JP6867367B2 - Cnsの疾患および損傷を処置するための全身における制御性t細胞のレベルまたは活性の低下 - Google Patents
Cnsの疾患および損傷を処置するための全身における制御性t細胞のレベルまたは活性の低下 Download PDFInfo
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Description
本発明は、概して、循環中の全身免疫抑制のレベルを一過性に低下させることによって、中枢神経系(CNS)の疾患、障害、状態または損傷を処置するための方法および組成物に関する。
ほとんどの中枢神経系(CNS)の病態は、疾患の進行の一部である、共通の神経炎症性の構成要素を共有する。これらの病態には、進行性の記憶喪失および認知機能喪失を特徴とする加齢性の神経変性疾患であるアルツハイマー病(AD)があり、アルツハイマー病では、アミロイド−ベータ(Aβ)ペプチド凝集物の蓄積が、CNSにおける炎症カスケードにおいて重要な役割を果たし、最終的には神経損傷および組織破壊に至ると示唆された(Akiyama et al,2000;Hardy & Selkoe,2002;Vom Berg et al,2012)。神経変性疾患における慢性神経炎症反応にもかかわらず、神経変性疾患における免疫抑制ベースの治療を研究した過去10年間にわたる臨床研究および前臨床研究は、なぜ抗炎症薬が不十分であるかについての問題を提起した(Breitner et al,2009;Group et al,2007;Wyss−Coray & Rogers,2012)。本発明者らは、ADおよび類似の疾患ならびにCNS損傷の既存の治療の欠点を克服する新規の解決策を提供する;この方法は、CNSの維持および修復における全身および中枢の免疫系の種々の構成要素の役割の本発明者らのユニークな理解に基づく。
1つの態様において、本発明は、自己免疫性神経炎症性疾患の再発寛解型多発性硬化症(RRMS)を含まないCNSの疾患、障害、状態または損傷の処置において使用するための、1つ以上の免疫チェックポイントによって免疫系に課された制限の解除によって個体における全身免疫抑制のレベルの低下を引き起こす活性な作用物質を含む薬学的組成物を提供し、ここで、前記薬学的組成物は、少なくとも2コースの治療を含む投与レジメンによる投与のための薬学的組成物であり、治療の各コースは、処置セッションに続く非処置のインターバルセッションを順に含み;前記1つ以上の免疫チェックポイントは、ICOS−B7RP1、T細胞活性化のVドメインIg抑制因子(V−domain Ig suppressor of T cell activation)(VISTA)、B7−CD28様分子、CD40L−CD40、CD28−CD80、CD28−CD86、B7H3、B7H4、B7H7、BTLA−HVEM、CD137−CD137L、OX40L、CD27−CD70、インターフェロン遺伝子刺激因子(STimulator of INterferon Genes)(STING)、T細胞免疫グロブリンおよび免疫受容抑制性チロシンモチーフ(immunoreceptor tyrosine−based inhibitory motif)ドメイン(TIGIT)およびA2aR−アデノシンおよびインドールアミン−2,3−ジオキシゲナーゼ(IDO)−L−トリプトファンからなる群より選択される。
免疫チェックポイント機構は、活性化T細胞の応答性の細胞固有のダウンレギュレーションおよび抑制性レセプターによるエフェクター機能を含み、全身の免疫ホメオスタシスおよび自己免疫寛容を維持している(Joller et al,2012;Pardoll,2012)。近年、プログラム死−1(PD−1)経路(Francisco et al,2010)などのこれらの免疫チェックポイントの遮断が、注目すべき抗腫瘍の有効性を示したことから、様々な悪性疾患と闘う際、免疫系の力の抑制を解くことの可能性に脚光が当てられた。最近、アルツハイマー病の動物モデルに抗PD−1抗体を投与することにより、Aβのクリアランス、認知機能低下の回復がもたらされ、その投与は、神経炎症反応の消散に関連することが示された(WO2015/136541;Baruch et al.,2016)。
(i)(a)抗ICOS;(b)抗B7RP1;(c)抗VISTA;(d)抗CD40;(e)抗CD40L;(f)抗CD80;(g)抗CD86;(h)抗B7−H3;(i)抗B7−H4;(j)B7−H7;(k)抗BTLA;(l)抗HVEM;(m)抗CD137;(n)抗CD137L;(o)抗OX40L;(p)抗CD−27;(q)抗CD70;(r)抗STING;(s)抗TIGIT;および(t)(a)〜(s)の任意の組み合わせからなる群より選択される抗体;
(ii)アジュバントと併用される(a)〜(s)の任意の組み合わせ;
(iii)(a)アデノシンA1レセプターアンタゴニスト;(b)アデノシンA2aレセプター;および(c)A3レセプターアンタゴニストからなる群より選択される小分子;
(iv)(iii)(a〜c)と(i)(a〜s)との任意の組み合わせ;および
(v)(i)〜(iv)の任意の組み合わせ
からなる群より選択され得る。
(動物)
家族性AD変異型のヒトAPP(Swedish変異、K670N/M671L;Florida変異、I716V;およびLondon変異、V717I)およびPS1(M146L/L286V)導入遺伝子をニューロン特異的マウスThy−1プロモーター(Oakley et al,2006)の転写制御下で共過剰発現する5XFADトランスジェニックマウス(Tg6799)、ならびにADダブルトランスジェニックB6.Cg−Tg(APPswe、PSEN1dE9)85Dbo/Jマウス(Borchelt et al,1997)をThe Jackson Laboratoryから購入した。先に記載されたように(Oakley et al,2006)、テイルDNAのPCR解析によって、ジェノタイピングを行った。ヘテロ接合性変異cx3cr1GFP/+マウス(Jung et al,2000)(CX3CR1ケモカインレセプターの対立遺伝子の1つがGFPをコードする遺伝子で置換されたB6.129P−cx3cr1tm1Litt/J)をBMキメラのドナーとして使用した。Foxp3+Tregの条件的枯渇を可能にするために、Foxp3.LuciDTRマウス(Suffner et al,2010)を5XFADマウスと交配させた。Animal Breeding Center of the Weizmann Institute of Scienceが動物を飼育し、維持した。本明細書中で詳述されるすべての実験が、Weizmann Institute of ScienceのInstitutional Animal Care and Use Committee(IACUC)によって策定された規則に従った。
海馬の歯状回(DG)の全RNAを、TRI試薬(Molecular Research Center)を用いて抽出し、RNeasy Kit(Qiagen)を用いて溶解産物から精製した。脈絡叢の全RNAを、RNA MicroPrep Kit(Zymo Research)を用いて抽出した。High Capacity cDNA Reverse Transcription Kit(Applied Biosystems)を用いて、mRNA(1μg)をcDNAに変換した。特定のmRNAの発現を、蛍光ベースの定量的リアルタイムPCR(RT−qPCR)を用いてアッセイした。RT−qPCR反応は、Fast−SYBR PCR Master Mix(Applied Biosystems)を用いて行った。定量反応は、検量線法を用いて各サンプルに対して3つ組で行った。ペプチジルプロリルイソメラーゼA(ppia)を参照(ハウスキーピング)遺伝子として選択した。増幅サイクルは、95℃5秒、60℃20秒および72℃15秒であった。アッセイの終わりに、融解曲線を構築することにより、その反応の特異性を評価した。ifn−γおよびppia遺伝子の解析のために、cDNAを、製造者のプロトコル(PreAmp Master Mix Kit;Applied Biosystems)に従って、非ランダムPCRプライマーを用いて14PCRサイクルで事前に増幅することによって、その後のリアルタイムPCR解析の感度を高めた。mRNA発現を、製造者の指示書(Applied Biosystems)に従って、TaqMan RT−qPCRを用いて測定した。すべてのRT−qPCR反応を、StepOneソフトウェアV2.2.2(Applied Biosystems)を用いて行い、解析した。以下のTaqMan Assays−on−DemandTMプローブを使用した:Mm02342430_g1(ppia)およびMm01168134_m1(ifn−γ)。
他のすべての遺伝子について調べるため、以下のプライマーを使用した:
ppia
forward 5’−AGCATACAGGTCCTGGCATCTTGT−3’(配列番号33)および
reverse 5’−CAAAGACCACATGCTTGCCATCCA−3’(配列番号34);
icam1
forward 5’−AGATCACATTCACGGTGCTGGCTA−3’(配列番号35)および
reverse 5’−AGCTTTGGGATGGTAGCTGGAAGA−3’(配列番号36);
vcam1
forward 5’−TGTGAAGGGATTAACGAGGCTGGA−3’(配列番号37)および
reverse 5’−CCATGTTTCGGGCACATTTCCACA−3’(配列番号38);
cxcl10
forward 5’−AACTGCATCCATATCGATGAC−3’(配列番号39)および
reverse 5’−GTGGCAATGATCTCAACAC−3’(配列番号40);
ccl2
forward 5’−CATCCACGTGTTGGCTCA−3’(配列番号41)および
reverse 5’−GATCATCTTGCTGGTGAATGAGT−3’(配列番号42);
tnf−γ
forward 5’−GCCTCTTCTCATTCCTGCTT−3’(配列番号43)
reverse CTCCTCCACTTGGTGGTTTG−3’(配列番号44);
il−1β
forward 5’−CCAAAAGATGAAGGGCTGCTT−3’(配列番号45)および
reverse 5’−TGCTGCTGCGAGATTTGAAG−3’(配列番号46);
il−12p40
forward 5’−GAAGTTCAACATCAAGAGCA−3’(配列番号47)および
reverse 5’−CATAGTCCCTTTGGTCCAG−3’(配列番号48);
il−10
forward 5’−TGAATTCCCTGGGTGAGAAGCTGA−3’(配列番号49)および
reverse 5’−TGGCCTTGTAGACACCTTGGTCTT−3’(配列番号50);
tgfβ2
forward 5’−AATTGCTGCCTTCGCCCTCTTTAC−3’(配列番号51)および
reverse 5’−TGTACAGGCTGAGGACTTTGGTGT−3’(配列番号52);
igf−1
forward 5’−CCGGACCAGAGACCCTTTG(配列番号53)および
reverse 5’−CCTGTGGGCTTGTTGAAGTAAAA−3’(配列番号54);
bdnf
forward 5’−GATGCTCAGCAGTCAAGTGCCTTT−3’(配列番号55)および
reverse 5’−GACATGTTTGCGGCATCCAGGTAA−3’(配列番号56);
パラフィン包埋切片にしたマウス(6μm厚)およびヒト(10μm厚)脳において、組織の処理および免疫組織化学を行った。ヒトICAM−1染色の場合、1次マウス抗ICAM(1:20 Abcam;ab2213)抗体を使用した。スライドを、3%H2O2とともに10分間インキュベートし、2次ビオチンコンジュゲート抗マウス抗体を使用した後、Vectastain ABCキット(Vector Laboratories)を用いてビオチン/アビジン増幅を行った。続いて、3,3’−ジアミノベンジジン(DAB基質)(Zytomedキット)を適用し;スライドを脱水し、キシレンベースのマウント液を用いてマウントした。組織染色の場合、マウスをPBSで経心的に灌流した後、組織切除および固定を行った。解剖顕微鏡(Stemi DV4;Zeiss)下で、脳の側脳室、第3脳室および第4脳室からCP組織を単離した。ホールマウントCP染色の場合、組織を2.5%パラホルムアルデヒド(PFA)で4℃にて1時間固定し、続いて、0.05%アジ化ナトリウムを含むPBSに移した。染色の前に、解剖した組織をPBSで洗浄し、室温で1時間ブロッキングした(20%ウマ血清、0.3%Triton X−100およびPBS)。1次抗体(2%ウマ血清および0.3%Triton X−100を含むPBS中)または二次抗体によるホールマウント染色を室温で1時間行った。各工程の後、PBSで3回洗浄した。組織をスライドに載せ、Immu−mount(9990402、Thermo Scientific製)を用いてマウントし、カバーガラスで覆った。切片にした脳の染色の場合、先に記載されたような(Baruch et al,2013;Kunis et al,2013)2つの異なる組織調製プロトコル(パラフィン包埋切片またはミクロトームで切片にした浮遊切片)を適用した。以下の1次抗体を使用した:マウス抗Aβ(1:300,Covance,#SIG−39320);ウサギ抗GFP(1:100,MBL,#598);ラット抗CD68(1:300,eBioscience,#14−0681);ラット抗ICAM−1(1:200,Abcam,#AB2213);ヤギ抗GFP(1:100,Abcam,#ab6658);ウサギ抗IBA−1(1:300,Wako,#019−19741);ヤギ抗IL−10(1:20,R&D systems,#AF519);ラット抗Foxp3(1:20,eBioscience,#13−5773−80);ウサギ抗CD3(1:500,Dako,#IS503);;マウス抗ZO−1、マウス抗E−カヘドリン(Cahedrin)およびウサギ抗クローディン−1(すべて1:100,Invitrogen,#33−9100,#33−4000,#51−9000);ウサギ抗GFAP(1:200,Dako,#Z0334)。二次抗体には、Cy2/Cy3/Cy5コンジュゲートロバ抗マウス/ヤギ/ウサギ/ラット抗体(1:200;すべてJackson Immunoresearch製)が含まれた。スライドをHoechst核染色(1:4000;Invitrogen Probes)に1分間曝露した。免疫染色手順では、2つのネガティブコントロールを日常的に使用し、アイソタイプコントロール抗体で染色した後、二次抗体で染色するか、または二次抗体のみで染色した。Foxp3細胞内染色の場合、パラフィン包埋スライドからの抗原回復を、Retreivagen Kit(#550524,#550527;BD PharmingenTM)を用いて行った。顕微鏡解析は、蛍光顕微鏡(E800;Nikon)またはレーザー走査型共焦点顕微鏡(Carl Zeiss,Inc.)を用いて行った。蛍光顕微鏡には、デジタルカメラ(DXM 1200F;Nikon)、および20×NA0.50または40×NA0.75対物レンズ(Plan Fluor;Nikon)が備え付けられていた。共焦点顕微鏡には、LSM510レーザー走査能(3つのレーザー:Ar488、HeNe543およびHeNe633)が備わっていた。後固定した組織に対して、取得ソフトウェア(NIS−Elements,F3[Nikon]またはLSM[Carl Zeiss,Inc.])を用いて、記録を行った。染色強度の定量の場合、細胞およびバックグラウンドの全染色を、ImageJソフトウェア(NIH)を用いて測定し、特定の染色の強度を、先に記載されたように(Burgess et al,2010)計算した。Photoshop CS6 13.0(Adobe)を用いて像を切り取り、マージし、最適化し、Illustrator CS5 15.1(Adobe)を用いて並べた。
若年および高齢の死後の非CNS疾患個体ならびにAD患者のヒト脳切片を、適切な同意および倫理委員会の承認(TW220)を得て、Oxford Brain Bank(かつてはThomas Willis Oxford Brain Collection(TWOBC)として知られた)から入手した。これらの切片が関わる実験は、Weizmann Institute of Science Bioethics Committeeによって承認された。
マウスをPBSで経心的に灌流し、組織を先に記載されたように(Baruch et al,2013)処理した。脳を解剖し、解剖顕微鏡(Stemi DV4;Zeiss)下にてPBS中で種々の脳領域を取り出し、gentleMACSTM分離機(dissociator)(Miltenyi Biotec)を用いて組織を分離させた。脈絡叢組織を、脳の側脳室、第3脳室および第4脳室から単離し、400U/mlコラゲナーゼIV型(Worthington Biochemical Corporation)を含むPBS(Ca2+/Mg2+を含む)中、37℃で45分間インキュベートし、次いで、手作業でピペッティングすることによってホモゲナイズした。脾臓をシリンジのプランジャーですりつぶし、ACK(塩化アンモニウムカリウム)溶解緩衝液で処理して、赤血球を除去した。すべての場合において、製造者のプロトコルに従ってサンプルを染色した。すべてのサンプルを70μmナイロンメッシュで濾過し、抗Fc CD16/32(1:100;BD Biosciences)でブロッキングした。IFN−γの細胞内染色の場合、細胞をパラ−メトキシアンフェタミン(10ng/ml;Sigma−Aldrich)およびイオノマイシン(250ng/ml;Sigma−Aldrich)とともに6時間インキュベートし、最後の4時間にわたって、ブレフェルジン−A(10μg/ml;Sigma−Aldrich)を加えた。サイトカインの細胞内標識を、BD Cytofix/CytopermTMPlus固定/透過処理キット(cat.no.555028)を用いて行った。Treg染色の場合、eBioscience FoxP3染色緩衝液セット(cat.no.00−5523−00)を使用した。以下の蛍光色素で標識されたモノクローナル抗体を、BD Pharmingen、BioLegend、R&D SystemsまたはeBiosciencesから購入し、製造者のプロトコルに従って使用した:PEまたはAlexa Fluor 450コンジュゲート抗CD4;PEコンジュゲート抗CD25;PerCP−Cy5.5コンジュゲート抗CD45;FITCコンジュゲート抗TCRβ;APCコンジュゲート抗IFN−γ;APCコンジュゲート抗FoxP3;Brilliant−violetコンジュゲート抗CD45。細胞を、FlowJoソフトウェアを用いてLSRII血球計算器(BD Biosciences)において解析した。各実験において、各組織に対する妥当なネガティブコントロール群、ポジティブコントロールおよび単一染色サンプルを用いて、目的の集団を特定し、他の集団を排除した。
BMキメラを、先に記載されたように(Shechter et al,2009;Shechter et al,2013)調製した。手短に言えば、同性のレシピエントマウスを、頭部を遮蔽しながら致死性の全身照射(950rad)にさらした(Shechter et al,2009)。次いで、それらのマウスの静脈内に、CX3CR1GFP/+ドナー由来の5×106個のBM細胞を注射した。BM移植後、マウスを8〜10週間放置することにより、造血系の再構成を可能にした後、実験で使用した。血液サンプルのFACS解析によって、キメラ化のパーセンテージを、循環単球(CD11b+)のうちのGFP発現細胞のパーセンテージに従って測定した。この頭部遮蔽モデルでは、60%のキメラ化の平均値が達成され、CNSに浸潤するGFP+骨髄性細胞が、単球由来のマクロファージであってミクログリアではないCD45high/CD11bhigh(Shechter et al,2013)であると立証された。
プール(直径1.1m)内の水面の1.5cm下に配置された隠れたプラットフォームを探す方法を習得させるために、マウスに、4日連続して、1日あたり3回の試行を行わせた。水の温度は、21〜22℃で維持した。水を粉乳で不透明にした。試験室内において、水没したプラットフォームの位置の特定を助けるためにマウスにとって利用可能な手がかりは遠位の視覚的形状および物体だけであった。逃避潜時、すなわち、プラットフォームを探してその上に上がるのに要した時間を最大60秒間、記録した。各マウスをプラットフォーム上に15秒間とどまらせ、次いで、迷路から取り出してホームケージに戻した。マウスが、60秒以内にプラットフォームを探せなかった場合、そのマウスを手作業でプラットフォーム上に置き、15秒後にホームケージに戻した。各マウスに対する試行の間のインターバルは、10分間であった。5日目に、プラットフォームを除去し、マウスに、利用可能な逃避場所なしで60秒間続く1回の試行を行わせた。6および7日目に、プラットフォームを、元の訓練の四半分と反対の四半分に置き、1日あたり3セッションでマウスを再訓練した。Etho Vision V7.1自動追跡システム(Noldus Information Technology)を用いて、データを記録した。統計解析を、分散分析(ANOVA)およびボンフェローニのpost−hocテストを用いて行った。すべてのMWM試験を、消灯期の間の午前10時〜午後5時に行った。
先に詳細に記載された(Alamed et al,2006)放射状アーム水迷路(RAWM)を用いることにより、空間学習および空間記憶を試験した。簡潔には、6本のステンレス鋼挿入物をタンク内に置き、中央の開けた領域から放射状に伸びる6本の水泳アームを形成させた。逃避プラットフォームを、1本のアーム(ゴールアーム)の末端の、直径1.1mのプール内の水面の1.5cm下に配置した。水の温度を21〜22℃で維持した。水を粉乳で不透明にした。試験室内において、水没したプラットフォームの位置の特定を助けるためにマウスにとって利用可能な手がかりは遠位の視覚的形状および物体だけであった。ゴールアームの位置は、所与のマウスにおいて一定のままであった。1日目に、マウスを15回の試行(3時間超、間隔をあける)で訓練し、試行は、見えるプラットフォームと隠れたプラットフォームとを交互に用い、最後の4回の試行は、隠れたプラットフォームだけを用いた。2日目に、隠れたプラットフォームを用いる15回の試行でマウスを訓練した。間違ったアームに進入したとき、または15秒以内にアームの選択をしなかったときは、エラーとしてスコア付けした。各試行におけるマウスのアーム進入エラーの回数または逃避潜時をカウントすることによって、空間学習および空間記憶を測定した。3回連続した試行の訓練ブロックについて、訓練データをエラーまたは逃避潜時の平均値として解析した。
各マウスの皮下に(s.c.)、200μlのPBSに溶解された100μgの総用量のGA(バッチno.P53640;Teva Pharmaceutical Industries,Petah Tiqva,Israel)を注射した。毎週のGAレジメン(Butovsky et al,2006)または毎日のGA投与(図8および図16)に従って、マウスに注射した。各実験に対して示されているように、最後のGA注射の1週間後または処置の1ヶ月後に、マウスを安楽死させた。
ジフテリア毒素(DTx;8ng/g体重;Sigma)を、4日連続して、Foxp3.LuciDTRマウスの腹腔内に(i.p.)毎日注射した(Suffner et al,2010)。DTxの効率を血液および脾臓における免疫細胞のフローサイトメトリー解析によって確認したところ、GFPを発現しているFoxP3+CD4+Treg細胞のほぼ完全な(>99%)枯渇が達成された(図4)。
マウスにおけるp300の阻害を、先の記載(Liu et al,2013)と同様に行った。p300i(C646;Tocris Bioscience)をDMSOに溶解し、1週間にわたって毎日i.p.注射した(8.9mgkg−1d−1、i.p.)。ビヒクルで処置されるマウスにはDMSOを同様に注射した。
マウスへのオールトランスレチノイン酸(ATRA)投与を、先の記載(Walsh et al,2014)と同様に行った。ATRA(Sigma)をDMSOに溶解し、1週間にわたって1日おきにi.p.注射した(8mgkg−1d−1)。ビヒクルで処置されるマウスにはDMSOを同様に注射した。
組織の均質化およびsAβタンパク質の抽出を、先に記載されたように(Schmidt et al,2005)行った。簡潔には、大脳実質を解剖し、急凍し、ホモゲナイズするまで−80℃で維持した。タンパク質をサンプルから連続的に抽出することにより、異なる溶解度のタンパク質を含む別個の画分を得た。サンプルを、250mMのスクロース、20mMのTris塩基、1mMのエチレンジアミン四酢酸(EDTA)および1mMのエチレングリコール四酢酸(pH7.4)を含む10体積の氷冷組織均質化緩衝液中で、Dounceホモジナイザーにおいてすりガラス乳棒を用いてホモゲナイズした。6ストロークの後、ホモジネートを100mM NaCl溶液中の0.4%ジエチルアミン(DEA)と1:1混合した後、さらに6ストローク行い、次いで、4℃にて135,000gで45分間遠心した。上清(細胞外およびサイトゾルのタンパク質を含むDEA可溶性画分)を回収し、10%の0.5M Tris−HCl(pH6.8)で中和した。Aβ1−40およびAβ1−42を、商業的に入手可能なキット(それぞれBiolegend;#SIG−38954および#SIG−38956)を製造者の指示書に従って使用して、可溶性画分から酵素結合免疫吸着測定法(ELISA)によって個別に測定した。
各脳から、目的の領域(歯状回または大脳皮質)全体にわたる4つの異なる所定の深さから、6μmの冠状切片を回収し、マウス1匹あたり8枚の切片を免疫染色した。陽染されたピクセルのヒストグラムベースの区分けを、Image−Pro Plusソフトウェア(Media Cybernetics,Bethesda,MD,USA)を用いて行った。歯状回の領域または皮質V層において、区分けのアルゴリズムを各像に手作業で適用し、全Aβ免疫染色によって占有された領域のパーセンテージを測定した。プラークの数を同じ6μm脳冠状切片から定量し、脳領域1つあたりのプラークの平均数として提示する。定量の前に、切片をコード化して実験群の同一性を隠し、群の同一性について盲検の観察者がプラーク量を定量した。
各実験セットを解析するために用いられた具体的な試験を図の説明文に示す。2群間を比較するために両側スチューデントt検定を用いてデータを解析し、いくつかの群を比較するために1元配置分散分析を使用し、続いて帰無仮説が棄却された後(P<0.05)、群の対ごとの比較のためにNewman−Keulsのpost−hocテストを用いた。行動試験のデータは、2元配置反復測定分散分析を用いて解析し、追跡の対ごとの比較のために、ボンフェローニのpost−hocテストを用いた。サンプルサイズは、文献および過去の経験に基づいて適切な統計的検出力によって選択し、マウスを齢、性別および遺伝子型に従って実験群に割り当てた。研究者は、実験中および結果の評価中、群の同一性について盲検であった。すべての選択規準および除外規準は、IACUCガイドラインに従って予め決められていた。結果は、平均値±s.e.m.として示される。グラフにおいて、y軸のエラーバーは、s.e.m.を表す。統計的計算は、GraphPad Prismソフトウェア(GraphPad Software,San Diego,CA)を用いて行った。
実施例1.ADのマウスモデルにおける疾患進行に沿った脈絡叢(CP)ゲートウェイ活性(gateway activity)
実施例2.Treg媒介性全身免疫抑制とCPゲートウェイ活性とADの病態との間の機能的関係性
実施例3.コポリマ−1の毎週投与は、Treg媒介性の全身免疫抑制を減少させ、CPゲートウェイ活性を改善し、ADの病態を緩和する。
実施例4.小分子ヒストンアセチルトランスフェラーゼ阻害剤を用いたTreg活性の干渉
実施例5.アルツハイマー病におけるPD−1免疫チェックポイント遮断の治療的可能性
実施例6.アルツハイマー病における免疫チェックポイント遮断の治療的可能性
実施例7.PTSD病態における免疫チェックポイント遮断アプローチの治療的可能性
実施例8.パーキンソン病の病態における免疫チェックポイント遮断アプローチの治療的可能性
実施例9.ハンチントン病の病態における免疫チェックポイント遮断の治療的可能性
実施例10.萎縮性側索硬化症の病態における免疫チェックポイント遮断アプローチの治療的可能性
Claims (14)
- アルツハイマー病及び筋委縮性側索硬化症から選ばれる中枢神経系(CNS)の疾患の処置において使用するための、1つ以上の免疫チェックポイントによって免疫系に課された制限の解除によって全身免疫抑制のレベルの低下を引き起こす活性な作用物質を含む、薬学的組成物であって、
ここで、前記活性な作用物質は、OX40−OX40L免疫チェックポイントに対する抗体であり、
前記薬学的組成物は、少なくとも2コースの治療を含む投与レジメンによって投与され、治療の各コースは、処置セッションに続く、前記薬学的組成物を個体に投与しない非処置のセッションを順に含み、
前記処置セッション中の投与が反復投与である場合、前記非処置セッションの期間が前記処置セッション中の反復投与間の期間よりも長く;
前記薬学的組成物の投与が、IFNγ産生白血球の全身における存在又は活性の増加を伴う全身免疫抑制のレベルを一過性に低下させる、薬学的組成物。 - 前記全身免疫抑制のレベルの低下を引き起こし、それによって、エフェクターT細胞の全身における存在または活性の増加を引き起こす、請求項1に記載の薬学的組成物。
- 前記1つ以上の免疫チェックポイントの遮断によって免疫抑制の解除を引き起こす、請求項1に記載の薬学的組成物。
- 前記活性な作用物質が、抗OX40L抗体である、請求項1〜3のいずれか1項に記載の薬学的組成物。
- 前記処置セッションが、前記個体への前記薬学的組成物の投与を含み、前記処置セッションは、少なくともIFNγ産生白血球の全身における存在またはレベルが基準より高くなるまで維持され、前記投与は、前記非処置セッション中は休止され、前記非処置セッションは、前記レベルが前記基準より高い限り維持され、
前記基準は、
(a)前記投与前の前記個体から得られた最新の血液サンプルにおいて測定されたIFNγ産生白血球の全身における存在または活性のレベル;または
(b)CNSの疾患、障害、状態または損傷に苦しんでいる個体の集団に特徴的なIFNγ産生白血球の全身における存在または活性のレベル
から選択される、請求項1〜4のいずれか1項に記載の薬学的組成物。 - 前記処置セッション中の投与が、単回投与である、請求項1〜5のいずれか1項に記載の薬学的組成物。
- 前記処置セッション中の投与が、反復投与である、請求項1〜5のいずれか1項に記載の薬学的組成物。
- 前記反復投与が、1、2、3、4、5、6日、1週間、2週間、3週間、又は4週間ごとに1回行われる、請求項7に記載の薬学的組成物。
- 前記反復投与が、1週間に1回行われる、請求項7に記載の薬学的組成物。
- 前記反復投与が、4週間ごとに1回行われる、請求項7に記載の薬学的組成物。
- 前記処置セッションが、3日〜4週間である、請求項1〜10のいずれか1項に記載の薬学的組成物。
- 前記非処置期間が、1週間〜6ヶ月である、請求項1〜11のいずれか1項に記載の薬学的組成物。
- 前記処置が、CNSの認知機能を改善する、請求項1〜12のいずれか1項に記載の薬学的組成物。
- 前記認知機能が、学習、記憶、心象の創造、思考、自覚、推理、空間能力、発話および言語技能、言語習得および判断注意の能力からなる群より選ばれる1種以上である、請求項13に記載の薬学的組成物。
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