JP2020508642A - 耐性を誘導するための操作された細胞 - Google Patents
耐性を誘導するための操作された細胞 Download PDFInfo
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Abstract
Description
本発明は、抗原に対する免疫応答の抑制により定義される免疫抑制及び耐性を誘導するための、組成物、方法及び使用を包含する。
本発明者らは、CFLARL(図1A)又はCFLARS(図1B)の配列を含む二つのプラスミドコンストラクトを作製した。二つのコンストラクトはレポーター遺伝子:追跡及びマーカー機能を有する緑色蛍光性タンパク質(GFP)を含んでいた。レンチウイルス性の組み換えタンパク質の生成のために、塩化カルシウムを用いた沈殿方法を使用した。簡潔には、ウイルス構築のための重要なタンパク質をコードするプラスミドベクターを、Takara社(Takara Clontech,CA,U.S.A.)により購入した。塩化カルシウムCaCl2(2mM)を、pGpベクター、pE−ecoベクター及びCFLARL若しくはCFLARSをコードするベクター、又はルシフェラーゼ(コントロール)(25μg)を含む溶液に加えた。その後、バッファーHBS 2X(274mM NaCl2、10mM KCl、1.5mM Na2HPO4、12mM デキストロース、42mM HEPES、pH7.1)を撹拌下で加えた。次いでトランスフェクション混合物を293T細胞の培養プレートに滴下し、ウイルス性粒子を含有する培地を48時間後に回収し、遠心分離し、0.45μm孔のフィルターでろ過し、細胞及びデブリを除去し、50,000gで140分間室温で超遠心分離することにより濃縮した。感染はスピン接種(spin−inoculation)により行った:細胞(ヒト幹細胞又は単球)をマルチウェルプレートスインギングバケットローターに置き、遠心分離した;プレートを2500rpmで4時間30℃でスピンさせた。この工程の後、本発明者らは、免疫抑制アッセイを設定した。ヒト幹細胞(骨髄CD34+細胞、100万個、cat.2M−101C、Lonza,Switzerland)の場合、感染したCD34+細胞をG−CSF(40ng/ml;Miltenyi Biotec S.r.l.,Italy)及びGM−CSF(40ng/ml、Miltenyi Biotec S.r.l.,Italy)の存在下でin vitroで四日間分化させ、MDSC関連免疫抑制活性の獲得を促進した。四日後、細胞を回収し、活性化された細胞追跡標識PBMCの存在下で共培養した(図2A、左パネル)。簡潔には、PBMCを回収し、IMDM培地(Lonza、Switzerland)中で洗浄し、10% FBS(EuroClone,Italy)、100U/mlのペニシリン/ストレプトマイシン(Lonza,Switzerland)、β−メルカプトエタノール(Sigma−Aldrich,Italy)及び10mMのHEPES(Lonza,Switzerland)を補充した。PBMCを、PBS中で107細胞/mlの最終濃度に再懸濁し、最終作用濃度2.5μMのCell Trace Violet保存溶液(Invitrogen Molecular Probe,U.K.)で染色し、続いて5分間37℃でインキュベートし、光から保護した。色素は容易に細胞中に拡散し、細胞内エステラーゼにより切断されて高度に蛍光性の化合物を生じさせた。この化合物は共有結合的に細胞内アミンに結合し、その結果安定でよく保持された蛍光染色が得られた。各分裂後に色素は娘細胞に均等に分配されるため、細胞蛍光性は半減する。フローサイトメトリーヒストグラムでは、左側に向かって離散ピークが現れており、各細胞分裂又は生成を表している。次いで細胞を洗浄し、培地中に再懸濁した。標識された「標的」PBMCを、コーティングされた1μg/mlの抗CD3(クローン、OKT−3;eBioscience,CA,U.S.A.)及び5μg/mlの可溶型抗CD28(クローン、CD28.2、eBioscience,CA,U.S.A.)を用いて四日間刺激し、384平底ウェルプレート(BD Biosciences,NJ,U.S.A.)において、異なるエフェクター対標的率で、「エフェクター」in vitro分化CD34+細胞と共に共培養した。細胞培養物を、アルギニン及びグルタミンを含有しないRPMI(Biochrom AG,Germany)中5% CO2で37℃でインキュベートし、2mMのL−グルタミン、150μMのアルギニン、10% FBS(Sigma−Aldrich,MO,U.S.A.)、10U/mlのペニシリン及びストレプトマイシン(Lonza,Switzerland)、及び0,1mMのHEPES(Lonza,Switzerland)を補充した。培養の最後に、細胞をPE−Cy7コンジュゲート抗CD3(UCHT1,eBioscience,CA,U.S.A.)で染色し、すべての試料をFACS−CantoII(BD Biosciences,NJ,U.S.A.)で獲得し、ゲーティングされたリンパ球の細胞追跡シグナルをFlowJoソフトウェア(Treestar Inc.)により分析した。細胞増殖の範囲は、増殖細胞の数を分析して定量化され、in vitroで分化したCD34+細胞なしで100%と想定された。本発明者らは、CFLARの上方制御により増強されたin vitroでの免疫抑制能力が、MDSCを分化させることを実証した。このことは、このタンパク質の新規の生物学的役割を示唆するものである。実際、CFLAR発現CD34+細胞は、ルシフェラーゼ発現CD34+細胞(図2A、右パネル)と比較して、有意に増加した抑制活性を示した。これらデータをさらに検証するために、本発明者らは、通常はなんら免疫抑制機能を示さない、使用するバフィーコート由来の精製されたCD14+単球を、CFLAR又はルシフェラーゼ発現レンチウイルスを用いて免疫磁気的に感染させ(cat.130−050−201;Miltenyi Biotec S.r.l.,Italy)、それらを抗ヒトCD3/CD28によって活性化された細胞追跡標識PBMCの存在下において共培養した(図2B、左パネル)。また、この実験の設定において、CFLAR感染CD14+細胞は、ルシフェラーゼ感染単球(図2B、右パネル)と比較して、より強力な抑制能を獲得した。7−AADを用いるAPC−AnnexinVアポトーシス検出キット(cat.640930,Biolegend,CA,U.S.A.)によるフローサイトメトリーを用いたとき、in vitroでの共培養後のCD14+7−AAD−アネキシン−V−細胞のパーセンテージは同等であった(データは示さない)ため、この強力な免疫抑制機能は、コントロールと比較して、CFLAR発現CD14+細胞のよりよい生存率とは相関していなかった。すべての試料は、FACS−CantoII(BD Biosciences,NJ.U.S.A.)により獲得され、FlowJoソフトウェア(Treestar Inc.)により分析された。
骨髄細胞における免疫抑制機能プログラムの基礎となるCFLAR活性化分子経路の同定を改善するために、本発明者らは、四名の健常ドナーから単離されたCFLAR感染及びルシフェラーゼ感染CD14+細胞のトランスクリプトーム分析を実施した。簡潔には、全RNAを、TRIzol試薬(Life technology,CA,U.S.A.)を用いて単離し、RNA完全性を、Agilent−2100−Bioanalyzer(Agilent Technologies,CA,U.S.A.)を用いて評価した。RNAをさらに、RNeasy MinElute Cleanupキット(Qiagen,Venlo,Netherlands)を用いて精製し、Ovation Pico WTA System V2(NuGEN,CA,U.S.A.)により全精製RNAからcDNAを合成し増幅した。すべての試料をAffymetrix U133 PLUS 2.0アレイにハイブリダイズし、Affymetrix GCS 3000 7Gスキャナでスキャンした。試料及び遺伝子は、それぞれ距離メトリック及び結合としてのピアソン相関係数及び平均を用いてクラスター化される。図3に示すように、監視クラスタリング(q値<0.05、倍の変化>2)は、CFLAR感染単球に、コントロールと比較して、750の上方制御された遺伝子(図4)と1,130の下方制御された遺伝子(データは示さない)のリストを生成した。特に、この結果、これら差次的に発現される遺伝子は、炎症経路、Notch関連経路及びIL−10関連経路に関与するカテゴリーにおいて有意に濃縮された。さらに、CFLARの強制発現は、SOCS2、FAS、CCR7、CCL5、NF−kB、STAT3、CD38、CD274、CD273、IL4R、IL6、IL10、CFS3、PTGS2及びIDO1といったMDSC関連免疫抑制遺伝子の上方制御を活性化する。推定されるCFLAR関連標的のいくつかを試験し、検証した(図5)。特に、本発明者らは、CFLARを形質導入された単球がCFLARL及びCFLARS両方の上方制御、並びにIDO1の上方制御を示すことをReal Time PCRにより実証した。この目的のために、本発明者らは、全RNAを、CFLAR感染又はルシフェラーゼ感染単球の両方から、TRIzol試薬(Life technology,CA,U.S.A.)により単離し、RNA完全性を、Agilent−2100−Bioanalyzer(Agilent Technologies,CA,U.S.A.)を用いて評価した。RNAをさらに、RNeasy MinElute Cleanupキット(Qiagen,Venlo,Netherlands)を用いて精製し、Ovation Pico WTA System V2(NuGEN,CA,U.S.A.)により全精製RNAからcDNAを合成し増幅した。すべての試料を使用して、Primer Express社のABI Biosystemsにより設計されたカスタムプライマーを用いてReal Time PCRを設定した。相対的遺伝子発現を定量化する事後qRT−PCR分析が、比較Ct法(2−ΔΔCt)により実施された。図5Aに示すように、CFLAR形質導入単球は、有意に高いレベルの推定標的遺伝子を発現した。さらに、本発明者らは、CFLAR形質導入CD14+細胞が、ルシフェラーゼ−形質導入CD14+細胞より有意に高いレベルのIL−10を分泌することを、ELISA(Enzyme Linked ImmunoSorbent Assay)アッセイ(R&D System,MN,U.S.A.)により検証した。つまり、このアッセイは、IL−10に特異的な精製された抗体と共に事前にインキュベートした特定の96ウェルプレートに培地を移行することからなる。いくつかのウェルにおいて、試料の代わりに、問題のサイトカインの1:2のスカラー希釈を用いて、較正曲線を作成した。37℃での2時間のインキュベーション後、プレートを、ビオチン化した抗IL−10抗体で1時間マーキングし、次いでペルオキシダーゼ(peroxidise)に結合したストレプトアビジンを用いた30分間のインキュベーションを室温で行った。ペルオキシダーゼ(peroxidise)とその基質(TMB−3,3’,5,5’−テトラメチルベンジジン)との反応により、450nmにおける読み取りによる対象のサイトカインの定量化が可能である。最後に、本発明者らは、単球上の強制CFLAR−発現が特異的表面マーカーの上方制御を促進することを、フローサイトメトリーにより実証した。簡潔には、上述のように、感染から24時間後のCD14+細胞が、マウス抗ヒトCD273−PE(cat.557926、BD Biosciences,NJ,U.S.A.)、マウス抗ヒトCD274−APC(cat.228489、BD Biosciences,NJ,U.S.A.)、マウス抗ヒトCD80−APC(cat.305220、Biolegend CA,U.S.A.)、抗ヒトCD163−PE(cat.556018、BD Biosciences,NJ,U.S.A.)、抗ヒトCD44−PE(cat.103024、Biolegend,NJ,U.S.A.)、抗ヒトCD38−APC(cat.554262、BD Biosciences,NJ,U.S.A.)及び抗ヒトCD124−APC(cat.FAB23OP、R&D System,MN,U.S.A.)を含む100μlのFACSバッファー(2%のBSA及び0.02%のNaN3(いずれもSigma−Aldrich)を含む0.9%のNaCl溶液)に再懸濁された。すべての試料は、FACS−CantoII(BD Biosciences,NJ.U.S.A.)により獲得され、FlowJoソフトウェア(Treestar Inc.)により分析された。
これら観察に基づいて、本発明者らは、移植片対宿主病(GvHD)の発生を制御するCFLAR感染CD14+細胞(上述)の免疫抑制機能を、異種マウスモデルを用いてin vivoで評価することを決定した。この目的のために、本発明者らは、半致死的に放射線照射した(137Cs線源照射器を用いて)、免疫不全NOD.Cg−Prkdcscid Il2rgtm1Sug/JicTac(NOG)(Taconic、NY,U.S.A.により購入)マウスに対し、バフィーコートから単離した106個のヒトPBMCを静脈内(i.v.)注射した。循環するヒトCD3+リンパ球の頻度が全細胞の〜5%のパーセンテージに到達したとき、106個のCFLAR発現又はルシフェラーゼ発現単球のi.v.移入によるマウスの治療を開始した。簡潔には後眼窩出血により100μlの血液を単離した;赤血球をACK(アンモニウム−クロリド−カリウム)リジンバッファーにより排除し、細胞を、ラット抗マウスCD45−APC(クローンA20、Biolegend,NJ,U.S.A.)、抗ヒトCD45−PerPC−Cy5.5(クローン2D1、Biolegend,NJ,U.S.A.)及び抗ヒトCD3−PE−Cy7(クローンUHCT1,Biolegend,NJ,U.S.A.)を用いて染色した。すべての試料は、FACSCanto II(BD Biosciences,NJ,USA)により獲得し、FlowJoソフトウェア(Treestar Inc.)を用いて分析した。処置を、初回負荷後四回、21、28、42及び49日目に繰り返し、マウスを、免疫学的、臨床的、及び病理組織学的なGvHDスコアについて監視した(図6A)。CFLAR感染CD14+細胞の注射は、GvHDの発生を効率的に減少させ、その結果、ルシフェラーゼ発現単球で処置した又は未処置のGvHD罹患マウスと比較して、移植マウスの長期生存率を改善した(図6B)。加えて、組織浸潤ヒトCD3+ T細胞の組織学的解析及び定量化により、CFLAR発現単球で処置したマウスの解析された器官のすべてにおいて、攻撃性の低下したGvHD病理学が示された(図6C)。簡潔には、検死において組織を除去し、10%の緩衝ホルマリンで固定し、パラフィンに埋設した。病理組織学的評価を、標準のヘマトキシリン及びエオシン切片で実施した。病理学的スコアを、以前に出版された基準線ガイドを用いて二人の病理学者が盲検により評価した(Cooke KR, Kobzik L, Martin TR, Brewer J, Delmonte J, Crawford JM, Ferrara JLM: An experimental model of idiopathic pneumonia syndrome after bone marrow transplantation: The roles of minor H antigens and endotoxin. Blood 8:3230, 199)。最後に、脾臓、肝臓、肺、皮膚、結腸、腎臓及び胃のパラフィン切片を、免疫組織化学に使用した:切片を抗ヒトCD3(クローン ab5690、Abcam,United Kingdom)抗体で染色してヒト組織浸潤リンパ球を定量化した。
CFLARに誘導される分子経路をよりよく理解するために、本発明者らは、ウイルス形態のCFLARを発現するトランスジェニックマウスモデル:Rosa26.vFLIPノックインマウスを利用した。カポジ肉腫関連のヘルペスウイルスは、そのゲノム中においてFADD様インターフェロン変換酵素又はカスパーゼ8(FLICE)阻害タンパク質(vFLIP)をコードする。Rosa26.vFLIPノックインマウスを、内因性のLyz2プロモーター(LysM−Cre)の制御下において、Creリコンビナーゼを発現するマウスと交配し、その結果骨髄細胞系譜に制限されたvFLIP発現を有するマウスを得た。骨髄細胞及び脾細胞をRosa26.vFLIP;LysMcre及びRosa26.vFLIPマウスの両方から取得し、蛍光活性化セルソーティング(FACS)によりCD11B+ Ly6G− Ly6Chigh及びCD11B+ Ly6G+ Ly6Clowサブセットを単離した。次いで、新しく単離した骨髄細胞を96ウェルプレートに、トランスジェニック37B7マウス由来の脾細胞の存在下で、培養物中の全細胞の24%の最終濃度で蒔き、これら細胞の免疫抑制活性を評価した。(メラノーマ関連抗原TRP2に特異的な操作されたT細胞受容体(TCR)を含むすべてのCD8+ T細胞を提示するマウスモデル。CFSE 1 μMで標識+TRP−2180-188ペプチド(1μg/ml)の存在下でCD45.1+脾細胞で1:10に希釈。3日間の共培養の後、本発明者らは、FACS−Canto(BD Biosciences,NJ,U.S.A.)によるFACS解析を実施し、増殖の抑制を評価するために、プロットをCD8+ T細胞にゲーティングし、CFSEを希釈した細胞のパーセンテージを、FlowJoソフトウェア(Treestar Inc.)を用いて評価した。次いで、増殖細胞のパーセンテージを使用し、式:1−(骨髄細胞がある場合の増殖(%)/骨髄細胞がない場合の増殖(%))×100を用いて増殖の抑制のパーセントを計算した(図8)。
健常ドナー(HD)のバフィーコートから開始して、本発明者らは、CD14+単球を精製し、c−FLARコード化又はルシフェラーゼコード化レンチウイルスで感染させ、c−FLARの免疫調節特性が、単球を単独で培養したとき及びCD3/CD28活性化PBMCと共に培養したとき両方のコントロールと比較して、c−FLAR発現単球の生存率の改善と相関しないことを実証した。実際、異なる時点における生存(7−AAD−アネキシン−V−)CD14+細胞のパーセンテージは、c−FLAR−単球又はルシフェラーゼ−単球間で有意に異ならず(図9a)、このことは、免疫調節活性が、少なくとも成熟単球においては、c−FLARの抗アポトーシス特性から分離している可能性を示している。加えて、生存促進性と免疫抑制機能の誘導とを区別するために、本発明者らは、他の抗アポトーシス遺伝子のレンチウイルス性発現ベクターを生成し(即ち、Bcl−2及びBcl−xL)、ヒト単球におけるその強制発現後に免疫抑制特性を試験した。図9bに示すように、c−FLARの強制発現だけが、in vitroでのT細胞活性化及び増殖を有意に抑制することができる。
遺伝子オントロジー(GO)エンリッチメント分析を用いることにより、差次的に発現される遺伝子を、炎症、サイトカインネットワーク及びインターフェロンタンパク質に応答して上方制御された遺伝子、並びにIL−10経路、全体としてNF−κB関連経路に関連するカテゴリーにおいて有意に濃縮した(図10a,b)。
c−FLARの強制発現は、正準のNF−κB経路をトリガーする。遺伝子発現データは、恐らくはNF−κB経路にリンクする、予測外のc−FLARの転写活性及びシグナル伝達活性を示唆した。c−FLARの制御下における分子プログラムを明らかにするために、本発明者らは、in vitro転写(IVT)c−FLAR−コード化RNAを用いてTHP1単球性細胞を一過性にトランスフェクトした。合理的なのは、標的タンパク質の、持続性且つウイルス依存性の生成を誘導することであった;さらに、IVT−RNAは自然免疫受容体及びI型インターフェロンの生成を活性化しない。合成c−FLAR RNAのTHP1細胞への強制導入は、これまでレンチウイルス発現ベクターに関して示されたデータと一貫する免疫抑制プログラムをトリガーした(図11a)。c−FLAR RNAのトランスフェクションは、正準のNF−κB活性化経路のメディエーターである、NF−κBサブユニットp65及びp50の核転座を有意に促進し、一方p52サブユニットの転座には差異は検出されなかった(図11b)。NF−κBシグナル伝達が、FLARの下流の免疫調節プログラムに必要かどうかを試験するために、本発明者らは、共に正準のNF−κB活性化に不可欠なキナーゼIKKα(Chukによってコード化)、及びIKKβ(Ikbkbによってコード化)を発現停止させた。本発明者らは、Tgマウスから単離したv−FLAR発現Ly6C+細胞の免疫抑制活性が、IKKα又はIKKβの発現停止後に有意に低下することを実証した(図11c)。総括すると、本発明のデータは、c−FLARが、NF−κB活性化により単球における免疫抑制プログラムを制御するシグナル伝達経路を活性化することを示すものである。
Claims (54)
- 細胞FLICE[Fas関連デスドメイン(FADD)様IL−1β−変換酵素]−阻害タンパク質(CFLAR)の細胞レベルを上昇させるように操作される骨髄細胞又はその前駆細胞を含む細胞の集団。
- CFLARの細胞レベルを上昇させることが、細胞の免疫抑制活性を増大させる、請求項1に記載の細胞の集団。
- 骨髄細胞又はその前駆細胞が、CFLARの細胞発現を増大させるように操作される、請求項1又は2に記載の細胞の集団。
- 骨髄細胞又はその前駆細胞が、CFLARをコードする核酸でトランスフェクトされる、請求項1から3のいずれか一項に記載の細胞の集団。
- 前記トランスフェクションが、安定又は一過性トランスフェクションである、請求項4に記載の細胞の集団。
- 骨髄細胞又はその前駆細胞が、担体としてレンチウイルスベクターといったウイルス性ベクターを用いてトランスフェクトされる、請求項4又は5に記載の細胞の集団。
- 前記核酸がRNAである、請求項4又は5に記載の細胞の集団。
- CFLARがCFLARL及び/又はCFLARSである、請求項1から7のいずれか一項に記載の細胞の集団。
- 骨髄細胞又はその前駆細胞が、単離及び/又は精製された細胞、特に磁気細胞分離により単離及び/又は精製された細胞である、請求項1から8のいずれか一項に記載の細胞の集団。
- 骨髄細胞又はその前駆細胞が単球である、請求項1から9のいずれか一項に記載の細胞の集団。
- 骨髄細胞又はその前駆細胞がCD14+単球である、請求項1から10のいずれか一項に記載の細胞の集団。
- 骨髄細胞又はその前駆細胞が、バフィーコートから単離されたCD14+単球である、請求項1から11のいずれか一項に記載の細胞の集団。
- 骨髄細胞又はその前駆細胞が幹細胞である、請求項1から9のいずれか一項に記載の細胞の集団。
- 骨髄細胞又はその前駆細胞が骨髄CD34+細胞である、請求項1から9及び13のいずれか一項に記載の細胞の集団。
- 骨髄細胞又はその前駆細胞が、骨髄単核細胞(MNC)から単離された骨髄CD34+細胞である、請求項1から9、13及び14のうちのいずれか一項に記載の細胞の集団。
- 細胞が、免疫抑制活性の獲得を促進するように処置されている、請求項1から15のいずれか一項に記載の細胞の集団。
- 免疫抑制活性の獲得を促進するための処置が、G−CSF及びGM−CSFの存在下におけるin vitroでの分化を含む、請求項1から16のいずれか一項に記載の細胞の集団。
- 治療法のための、請求項1から17のいずれか一項に記載の細胞の集団。
- 治療法が免疫抑制を必要とする、請求項18に記載の細胞の集団。
- 免疫抑制を必要とする患者を治療するための、請求項1から17のいずれか一項に記載の細胞の集団。
- 患者にとって自家性である、請求項20に記載の細胞の集団。
- 請求項1から17のいずれか一項に記載の細胞の集団を含む薬学的組成物。
- 治療法のための、請求項22に記載の薬学的組成物。
- 治療法が免疫抑制を必要とする、請求項23に記載の薬学的組成物。
- 免疫抑制を必要とする患者を治療するための、請求項22に記載の薬学的組成物。
- 細胞の集団が患者にとって自家性である、請求項25に記載の薬学的組成物。
- 治療法のための医薬の製造のための、請求項1から17のいずれか一項に記載の細胞の集団の使用。
- 治療法が免疫抑制を必要とする、請求項27に記載の使用。
- 免疫抑制を必要とする患者を治療するための医薬の製造のための、請求項1から17のいずれか一項に記載の細胞の集団の使用。
- 細胞の集団が患者にとって自家性である、請求項29に記載の使用。
- 請求項1から17のいずれか一項に記載の細胞の集団を投与することを含む、免疫抑制を必要とする患者を治療するための方法。
- 細胞の集団が患者にとって自家性である、請求項31に記載の方法。
- 患者の骨髄細胞又はその前駆細胞中のCFLARの細胞レベルを上昇させることを含む、免疫抑制を必要とする患者を治療するための方法。
- CFLARの細胞レベルを上昇させることが、細胞の免疫抑制活性を増大させる、請求項33に記載の方法。
- 患者の骨髄細胞又はその前駆細胞中のCFLARの細胞レベルを上昇させることが、CFLARをコードする核酸を投与することを含む、請求項33又は34に記載の方法。
- CFLARをコードする核酸が、骨髄細胞又はその前駆細胞をトランスフェクトする、請求項35に記載の方法。
- 前記トランスフェクションが、安定又は一過性トランスフェクションである、請求項36に記載の方法。
- 骨髄細胞又はその前駆細胞が、担体としてレンチウイルスベクターといったウイルス性ベクターを用いてトランスフェクトされる、請求項37に記載の方法。
- 前記核酸がRNAである、請求項35から37のいずれか一項に記載の方法。
- CFLARがCFLARL及び/又はCFLARSである、請求項33から39のいずれか一項に記載の方法。
- 骨髄細胞又はその前駆細胞が単球である、請求項33から40のいずれか一項に記載の方法。
- 骨髄細胞又はその前駆細胞がCD14+単球である、請求項33から41のいずれか一項に記載の方法。
- 骨髄細胞又はその前駆細胞が幹細胞である、請求項33から40のいずれか一項に記載の方法。
- 骨髄細胞又はその前駆細胞が骨髄CD34+細胞である、請求項33から40、及び43のいずれか一項に記載の方法。
- 治療法のための、CFLARをコードする核酸。
- 治療法が免疫抑制を必要とする、請求項45に記載の核酸。
- 免疫抑制を必要とする患者を治療するための、CFLARをコードする核酸。
- CFLARをコードする核酸を含む薬学的組成物。
- 治療法のための、請求項48に記載の薬学的組成物。
- 治療法が免疫抑制を必要とする、請求項49に記載の薬学的組成物。
- 免疫抑制を必要とする患者を治療するための、請求項48に記載の薬学的組成物。
- 治療法のための医薬の製造のための、CFLARをコードする核酸の使用。
- 治療法が免疫抑制を必要とする、請求項52に記載の使用。
- 免疫抑制を必要とする患者を治療するための医薬の製造のための、CFLARをコードする核酸の使用。
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