JP5009327B2 - 小グリア細胞活性化および全身炎症性反応を抑制する方法 - Google Patents
小グリア細胞活性化および全身炎症性反応を抑制する方法 Download PDFInfo
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Description
本出願は、1998年3月11日出願の米国特許仮出願第60/077,551号(現在放棄されている)の利益を主張する、1999年3月1日出願の米国特許出願第09/260,430号(現在放棄されている)の一部継続出願である、2001年9月21日出願の米国特許出願第09/957,909号の一部継続出願である。これらの出願の開示全体が本明細書中で参考として援用される。
本発明は、NIH助成金NS368087−01A2、K08NS01949、およびRO3 AG16507−01の政府援助の下で行なわれた。政府は、本発明について一定の権利を有する。
本発明は、中枢神経系(CNS)中の小グリア細胞の活性化を抑制する方法、グリア細胞または小グリア細胞の活性化を軽減または抑制する方法、脳虚血または脳炎症の神経学的影響を緩和または治療する方法、小グリア細胞受容体に結合して小グリア細胞の活性化を予防または軽減する化合物の投与によってCNSに影響を与える特異的疾患と戦う方法、および小グリア細胞の活性化を予防または軽減する能力について化合物をスクリーニングする方法に関する。本発明は、さらに、グルタミン酸興奮毒性およびN−メチル−D−アスパラギン酸(NMDA)曝露に関する神経細胞死の抑制方法ならびに敗血症で認められるような全身炎症性反応の抑制方法に関する。
中枢神経系(CNS)は、長い間、相対的免疫特権部位(relative immune privilege)であると考えられている。しかし、急性および慢性神経疾患におけるCNS組織損傷はCNS炎症反応によって媒介され得ると認識されつつある。CNS炎症反応は、主に、炎症性サイトカインによって媒介される。
本発明者らは、apoEがCNS中のグリア細胞の活性化を調整することを決定し、小グリア細胞の活性化を抑制するいくつかのペプチドをさらに同定した。1つの理論に拘束されることを望まないが、本発明者らは、小グリア細胞受容体へのApoE結合は小グリア細胞の表現型に影響を与え、種々のアクチベーターに対する小グリア細胞の反応性を減少させ、それによりこのようなアクチベーターの存在下で起こる小グリア細胞からの炎症性化合物の放出を減少させると仮定した。ApoEは活性化化合物によって結合されるのと同一の受容体に結合することができるか、アクチベーターと結合した化合物から独立して受容体に結合することができる。
本研究は、小グリア細胞のリポ多糖類(LPS)刺激後の亜硝酸塩蓄積によって測定した、小グリア細胞の一酸化窒素(NO)産生の調節における内因性apoEの役割を試験した。
(培養物の特徴づけ)ApoE欠損マウス、ApoE3マウス、および野生型マウスから調製した培養物のグリア細胞集団において有意差は認められなかった。培養物は、約70%星状細胞、15%小グリア細胞、および15%ニューロンを含んでいた。野生型マウス、ApoE欠損マウス、およびApoE3マウス由来の細胞調製物の比較により、グリア細胞集団における差は認められなかった。特に、小グリア細胞レベル(NO産生についての初代効果細胞)は、レクチン結合で検出したところ、3つ全ての培養物集団で類似していた(データ示さず)。
富化小グリア細胞初代培養物を、上記の実施例1に記載のapoE欠損幼若マウスの脳から調製した。小グリア細胞を、リポ多糖類(100ng/ml)で刺激して、実施例1に記載の小グリア細胞を活性化した。活性化小グリア細胞は、炎症性サイトカインおよび一酸化窒素を分泌し、一酸化窒素分泌を、小グリア細胞活性化のマーカーとして本実験で使用した。一酸化窒素産生を、実施例1に記載のように評価した。
腹腔マクロファージを使用して、ApoEの細胞内シグナル伝達経路を調査した。
アミノ酸130〜149(配列番号6)を含むapoEの受容体結合領域由来の20アミノ酸ペプチドを、当該分野で公知の方法に従って調製した。
配列番号6のペプチドの中毒作用を調査した。実施例5に記載の活性化(LPS)および非活性化小グリア細胞の培養物を使用した。配列番号6を有するペプチドを、0μM(コントロール)、10μM、100μM、および1000μMの量で細胞培養物に添加し、各投薬量レベルのペプチドを、単独(四角形)およびLPS(100ng/ml)と組み合わせて試験した。次いで、ペプチド添加から24時間後の光学密度によって、細胞生存度を測定した。
0μM(コントロール)、1μM、10μM、100μM、および1000μMのペプチド用量を使用して、実施例5および6に記載の実験を繰り返した。各投薬量レベルのペプチドを、単独(四角形)およびLPS(100ng/ml;円形)と組み合わせて試験した。ペプチド投与から24時間後にTNFαの産生を測定し、結果を図6に示す。細胞生存度を評価するために、細胞培養物の光学密度も測定した(24時間);結果を図7に示す。
局所虚血再灌流のマウスモデルを使用して、apoE LDL受容体領域を含む小治療ペプチド(30アミノ酸長未満)の髄腔内、静脈内、または腹腔内投与の効果を評価する。1つのこのようなペプチドは、配列番号6を有する。
全脳虚血の2匹の血管梗塞モデルから適合した全脳虚血のマウスモデルを使用して、apoE LDL受容体領域を含む小治療ペプチド(30アミノ酸長未満)の髄腔内投与の効果を評価する。1つのこのようなペプチドは、配列番号6のペプチドを有する。
この実施例は、apoEにより、イノシトール三リン酸産生の増大後の細胞内Ca2+貯蔵物の動員に関連するマウスの腹腔マクロファージのシグナル伝達カスケードが開始されることを示す。受容体結合タンパク質およびNi2+との前処置によって、このカスケードを阻害した。百日咳毒素感受性Gタンパク質によって、シグナル伝達が媒介された。これらは、リポタンパク質受容体関連タンパク質(LRP)受容体に結合するリガンドを介して誘導されるシグナル伝達の特性である。apoEの受容体結合領域由来のペプチドにより、インタクトなタンパク質と同一の様式でシグナル伝達が開始された。交差脱感作の存在により、apoEおよびapoE模倣ペプチドは、同一の結合部位で競合することが示唆される。放射性標識apoE模倣ペプチドはインタクトなタンパク質と受容体結合について競合するという本発明の所見によってこれを確認した。これらのデータは、ApoE依存性シグナル伝達がこのリポタンパク質の免疫調整特性を媒介することを示す。
本実施例は、頭部外傷後の17アミノ酸apoE模倣ペプチド(アミノ酸133〜149を含むApoEのフラグメント)の静脈内投与の保護効果を証明する。
本発明者らは、apoEが虚血に対する脳の応答を改変する役割を果たす1つの機構がグルタミン酸興奮毒性からの保護によるという仮説を立てた。グルタミン酸は、虚血環境における神経損傷に寄与すると考えられている。異なるクラスのグルタミン酸活性化チャネルのうち、N−メチル−D−アスパラギン酸(NMDA)受容体の特異的活性化は、主にカルシウム流入および種々のニューロン型におけるニューロン損傷の悪化の媒介を担うと考えられている(MeldrumおよびGarthwaite、1990)。
敗血症ショックは、集中治療室での最も一般的な死因であり、有意に対処されていない医学上の難問である。リポ多糖類(LPS)は、グラム陰性敗血症の主なメディエーターであり、LPSによって誘導された炎症性サイトカインの上方制御は、敗血症に関連する全身性炎症反応の媒介で重要な役割を果たす。LPSの静脈内投与は、グラム陰性敗血症ショックの一般的な動物モデルであり、臨床的に関連する全身性炎症反応を複製する。特に、LPSの静脈内投与により、全身性炎症の媒介で重要な役割を果たすマクロファージ由来サイトカインであるTNFαおよびIL−6が初期に上方制御される。
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Claims (8)
- 敗血症に起因する炎症の治療または軽減のための薬物の製造のためのApoEペプチドの使用であって、
前記ペプチドが配列番号10の配列を含む18乃至50アミノ酸からなるか、配列番号10からなり、LDL受容体結合能力を有する、
使用。 - 前記薬物の被験体への投与により、前記化合物の非存在下と比較して炎症性サイトカインが減少する、請求項1に記載の使用。
- 前記炎症性サイトカインには、TNFαまたはIL−6が含まれる、請求項2に記載の使用。
- 前記薬物が、抗炎症性サイトカインおよびモノクローナル抗体からなる群から選択される1つまたは複数の化合物をさらに含む、請求項1に記載の使用。
- 前記抗炎症性サイトカインが、IL−10、形質転換成長β因子、顆粒球コロニー刺激因子、IFN−φ、マクロファージ遊走阻止因子、および高速移動性1群タンパク質からなる群から選択される、請求項4に記載の使用。
- 前記モノクローナル抗体が、抗内毒素抗体、抗腫瘍壊死因子抗体、および抗CD14抗体からなる群から選択される、請求項4に記載の使用。
- 前記ApoEペプチドが受容体結合ペプチドである、請求項1に記載の使用。
- 前記ペプチドが、配列番号4、配列番号5、配列番号6、および配列番号10からなる群から選択される配列を有する、請求項7に記載の使用。
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JP2005511514A (ja) | 2005-04-28 |
CA2461305C (en) | 2013-11-05 |
US7915226B2 (en) | 2011-03-29 |
EP1437961B1 (en) | 2012-07-18 |
US20080146506A1 (en) | 2008-06-19 |
US8198234B2 (en) | 2012-06-12 |
JP5060703B2 (ja) | 2012-10-31 |
AU2002341739B2 (en) | 2008-04-03 |
WO2003026479A2 (en) | 2003-04-03 |
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AU2008202920A1 (en) | 2008-07-31 |
US7319092B2 (en) | 2008-01-15 |
US7205280B2 (en) | 2007-04-17 |
EP1437961A4 (en) | 2007-04-11 |
EP1437961A2 (en) | 2004-07-21 |
AU2008202920B2 (en) | 2011-01-20 |
US20020164789A1 (en) | 2002-11-07 |
US20060008797A1 (en) | 2006-01-12 |
US20090169614A1 (en) | 2009-07-02 |
JP2009161548A (ja) | 2009-07-23 |
WO2003026479A3 (en) | 2004-03-11 |
CA2461305A1 (en) | 2003-04-03 |
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