Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice.
Inhibition of the alternative complement activation pathway in traumatic brain injury by a monoclonal anti-factor B antibody: a randomized placebo-controlled study in mice.
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DOI：
10.1186/1742-2094-4-13
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发表时间：
2007-05-02
影响因子：
9.3
通讯作者：
Stahel, Philip F.
中科院分区：
文献类型：
--
作者：
Leinhase, Iris;Rozanski, Michal;Harhausen, Denise;Thurman, Joshua M.;Schmidt, Oliver I.;Hossini, Amir M.;Taha, Mohy E.;Rittirsch, Daniel;Ward, Peter A.;Holers, V. Michael;Ertel, Wolfgang;Stahel, Philip F.
创伤性脑损伤（TBI）的创伤后反应的部分特征是先天免疫反应的激活，包括补体系统。我们最近的研究表明，缺乏补体激活的功能性替代途径的小鼠（因子B-/-小鼠）在TBI后免受补体介导的神经炎症和神经病理的影响。在目前的研究中，我们从基因工程小鼠的研究中推断出这一知识，并使用单克隆抗因子B抗体进行药理学研究。这种中和抗体代表了小鼠替代补体途径的特异性和有效抑制剂。采用标准化电失重模型对C57BL/6小鼠（n = 89）左半球进行局灶性损伤。将动物随机分为两组：(1)创伤后1小时和24小时，在400 μl磷酸盐缓冲盐水（PBS）中全身注射单克隆抗因子B抗体（mAb 1379） 1 mg；(2)创伤后相同时间点全身仅注射载体（400 μl PBS）作为安慰剂对照。假手术和未治疗小鼠作为另外的阴性对照。在规定的时间点进行长达1周的神经学评分评估和脑组织标本和血清样本分析。采用酶聚糖法和小鼠C5a酶联免疫吸附测定血清补体活化程度。采用免疫组织化学、末端脱氧核苷酸转移酶dUTP镍端标记（TUNEL）组织化学和实时RT-PCR对脑样本进行分析。与头部受伤的安慰剂对照组小鼠相比，mAb 1379可显著抑制替代途径补体活性，并显著降低血清中C5a水平。TBI诱导安慰剂对照组小鼠损伤脑半球出现神经炎症和神经元凋亡的组织形态学征象长达7天。相反，全身给予抑制性抗因子B抗体导致脑组织损伤和神经元细胞死亡的实质性衰减。此外，创伤后给药mAb 1379诱导了脑内基因表达的神经保护模式。通过创伤后给予中和性抗因子B抗体来抑制替代补体途径似乎代表了头部损伤后补体介导的神经炎症反应的药理学衰减的新途径。
The posttraumatic response to traumatic brain injury (TBI) is characterized, in part, by activation of the innate immune response, including the complement system. We have recently shown that mice devoid of a functional alternative pathway of complement activation (factor B-/- mice) are protected from complement-mediated neuroinflammation and neuropathology after TBI. In the present study, we extrapolated this knowledge from studies in genetically engineered mice to a pharmacological approach using a monoclonal anti-factor B antibody. This neutralizing antibody represents a specific and potent inhibitor of the alternative complement pathway in mice. A focal trauma was applied to the left hemisphere of C57BL/6 mice (n = 89) using a standardized electric weight-drop model. Animals were randomly assigned to two treatment groups: (1) Systemic injection of 1 mg monoclonal anti-factor B antibody (mAb 1379) in 400 μl phosphate-buffered saline (PBS) at 1 hour and 24 hours after trauma; (2) Systemic injection of vehicle only (400 μl PBS), as placebo control, at identical time-points after trauma. Sham-operated and untreated mice served as additional negative controls. Evaluation of neurological scores and analysis of brain tissue specimens and serum samples was performed at defined time-points for up to 1 week. Complement activation in serum was assessed by zymosan assay and by murine C5a ELISA. Brain samples were analyzed by immunohistochemistry, terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) histochemistry, and real-time RT-PCR. The mAb 1379 leads to a significant inhibition of alternative pathway complement activity and to significantly attenuated C5a levels in serum, as compared to head-injured placebo-treated control mice. TBI induced histomorphological signs of neuroinflammation and neuronal apoptosis in the injured brain hemisphere of placebo-treated control mice for up to 7 days. In contrast, the systemic administration of an inhibitory anti-factor B antibody led to a substantial attenuation of cerebral tissue damage and neuronal cell death. In addition, the posttraumatic administration of the mAb 1379 induced a neuroprotective pattern of intracerebral gene expression. Inhibition of the alternative complement pathway by posttraumatic administration of a neutralizing anti-factor B antibody appears to represent a new promising avenue for pharmacological attenuation of the complement-mediated neuroinflammatory response after head injury.
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影响因子：
82.9
作者：
Huber-Lang, Markus;Sarma, J. Vidya;Ward, Peter A.
通讯作者：
Ward, Peter A.
影响因子：
3.6
作者：
Elward, K;Gasque, P
通讯作者：
Gasque, P
影响因子：
3.9
作者：
Harris, CL;Fraser, DA;Morgan, BP
通讯作者：
Morgan, BP
影响因子：
3.6
作者：
Holers, VM;Thurman, JM
通讯作者：
Thurman, JM
DOI：
10.1196/annals.1352.020
发表时间：
2005-01-01
期刊：
NATURAL PRODUCTS AND MOLECULAR THERAPY
影响因子：
--
作者：
Kulkarni, AP;Kellaway, LA;Kotwal, GJ
通讯作者：
Kotwal, GJ