一個國際科研小組在新一期《自然-醫(yī)學》雜志上報告說,,他們發(fā)現(xiàn)了免疫細胞入侵引發(fā)大腦炎癥的關鍵受體“調(diào)節(jié)器”,。
德國馬克斯·德爾布呂克分子醫(yī)學中心研究人員與美國和加拿大同行合作完成了這項研究,。他們在最新的研究中發(fā)現(xiàn),,在患多發(fā)性硬化癥的患者和患腦炎的實驗鼠的T細胞表面,,有一種名為緩激肽受體1的受體,,對T細胞入侵中樞系統(tǒng)起到關鍵的控制作用。當T細胞表面缺乏這種受體時,,實驗鼠的腦炎癥狀會更加嚴重。
研究人員用特殊物質(zhì)將患腦炎實驗鼠T細胞表面的緩激肽受體1激活,。結(jié)果顯示,,病鼠的T細胞入侵中樞神經(jīng)系統(tǒng)的速度減緩,大腦炎癥明顯緩解,。
研究人員希望,,這一新發(fā)現(xiàn)能夠有助于開發(fā)出針對多發(fā)性硬化癥等中樞神經(jīng)系統(tǒng)炎癥的臨床治療新方法。(生物谷Bioon.com)
生物谷推薦原始出處:
Nature Medicine 28 June 2009 | doi:10.1038/nm.1980
Activation of kinin receptor B1 limits encephalitogenic T lymphocyte recruitment to the central nervous system
Ulf Schulze-Topphoff1, Alexandre Prat2, Timour Prozorovski1,6, Volker Siffrin1, Magdalena Paterka1, Josephine Herz1, Ivo Bendix1, Igal Ifergan2, Ines Schadock3, Marcelo A Mori3, Jack Van Horssen4, Friederike Schr?ter1,6, Alina Smorodchenko1, May Htwe Han5, Michael Bader3, Lawrence Steinman5, Orhan Aktas1,6,7 & Frauke Zipp1,7
Previous proteomic and transcriptional analyses of multiple sclerosis lesions1, 2, 3 revealed modulation of the renin-angiotensin and the opposing kallikrein-kinin pathways. Here we identify kinin receptor B1 (Bdkrb1) as a specific modulator of immune cell entry into the central nervous system (CNS). We demonstrate that the Bdkrb1 agonist R838 (Sar-[D-Phe]des-Arg9-bradykinin) markedly decreases the clinical symptoms of experimental autoimmune encephalomyelitis (EAE) in SJL mice4, 5, 6, whereas the Bdkrb1 antagonist R715 (Ac-Lys-[D-Nal7, Ile8]des-Arg9-bradykinin) resulted in earlier onset and greater severity of the disease. Bdkrb1-deficient (Bdkrb1-/-) C57BL/6 mice7 immunized with a myelin oligodendrocyte glycoprotein fragment, MOG35–55, showed more severe disease with enhanced CNS-immune cell infiltration. The same held true for mixed bone marrow–chimeric mice reconstituted with Bdkrb1-/- T lymphocytes, which showed enhanced T helper type 17 (TH17) cell invasion into the CNS. Pharmacological modulation of Bdkrb1 revealed that in vitro migration of human TH17 lymphocytes across blood-brain barrier endothelium is regulated by this receptor. Taken together, these results suggest that the kallikrein-kinin system is involved in the regulation of CNS inflammation, limiting encephalitogenic T lymphocyte infiltration into the CNS, and provide evidence that Bdkrb1 could be a new target for the treatment of chronic inflammatory diseases such as multiple sclerosis.
1 Cecilie Vogt Klinik, Charité–University Hospital Berlin, Max Delbrueck Center for Molecular Medicine and NeuroCure Research Center, Berlin, Germany.
2 Neuroimmunology Research Laboratory, Centre Hospitalier de l'Université de Montréal, Montréal, Québéc, Canada.
3 Max Delbrueck Center for Molecular Medicine, Berlin, Germany.
4 Department of Molecular Cell Biology and Immunology, Vrije Universiteit University Medical Center, Amsterdam, The Netherlands.
5 Department of Neurology and Neurological Sciences, Stanford University, Stanford, California, USA.
6 Current addresses: Molecular Neurology Research Group, Department of Neurology, Heinrich-Heine-University Duesseldorf, Germany (T.P., O.A.); Institute of Biochemistry, Charité–University Hospital Berlin, Germany (F.S.).
7 These authors contributed equally to this work.