JP2017206523A - 炎症状態の予防および処置 - Google Patents
炎症状態の予防および処置 Download PDFInfo
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を有する。
を有する。
再灌流傷害は、虚血期間後に臓器または組織に対して血液供給が回復される時に生じる。肝再灌流傷害は、一般的に、手術または外傷に関連して生じ、肝臓移植後の移植組織の質および機能において主要な役割を果たす。虚血再灌流傷害(IRI)の発症は、クップファー細胞活性化、反応性酸素種の放出、CD4+細胞動員および炎症促進性サイトカインの分泌により特色付けられる(約1〜約6時間の再灌流に続く)初期期間と、好中球蓄積および壊死の誘導により特徴付けられる(約6〜約48時間の再灌流の初期段階に続く)後期期間との、少なくとも2段階で起こる。図2aに示されるように、野生型(WT)マウスにおいて、骨髄系前駆細胞および単球を含む骨髄(CD11b+)細胞サブセットCD11b+Gr−1intは、虚血再灌流傷害の初期段階において、再灌流された組織中に動員される。好中球以外の骨髄細胞(例えば、CD11b+Gr−1intサブセット)の動員は、再灌流された組織中への炎症性単球の動員によって傷害が増強されるということを示唆している。
参照によりその全体が本明細書に援用される米国特許第8,044,029号明細書および米国特許出願第12/938,315号明細書に記載されているように、自己糖脂質リガンドであるスルファチド、および合成スルファチドアナログの投与は、I型およびII型NKT細胞の活性を調節する。スルファチドのCD1d依存性認識は、II型NKT細胞および主に形質細胞様樹状細胞(pDC)を活性化するが、通常樹状細胞(cDC)個体群(通常は1型NKT細胞により活性化される)を活性化せず、IL−12およびMIP2依存的な様式での肝臓中へのI型NKT細胞の迅速な動員に繋がる。しかしながら、動員されたI型NKT細胞は、活性化されず、サイトカインを分泌せず、アネルギーの状態になる。
アルコール性肝疾患(ALD)は、過剰のアルコール消費により引き起こされる肝細胞への損傷の結果として発症する。複数の傷害が、ALDの臨床的発現が観察されるまでに必要とされ得る。しかしながら、本明細書に記載されるように、慢性的アルコール消費に続いて、肝臓において、著しく増加した数のI型NKT細胞(αGalCer/CD1d−テトラマー+細胞)、CD4+細胞、およびCD11b+Gr−1+骨髄細胞が観察されるが、そのようなII型NKT細胞またはCD11b+Gr−1−細胞は観察されない。実施例6および図5を参照されたい。さらに、CD69マーカーの増強された発現が、I型NKT細胞が部分的に活性化されていることを示す。したがって、疾患のあらゆる臨床徴候の不在下(前臨床期)においてでさえ、炎症応答を媒介する細胞が、過剰のアルコール消費に続いて肝臓中に蓄積する。I型NKT細胞の不在下(Jα18−/−マウス)において、慢性的アルコール消費に続く肝臓へのCD11b+Gr−1+骨髄細胞の蓄積は、著しく減少する。実施例6および図5を参照されたい。これらのデータは、I型NKT細胞が、ALDの前臨床期をもたらすことに関与しているということを示唆している。
本明細書に記載されるように、レチノイン酸レセプター(RAR)アゴニストである全トランス型レチノイン酸(ATRA)の投与は、アルコール消費により引き起こされる肝損傷を著しく阻害する。エタノール摂取は、肝臓レチニルエステルを枯渇させ、かつ、多くの生物学的機能を支持しかつFoxP3+TregへのナイーブCD4+T細胞分化の発生、安定性および機能をIL−6の存在下においても高め得るビタミンAの生物学的に活性な形態である全トランス型レチノイン酸(ATRA)の生理学的レベルを変化させる。本明細書に記載されるいくつかの実施形態は、ATRAがI型NKT細胞のエフェクター機能を阻害する(これらの細胞によるサイトカイン分泌を抑制することを含む)という発見に関する。実施例8、9および11ならびに図8、10および11を参照されたい。さらに、ATRAは、I型NKT細胞活性に対する直接的な阻害効果を有し、抗原提示細胞の不在下においてその阻害効果を発揮する。実施例11、図11を参照されたい。さらに、ATRAは、タンパク質抗原(例えば、骨髄塩基性タンパク質またはMBPAc1−9)を認識する通常MHC拘束性CD4+T細胞の活性を直接的には阻害しない。特定の理論に拘束されることを望むものではないが、これらのデータは、ATRAが、I型NKT細胞を阻害することによって過度のアルコール消費により引き起こされる肝損傷を防ぐことを示している。
スルファチドはスルファチド/CD1d−テトラマー+細胞を活性化しつつI型NKT細胞の阻害を媒介する
20μgのスルファチドを1用量、マウスに腹膜内注射した。スルファチド注射に続いて、肝臓由来のMNCを単離し、CFSEで標識した。この細胞を、10ng/mlのサイトカインIL−2の存在下または不在下において、96時間にわたりαGalCer(10ng/ml)と共に培養した。コントロールとして、細胞を、10ng/mlのIL−12のみと共に培養した。培養に続いて、細胞を採取し、抗TCRβmAbおよびαGalCer/CD1d−テトラマーで染色し、FACs選別し、αGalCer/CD1d−テトラマー+(I型NKT)細胞に対してCFSE希薄化分析を行った。図1Aを参照されたい。図1Bに示されるように、スルファチド投与後は、I型NKT細胞は、αGalCerでのインビトロチャレンジに応答して増殖しない。
スルファチド投与はConA誘導性肝炎を防ぐ
雌C57BL/6マウスを、8.5mg/kgのコンカバリン(Concavalin)A(ConA)(発熱物質を含まないリン酸緩衝生理的食塩水(PBS)に溶解させたもの)で静脈内(i.v.)処置した。これにより、肝炎により引き起こされるものと同様の肝損傷が誘導される。ConA注射の直後に、マウスに20μg(1mg/kg/m)のウシ脳スルファチドまたはPBSを腹腔内(i.p.)注射した。
CD11b+Gr−1+細胞個体群の組成に対する肝虚血再灌流傷害への免疫応答の作用の分析
肝虚血再灌流傷害モデルを、Shen XD,Ke B,Zhai Y,et al.に記載されているように確立した。肝虚血/再灌流傷害機序においてはCD154−CD40T細胞の共刺激経路が必要とされ、その遮断は、ヘムオキシゲナーゼ−1媒介細胞保護を促進しかつこれに依存する。Transplantation 2002,74:315−9が、ほとんど変更することなくその全体が本明細書に援用される。
虚血再灌流傷害誘導に先立つスルファチド投与はI型NKT細胞によるIFN−γ分泌を著しく阻害する
1つのWTマウス群(n=3)に、虚血誘導の3時間前にスルファチド(20μg/マウス、i.p.)を注射し(スルファチド、IRI)、他の群(IRI(n=3)、シャム(n=2))には前処置を行わなかった。肝虚血再灌流傷害(90分間の虚血および6時間の再灌流)およびシャム手術を、実施例3に記載したように行った。
I型NKT細胞の抑制はIRIに続く肝臓壊死の減少を結果としてもたらす
Matreya Inc.,Pleasant Gap,PAから購入した精製ウシミエリン由来スルファチド(>90%純粋)を、ビヒクル(0.5%ポリソルベート−20(Tween−20)および0.9%NaCl溶液)に溶解させ、PBS中で希釈した。BL/6マウス(WTスルファチド)群およびJα18−/−マウス(Jα18−/−スルファチド)群を、虚血誘導またはシャム手術の3〜48時間前にスルファチド(20μg/マウス)で腹腔内処置した。肝虚血再灌流傷害およびシャム手術を、スルファチド処置および非処置のWTおよびJα18−/−マウスに対して、実施例3に記載したように実施した。90分間の虚血および24時間の再灌流に続いて、肝組織(頭側小葉)を、10%ホルマリン中で固定し、パラフィン中に包埋し、切片を、組織学的分析のためにヘマトトキシリン(hematotoxylin)およびエオシンで染色した(IDEXX Laboratories Inc.,Westbrook,Maine)。
WTおよび1型NKT細胞涸渇(Jα18−/−)マウスにおけるアルコール性肝疾患の誘導
1週間の栄養的に十分なLieber−DeCarli液体食餌での順化に続いて、6〜8週齢の雄C57BL/6Jマウス(B6)および1型NKT細胞はないが2型NKT細胞はあるJα18−/−マウスに、5%のエタノールを含有する液体食餌または等カロリーのデキストリンマルトース含有食餌(Bio−Serv,NJ)に自由に接近させた。滅菌した餌箱中にオートクレーブ処理された水を用いて毎日新たに食餌を調製し、餌を毎日取り換えるように注意した。
スルファチドまたは全トランス型レチノイン酸(ATRA)によるアルコール誘導性肝損傷の予防
7週齢のB6(WT)およびJα18−/−の雄マウスの群に、1日目および10日目に20マイクログラム/マウスのスルファチド;6〜10日目に0.3ミリグラム/マウスのATRA、またはビヒクル/DMSOを注射(i.p.)し、10日間にわたる5%のエタノールを含有する液体食餌、それに続く(11日目における)単回の高用量の強制飼養エタノール(5g/kg体重)(慢性的+過エタノール給餌群)または等カロリーのデキストリンマルトース含有食餌、それに続く等カロリーのデキストリンマルトース強制飼養(コントロール群)のいずれかを給餌した。強制飼養の6〜8時間後に、マウスを安楽死させ、血清および肝組織を採取した。
ATRAによるI型NKT細胞増殖の阻害
I型NKT細胞を、ナイーブB6マウスの脾臓から単離し、[3H]−チミジンおよび最適濃度のαGalCerのみ、最適濃度のαGalCer+0.15μg/ml、1.2μg/ml、もしくは18.8μg/mlのATRA、またはATRAのみと共に、インビトロで培養した。1型NKT細胞の増殖を、[3H]−チミジン取り込みにより測定した。図8aに示されるように、細胞増殖は、0.15μg/mlのATRAおよびαGalCerまたはαGalCerのみで培養された1型NKT細胞について同様であったが、比較すると、増殖は、1.2μg/mlまたは18.8μg/mlのATRAおよびαGalCerで培養された1型NKT細胞については減少した。αGalCer誘導1型NKT細胞増殖の最も大きな阻害を、18.8μg/mlのATRAについて観察した。ATRAのみで培養された1型NKT細胞については、増殖は、全くまたはほとんど観察されなかった。
ATRAによるI型NKT細胞活性の阻害
αGalCerでのインビトロチャレンジに応答したI型NKT細胞によるIL−2サイトカイン分泌に対するATRAの作用を、NKT細胞(Hy1.2)および放射線照射された抗原提示細胞(APC)を、ATRA(0.15μg/ml、1.2μg/ml、または18.8μg/ml)の存在下または不在下において、最適濃度のαGalCerと共に、インビトロで16時間にわたり共培養することによって試験した。上清を収集し、分泌されたIL−2レベルを、IL−2サンドイッチELISAを用いて測定した。
ATRAはクラスIIMHC拘束性通常CD4T細胞を阻害しない
クラスIIMHC拘束性通常CD4T細胞に対するATRAの作用を、ナイーブB10.PL Vβ8.2TCRトランスジェニックマウスからミエリン塩基性タンパク質MBPAc1−9反応性CD4+T細胞を単離し、段階的濃度のATRA(0.15、1.2、18.8μg/ml)の存在下または不在下において、細胞を[3H]−チミジンおよび最適濃度のMBPAc1−9と共にインビトロで培養することによって試験した。MBPAc1−9反応性CD4+T細胞の増殖を、[3H]−チミジン取り込みにより測定した。MBPAc1−9刺激増殖の阻害は、ATRA処理した培養物においては何ら観察されなかった。図10を参照されたい。これは、ATRAがMHC拘束性CD4+T細胞の活性を直接的に阻害しないということを示唆している。
抗原提示細胞の不在下におけるATRA処理は1型NKT細胞機能を阻害する
抗原提示細胞の不在下におけるI型NKT細胞に対するATRA処理の作用もまた測定した。I型NKTハイブリドーマ細胞(Hy1.2)を、ATRAなしかまたは5μg/ml、10μg/ml、もしくは20μg/mlのATRAと共に、24時間にわたりインビトロで培養した。次いで、細胞を3回洗浄し、段階的濃度の脂質抗原αGalCerの存在下において、放射線照射された脾細胞(APC)と共に共培養した。16時間後に上清を収集し、IL−2サンドイッチELISAを用いてIL−2レベルを測定した。図11に示されるように、ATRAによるI型NKTハイブリドーマ細胞(Hy1.2)の処理は、IL−2分泌を阻害する。これは、抗原提示細胞の不在下におけるATRA処理がI型NKT細胞のエフェクター機能を阻害するということを示唆している。
サブタイプ特異的RARアゴニストによるI型NKT細胞活性の阻害
レチノイン酸レセプター(RAR)は、RARα、RARβ、およびRARγという3つの主要な亜型を含む。RARアゴニストATRAは、特定の亜型に対する選択性はない。I型NKT細胞活性の阻害へのRAR亜型の寄与を、亜型選択的RARアゴニストを用いて次のように試験した。脾細胞を、ナイーブB6(WT)マウスから単離し、[3H]−チミジン、最適濃度のαGalCer、および段階的濃度の汎RARアゴニストATRA、RARαアゴニストAM580、RARβ2アゴニストAC55649またはRARγアゴニストCD1530の存在下において、インビトロで培養した。αGalCer刺激に応答したI型NKT細胞の増殖を、[3H]−チミジン取り込みにより測定した。
I型NKT細胞に対するPPAR−γ経路調節の作用
ペルオキシソーム増殖因子活性化レセプター(PPAR)は、甲状腺ホルモン、レチノイド、ステロイドホルモンおよびビタミンDに対するレセプターも含む核内ホルモンレセプタースーパーファミリーに属するリガンド誘導性転写因子である。PPARは、ヘテロ二量体パートナーとしてのレチノイドXレセプター(RXR)と共に、DNAにおける特定のペルオキシソーム増殖因子応答エレメント(PPRE)に結合することによって、遺伝子発現を調節する。PPARは、脂質代謝およびエネルギー代謝、炎症、胚移植、糖尿病および癌においてある役割を果たすと指摘されてきた。
I型NKT細胞活性に対するレチノールアナログの作用の調査
膵細胞を、ナイーブB6マウスから単離し、段階的濃度のATRA、レチノール、9−cis−RAまたは13−cis−RAの存在下または不在下において、[3H]−チミジンおよび最適濃度のαGalCerと共に、インビトロで培養した。αGalCer刺激に応答した膵臓I型NKT細胞の増殖を、[3H]−チミジン取り込みにより定量化した。図14に示されるように、101μg/mlのATRAにおいて培養された細胞については、増殖は、全くまたはほとんど観察されなかったが、I型NKT細胞増殖の同じレベルの阻害は、101μg/mlを超えるレチノール、9−cis−RAまたは13−cis−RAの濃度でしか観察されなかった。
I型NKT細胞活性に対するRARアゴニストの作用の調査
インビトロ増殖およびサイトカイン放出アッセイを、新たに単離された脾細胞およびI型NKT細胞ハイブリドーマ(1.2Hyb)に対して行った。細胞を、[3H]−チミジンおよび最適濃度のαGalCer(10ng/ml)の存在下において、滴定濃度のATRA、トレチノイン、RARαアゴニストAM580、RARβアゴニストAC55649またはRARγアゴニストCD1530と共に培養した。αGalCer刺激に応答したI型NKT細胞の増殖を、[3H]−チミジン取り込みにより定量化した。IL−2レベルを、IL−2サンドイッチELISAを用いて測定した。RARアゴニストの最適濃度を決定した。RARアゴニストのそれらの最適濃度における作用の比較を、図15に示す。最低レベルの増殖は、ATRA、トレチノイン、RARγアゴニストCD1530の存在下において培養された細胞について観察された。RARγアゴニストCD1530の存在下において培養された細胞が、最低レベルのIL−2分泌を示した。これらの結果は、RARγアゴニストCD1530が、I型NKT細胞活性の有効なインヒビターであることを示している。
タザロテンおよびATRAによるI型NKT細胞の阻害の比較
I型NKT細胞活性に対する選択的RARγアゴニストタザロテンの作用を、インビトロ増殖およびサイトカイン放出アッセイにより調べた。
タザロテンおよびATRAのインビボ投与に続くI型NKT細胞の阻害
タザロテンまたはATRAのインビボ投与に続くI型NKT細胞における機能変化を試験した。マウスの各群に、300μgのATRA(15mg/kg)、300μgのタザロテン(15mg/kg)またはビヒクル(DMSO)を、5日間にわたり毎日腹腔内注射した。脾臓I型NKT細胞を精製し、増加していく濃度のαGalCerと共にインビトロで培養した。細胞増殖を、[3H]−チミジン取り込みの定量化により測定した。その結果を図17にて示す。ATRA注射マウス、タザロテン注射マウス、またはビヒクル(DMSO)注射マウスから単離された細胞のαGalCer刺激に対する増殖応答の比較は、ATRAまたはタザロテンのインビボ投与がいずれもI型NKT細胞活性を阻害することを示している。しかしながら、最低レベルの増殖は、タザロテン注射マウスから単離されたI型NKT細胞について観察された。図17を参照されたい。
RARアゴニスト投与によるALDの予防
アルコール性肝疾患の予防または緩和におけるRARアゴニストの有効性を、有効量のATRA、タザロテン、トレチノイン、RARαアゴニストAM580、RARβアゴニストAC55649、RARγアゴニストCD1530、またはビヒクル/DMSOを、5日間にわたり毎日マウスの各群に注射することにより試験する。この期間中、マウスは、10日間にわたり5%のエタノールを含有する液体食餌、それに続く(11日目における)単回の高用量の強制飼養エタノール(5g/kg体重)(慢性的+過エタノール給餌群)または等カロリーのデキストリンマルトース含有食餌、それに続く等カロリーのデキストリンマルトース強制飼養(コントロール群)のいずれかである。マウスを強制飼養の6〜8時間後に安楽死させ、血清および肝組織を採取する。
ATRA処置されたまたはタザロテン処置されたBL/6マウスからのαGalCer/CD1d−テトラマー精製I型NKT細胞を用いる養子移入実験を使用して、段階的な数のこれらの細胞がナイーブBL/6レシピエントに移入された場合に慢性的+過エタノール給餌に続いて肝傷害を阻害し得るか否かを調べる。
上述の明細書は、当業者が本実施形態を実施することを可能にするのに十分であると考えられる。上述の記載は、特定の好ましい実施形態を詳述し、本発明者らにより企図される最良の態様を記載している。しかしながら、上述のものが本文中でいかに詳細であるように見えようとも、本実施形態は、いろいろなやり方で実施されることができ、添付の特許請求の範囲およびそのあらゆる均等物にしたがって解釈されるべきであることが理解されるであろう。
を有し、式中、R1は、結合、水素、C1〜C30アルキル、C1〜C30置換アルキル、C1〜C30アルケニル、C1〜C30置換アルケニルおよびC5〜C12糖からなる群から選択され;R2は、水素、ヒドロキシ基、メトキシ基、およびアルコキシ基からなる群から選択され;R3は、水素、ヒドロキシ基、メトキシ基、エトキシ基、およびアルコキシ基からなる群から選択され;R4は、水素、ヒドロキシ基およびアルコキシ基からなる群から選択され;R5は、水素、ヒドロキシル、カルボニル、アルコキシおよび結合からなる群から選択され;R6は、C1〜C40アルキル、C1〜C40置換アルキル、C1〜C40アルケニル、C1〜C40置換アルケニルおよびC1〜C40アルキンル(alkynl)からなる群から選択され;R7は、C1〜C40アルキル、C1〜C40置換アルキル、C1〜C40アルケニル、C1〜C40置換アルケニルおよびC1〜C40アルキンル(alkynl)からなる群から選択され;そしてR8は、水素、ヒドロキシル基、カルボニル、アルコキシ基および結合からなる群から選択される。いくつかの実施例では、スルファチドが以下の化学構造を有する:
を有し、式中、R1は、結合、水素、C1〜C30アルキル、C1〜C30置換アルキル、C1〜C30アルケニル、C1〜C30置換アルケニルおよびC5〜C12糖からなる群から選択され;R2は、水素、ヒドロキシ基、メトキシ基、およびアルコキシ基からなる群から選択され;R3は、水素、ヒドロキシ基、メトキシ基、エトキシ基、およびアルコキシ基からなる群から選択され;R4は、水素、ヒドロキシ基およびアルコキシ基からなる群から選択され;R5は、水素、ヒドロキシル、カルボニル、アルコキシおよび結合からなる群から選択され;R6は、C1〜C40アルキル、C1〜C40置換アルキル、C1〜C40アルケニル、C1〜C40置換アルケニルおよびC1〜C40アルキンル(alkynl)からなる群から選択され;R7は、C1〜C40アルキル、C1〜C40置換アルキル、C1〜C40アルケニル、C1〜C40置換アルケニルおよびC1〜C40アルキンル(alkynl)からなる群から選択され;そしてR8は、水素、ヒドロキシル基、カルボニル、アルコキシ基および結合からなる群から選択される。
を有し、式中、R1は、結合、水素、C1〜C30アルキル、C1〜C30置換アルキル、C1〜C30アルケニル、C1〜C30置換アルケニルおよびC5〜C12糖からなる群から選択され;R2は、水素、ヒドロキシ基、メトキシ基、およびアルコキシ基からなる群から選択され;R3は、水素、ヒドロキシ基、メトキシ基、エトキシ基、およびアルコキシ基からなる群から選択され;R4は、水素、ヒドロキシ基およびアルコキシ基からなる群から選択され;R5は、水素、ヒドロキシル、カルボニル、アルコキシおよび結合からなる群から選択され;R6は、C1〜C40アルキル、C1〜C40置換アルキル、C1〜C40アルケニル、C1〜C40置換アルケニルおよびC1〜C40アルキンル(alkynl)からなる群から選択され;R7は、C1〜C40アルキル、C1〜C40置換アルキル、C1〜C40アルケニル、C1〜C40置換アルケニルおよびC1〜C40アルキンル(alkynl)からなる群から選択され;そしてR8は、水素、ヒドロキシル基、カルボニル、アルコキシ基および結合からなる群から選択される。いくつかの実施例では、このスルファチドが以下の化学構造を有する:
Claims (1)
- 患者における少なくとも1つの炎症状態を処置または予防するための医薬の製造方法であって、前記方法がI型NKT細胞の活性化を阻害するのに十分な量のレチノイドを前記患者に投与するステップを具えることを特徴とする方法。
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