neutralizing mAb against mouse p402. The present study demonstrates the effectiveness of p402 mAb in treating the disease process of relapsing-remitting EAE in female SJL/J mice. The p402 mAb ameliorated clinical symptoms and disease progression of EAE in recipient mice and suppressed the generation of encephalitogenic T cells in donor mice. Histological and blood-brain barrier (BBB) and blood-spinal cord barrier (BSB) permeability studies reveal that p402 mAb effectively inhibited the infiltration of mononuclear cells into brain and spinal cord and improved the integrity of BBB and BSB in EAE mice. Consequently, p402 mAb also suppressed the expression of proinflammatory molecules, normalized the expression of myelin genes, and blocked demyelination in the CNS of EAE mice. On the other hand, recombinant mouse p402 increased the infiltration of mononuclear cells into the CNS, enhanced the permeability through BBB and BSB, stimulated CNS expression of proinflammatory molecules, and aggravated the disease process of EAE. Taken together, our results suggest that p402 participates in the pathogenesis of EAE and that neutralization of p402 may be beneficial in multiple sclerosis patients.
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影响因子：
32.4
作者：
Oppmann, B;Lesley, R;Kastelein, RA
通讯作者：
Kastelein, RA
影响因子：
3.6
作者：
Jana M;Pahan K
通讯作者：
Pahan K
DOI：
10.1084/jem.181.1.381
发表时间：
1995-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Leonard JP;Waldburger KE;Goldman SJ
通讯作者：
Goldman SJ
影响因子：
1.1
作者：
Miller, A
通讯作者：
Miller, A
影响因子：
3.3
作者：
ISSAZADEH, S;LJUNGDAHL, A;OLSSON, T
通讯作者：
OLSSON, T