A cell-impermeable cyclosporine A derivative reduces pathology in a mouse model of allergic lung inflammation.
A cell-impermeable cyclosporine A derivative reduces pathology in a mouse model of allergic lung inflammation.
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DOI：
10.4049/jimmunol.1001707
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发表时间：
2010-12-15
期刊：
影响因子：
--
通讯作者：
Constant SL
中科院分区：
文献类型：
--
作者：
Balsley MA;Malesevic M;Stemmy EJ;Gigley J;Jurjus RA;Herzog D;Bukrinsky MI;Fischer G;Constant SL
虽然白细胞运输的主要调节因子是趋化因子，但另一个趋化因子家族是亲环素。细胞内亲环蛋白作为肽基-蛋白基顺反异构酶发挥作用，是免疫抑制药物环孢素A（CsA）的靶点。亲环素也可以响应于应激因子而分泌，在几种炎性疾病中检测到细胞外亲环素水平升高。已知细胞外亲环素具有有效的趋化特性，这表明它们可能通过将白细胞募集到组织中来促进炎症反应。本研究的目的是确定使用CsA的细胞不可渗透衍生物MM 218阻断亲环素活性的影响，以特异性靶向亲环素的细胞外池。我们表明，在过敏性肺部炎症的小鼠模型中使用该化合物进行治疗：1）炎症减少高达80%，2）直接抑制抗原特异性CD 4 + T细胞的募集，3）当以100倍的低剂量递送至气道时同样有效。我们的研究结果表明，CsA的细胞不可渗透的类似物可以有效地减少炎症反应，通过靶向细胞外亲环素介导的白细胞募集。特异性阻断亲环素的细胞外功能可以提供一种新的方法，用于抑制过敏性肺部炎症的主要免疫调节因子之一，抗原特异性CD 4 + T细胞募集到发炎的气道和肺部。
Although the main regulators of leukocyte trafficking are chemokines, another family of chemotactic agents is cyclophilins. Intracellular cyclophilins function as peptidyl-protyl cis-trans isomerases and are targets of the immunosuppressive drug, cyclosporine A (CsA). Cyclophilins can also be secreted in response to stress factors, with elevated levels of extracellular cyclophilins detected in several inflammatory diseases. Extracellular cyclophilins are known to have potent chemotactic properties, suggesting they might contribute to inflammatory responses by recruiting leukocytes into tissues. The objective of the current study was to determine the impact of blocking cyclophilin activity using a cell-impermeable derivative of CsA, MM218, to specifically target extracellular pools of cyclophilins. We show that treatment with this compound in a mouse model of allergic lung inflammation: 1) demonstrates up to 80% reduction in inflammation, 2) directly inhibits the recruitment of antigen-specific CD4+ T cells, and 3) works equally well when delivered at 100-fold lower doses to the airways. Our findings suggest that cell-impermeable analogs of CsA can effectively reduce inflammatory responses by targeting leukocyte recruitment mediated by extracellular cyclophilins. Specifically blocking the extracellular function(s) of cyclophilins may provide a novel approach for inhibiting the recruitment of one of the principal immune regulators of allergic lung inflammation, antigen-specific CD4+ T cells, into inflamed airways and lungs.
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影响因子：
2.9
作者：
Daum, Sebastian;Schumann, Michael;Mathea, Sebastian;Aumueller, Tobias;Balsley, Molly A.;Constant, Stephanie L.;de Lacroix, Boris Feaux;Kruska, Fabian;Braun, Manfred;Schiene-Fischer, Cordelia
通讯作者：
Schiene-Fischer, Cordelia
影响因子：
4.4
作者：
Arora, K;Gwinn, WM;Constant, SL
通讯作者：
Constant, SL
影响因子：
16.6
作者：
Malesevic, Miroslav;Kuehling, Jan;Fischer, Gunter
通讯作者：
Fischer, Gunter
DOI：
10.1084/jem.185.5.975
发表时间：
1997-03-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Billich A;Winkler G;Aschauer H;Rot A;Peichl P
通讯作者：
Peichl P
DOI：
10.1073/pnas.90.24.11850
发表时间：
1993-12-15
影响因子：
11.1
作者：
KE, HM;ZHAO, YD;FRIEDMAN, J
通讯作者：
FRIEDMAN, J