JP2019504074A - 免疫を再構成するための造血ニッチの再現 - Google Patents
免疫を再構成するための造血ニッチの再現 Download PDFInfo
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Abstract
Description
本願は、2016年2月6日に出願された米国仮出願第62/292,288号の利益を主張し、その教示全体が本明細書に参照によって組み込まれる。
本発明は、国立衛生研究所によって授与された補助金番号NIH HL129903、NIH EB015498およびNIH EB014703、ならびに国立科学財団によって授与されたNSF1000099416のもとの政府援助により行われた。政府は、本発明において一定の権利を有する。
造血幹細胞移植(HSCT)を受けた患者における長期間の免疫不全は、依然として、多発性骨髄腫および白血病などの生命を脅かす血液または骨髄の疾患を管理する際の最も重大な障害の1つである。移植の前に、レシピエントは、罹患細胞を破壊するために、コンディショニングの細胞傷害性放射線照射および化学療法レジメンを受ける。そのコンディショニングプロセスの副作用が、適応免疫系のTおよびB細胞が破壊された結果としての重度のリンパ球減少症である。深刻な移植後の免疫不全は、T細胞数およびB細胞数の激減ならびにそれらの多様性の低下を特徴とし、1〜2年間持続し得る。免疫不全に関連する重度の日和見感染症(約30%)、がんの再発(急性骨髄性白血病の場合、>50%)および移植片対宿主病(GVHD)(約40%)が、HSCTを受けた患者における最も一般的な合併症であり、罹患および死亡の原因である。
被験体、例えば、幹細胞移植後の被験体の免疫系の再構成を補助するために有用な新規の組成物および関連する方法が、本明細書中に開示される。そのような組成物は、移植された幹細胞および前駆細胞の生着を高め、およびそれによって被験体の免疫系の再構成を補助するために、被験体に投与され得る。
造血幹細胞移植(HSCT)の後の基本的な課題は、自己免疫障害をもたらし得る過増殖反応を回避しながら新たな免疫学的応答を発生させることに関する。幹細胞レベルでは、骨髄ニッチに存在し、細胞および周辺のマトリックスを含む造血幹細胞(HSC)から、免疫系は生じる。骨髄は、リンパ系の発生の支援を通じた一次リンパ系器官としての役割に加えて、成熟した様々なリンパ系細胞型のための宿主として作用する。骨髄は、HSCの再生能およびHSCから免疫細胞への分化能に影響し、新しいT細胞およびB細胞のための前駆細胞集団を提供する。
本発明者らは、図2A〜2Eに示されているように、骨小結節を生み出すために、カチオン性の強力な骨形成成長因子である骨形成タンパク質(BMP−2)を組み込むために適合された天然のアニオン性多糖であるアルギネートをヒドロゲル足場材料として使用した。マウスへのインビボでの皮下注射後1〜2週間以内に機能的で活性な骨小結節を生み出すという目標で、そのアルギネートからのBMP−2成長因子の充填および放出挙動を最適化した(例えば、放出を制御するために、アルギネートの総注入量および架橋密度)。
ナイーブT細胞およびB細胞は、それぞれ細胞媒介性免疫および体液性免疫を介した、未知の病原体に対する持続的な応答にとって不可欠である。HSCT後のドナー細胞に由来するナイーブリンパ球の再構成を調べた。骨髄をドナーマウスから回収し、TおよびB細胞を枯渇させた(>95%)骨髄を、致死線量を照射されたコンジェニックレシピエントマウスに移植し、図4Aに示されているように、TおよびB細胞の再構成を追跡した。CD3+細胞のT細胞受容体(TCR)を配列決定すること、ならびにTCR遺伝子の可変(V)および連結(J)セグメントの頻度および分布を調べることによって、図4Bに示されているように、TCRの多様性を決定した。
UPアルギン酸ナトリウム(ProNova Biomedical)をメタクリレート基で官能化して、メタクリル化アルギネート(methacrylated alginate)(MA−Alg)を調製した。1〜10nmolのdelta様リガンド−4(DLL−4,R&D systems)を、EDC−NHSカップリングを用いてMA−Algに結合体化した。MA−アルギネートおよび4アームメタクリル化ポリエチレングリコール(MA−PEG)の、低温酸化還元によって誘導されるフリーラジカル重合によって、注射可能なマクロ多孔性ヒドロゲルを合成して、2.5wt%ヒドロゲルを調製した。骨形成タンパク質−2(BMP−2,R&D systems)および幹細胞分化因子−1(SDF−1,R&D systems)をその混合物に加えた後、低温重合を行った。骨髄から単離されたLin−c−kit+Sca−1+(LKS)細胞からCD4+およびCD8+T細胞への分化を用いて、DLL−4の生物活性を評価した。C57BL/6マウスにおける致死線量以下および致死線量の照射を用いて、それぞれ免疫不全および骨髄破壊的移植のコンディショニングを模倣した。CD45.2+マウス系統に移植を行い、コンジェニックCD45.1+B6.SJLマウスからのドナー由来細胞についてモニターした。ヒドロゲルを皮下に注射し、骨小結節の発生および関連する造血性ニッチ環境を、それぞれマイクロ−コンピュータ断層撮影法(μCT)および組織学的検査を用いてモニターした。末梢血における免疫細胞の回復を、FACS解析を用いて定期的にモニターした。T細胞受容体(TCR)の配列決定を用いて、T細胞レパートリーの多様性を決定した。
Claims (51)
- 多孔性の植え込み可能な足場材料、1種または複数種の成長因子および1種または複数種の分化因子ならびに任意選択で1種または複数種のホーミング因子を含む、組成物。
- 前記材料が、ヒドロゲルである、請求項1に記載の組成物。
- 前記材料が、アルギネートを含む、請求項1〜2に記載の組成物。
- 前記材料が、陰イオン性アルギネートを含む、請求項1〜3に記載の組成物。
- 前記材料が、ポリ乳酸、ポリグリコール酸、PLGAポリマー、アルギネートおよびアルギネート誘導体、ポリカプロラクトン、リン酸カルシウム系材料、ゼラチン、コラーゲン、フィブリン、ヒアルロン酸、ラミニンリッチゲル、アガロース、天然多糖類および合成多糖類、ポリアミノ酸、ポリペプチド、ポリエステル、ポリ酸無水物、ポリホスファジン、ポリ(ビニルアルコール)、ポリ(アルキレンオキシド)、ポリ(アリルアミン)(PAM)、ポリ(アクリレート)、改変スチレンポリマー、プルロニックポリオール、ポロキサマー、ポリ(ウロン酸)、ポリ(ビニルピロリドン)およびそれらの任意の組み合わせまたは共重合体からなる群より選択される、請求項1〜2に記載の組成物。
- 前記成長因子の1種または複数種が、骨形成タンパク質(BMP)を含む、請求項1〜5に記載の組成物。
- 前記成長因子の1種または複数種が、BMP−2、BMP−4、BMP−6、BMP−7、BMP−12およびBMP−14からなる群より選択される、請求項1〜6に記載の組成物。
- 前記成長因子の1種または複数種が、BMP−2を含む、請求項1〜6に記載の組成物。
- 前記成長因子の1種または複数種が、前記材料に被包されている、請求項1〜8に記載の組成物。
- 前記成長因子の1種または複数種が、約7〜30日間にわたって前記材料から放出される、請求項1〜8に記載の組成物。
- 前記分化因子の1種または複数種が、Notch受容体に結合する、請求項1〜10に記載の組成物。
- 前記Notch受容体が、Notch−1、Notch−2、Notch−3およびNotch−4からなる群より選択される、請求項11に記載の組成物。
- 前記分化因子の1種または複数種が、Delta様1、Delta様3、Delta様4、Jagged1およびJagged2からなる群より選択される、請求項1〜12に記載の組成物。
- 前記分化因子の1種または複数種が、前記材料に共有結合的に結合されているか、または該材料に共有結合的に結合されたつなぎ鎖に共有結合的に結合されている、請求項1〜13に記載の組成物。
- 前記分化因子の1種または複数種が、サイトカインを含む、請求項1〜14に記載の組成物。
- 前記サイトカインが、インターロイキン−7(IL−7)を含む、請求項15に記載の組成物。
- 前記サイトカインが、前記材料に被包されている、請求項15に記載の組成物。
- 前記サイトカインが、約7〜30日間にわたって前記材料から放出される、請求項1〜17に記載の組成物。
- 前記ホーミング因子の1種または複数種が、幹細胞分化因子(SDF−1)を含む、請求項1〜18に記載の組成物。
- 前記ホーミング因子の1種または複数種が、前記材料に被包されている、請求項1〜19に記載の組成物。
- 前記ホーミング因子の1種または複数種が、約7〜30日間にわたって前記材料から放出される、請求項1〜20に記載の組成物。
- 免疫系の再構成を必要とする被験体の免疫系の再構成を補助する方法であって、該方法は、
投与された足場材料上または投与された足場材料の周囲において組織の形成を促進して小結節を形成する1種または複数種の成長因子;
移植された幹細胞からリンパ系細胞への分化を促進する1種または複数種の分化因子;および任意選択で
該小結節への移植された幹細胞の浸潤を促進する1種または複数種のホーミング因子
を含む該足場材料を含む組成物を該被験体に投与することによって、
該被験体の該免疫系の再構成を補助する工程
を含む、方法。 - 異所性造血幹細胞ニッチの形成を必要とする被験体において異所性造血幹細胞ニッチを形成する方法であって、該方法は、
投与された足場材料上または投与された足場材料の周囲において組織の形成を促進して小結節を形成する1種または複数種の成長因子;
移植された幹細胞から1種または複数種のリンパ系細胞または骨髄系細胞への分化を促進する1種または複数種の分化因子;および任意選択で
該小結節への移植された造血幹細胞の浸潤を促進する1種または複数種のホーミング因子
を含む該足場材料を含む組成物を該被験体に投与することによって、
該被験体において異所性造血幹細胞ニッチを形成する工程
を含む、方法。 - 幹細胞ニッチにおける移植された造血幹細胞の生着の改善を必要とする被験体の、幹細胞ニッチにおける移植された造血幹細胞の生着を改善する方法であって、該方法は、
投与された足場材料上または投与された足場材料の周囲において組織の形成を促進して小結節を形成する1種または複数種の成長因子;
移植された該幹細胞から1種または複数種のリンパ系細胞または骨髄系細胞への分化を促進する1種または複数種の分化因子;および任意選択で
該小結節への移植された該造血幹細胞の浸潤を促進する1種または複数種のホーミング因子
を含む該足場材料を含む組成物を該被験体に投与することによって、
該被験体の該幹細胞ニッチにおける移植された該造血幹細胞の生着を改善する工程
を含む、方法。 - 生着すべき移植された幹細胞のための部位の増加を必要とする被験体において、生着すべき移植された幹細胞のための部位を増加させる方法であって、該方法は、
投与された足場材料上または投与された足場材料の周囲において組織の形成を促進して小結節を形成する1種または複数種の成長因子;
移植された該幹細胞から1種または複数種のリンパ系細胞または骨髄系細胞への分化を促進する1種または複数種の分化因子;および任意選択で
該小結節への移植された該幹細胞の浸潤を促進する1種または複数種のホーミング因子
を含む該足場材料を含む組成物を該被験体に投与することによって、
該被験体において生着すべき移植された該幹細胞のための部位を増加させる工程
を含む、方法。 - 前記足場材料が、ヒドロゲル材料を含む、請求項22〜25に記載の方法。
- 前記足場材料が、アルギネートを含む、請求項22〜26に記載の方法。
- 前記足場材料が、陰イオン性アルギネートを含む、請求項22〜27に記載の方法。
- 前記足場材料が、ポリ乳酸、ポリグリコール酸、PLGAポリマー、アルギネートおよびアルギネート誘導体、ポリカプロラクトン、リン酸カルシウム系材料、ゼラチン、コラーゲン、フィブリン、ヒアルロン酸、ラミニンリッチゲル、アガロース、天然多糖類および合成多糖類、ポリアミノ酸、ポリペプチド、ポリエステル、ポリ酸無水物、ポリホスファジン、ポリ(ビニルアルコール)、ポリ(アルキレンオキシド)、ポリ(アリルアミン)(PAM)、ポリ(アクリレート)、改変スチレンポリマー、プルロニックポリオール、ポロキサマー、ポリ(ウロン酸)、ポリ(ビニルピロリドン)およびそれらの任意の組み合わせまたは共重合体からなる群より選択される、請求項22〜25に記載の方法。
- 前記被験体への前記組成物の投与が、該被験体における該組成物の植え込みを含む、請求項22〜29に記載の方法。
- 前記組成物が、皮下に植え込まれる、請求項30に記載の方法。
- 前記成長因子の1種または複数種が、骨形成タンパク質(BMP)を含む、請求項22〜31に記載の方法。
- 前記成長因子の1種または複数種が、BMP−2、BMP−4、BMP−6、BMP−7、BMP−12およびBMP−14からなる群より選択される、請求項22〜32に記載の方法。
- 前記成長因子の1種または複数種が、BMP−2を含む、請求項22〜32に記載の方法。
- 前記成長因子の1種または複数種が、前記材料に被包されている、請求項22〜34に記載の方法。
- 前記成長因子の1種または複数種が、約7〜30日間にわたって前記材料から放出される、請求項22〜35に記載の方法。
- 前記分化因子の1種または複数種が、Notch受容体に結合する組成物を含む、請求項22〜36に記載の方法。
- 前記Notch受容体が、Notch−1、Notch−2、Notch−3およびNotch−4からなる群より選択される、請求項37に記載の方法。
- 前記分化因子の1種または複数種が、Delta様1、Delta様3、Delta様4、Jagged1およびJagged2からなる群より選択される、請求項22〜38に記載の方法。
- 前記分化因子の1種または複数種が、前記材料に共有結合的に結合されているか、または該材料に共有結合的に結合されたつなぎ鎖に共有結合的に結合されている、請求項22〜39に記載の方法。
- 前記分化因子の1種または複数種が、サイトカインを含む、請求項22〜40に記載の方法。
- 前記サイトカインが、インターロイキン−7(IL−7)を含む、請求項41に記載の方法。
- 前記サイトカインが、前記材料に被包されている、請求項22〜42に記載の方法。
- 前記サイトカインが、約7〜30日間にわたって前記材料から放出される、請求項22〜43に記載の方法。
- 前記ホーミング因子の1種または複数種が、幹細胞分化因子(SDF−1)を含む、請求項22〜44に記載の方法。
- 前記ホーミング因子の1種または複数種が、前記材料に被包されている、請求項22〜45に記載の方法。
- 前記ホーミング因子の1種または複数種が、約7〜30日間にわたって前記材料から放出される、請求項22〜46に記載の方法。
- 前記分化因子の1種または複数種が、移植された前記幹細胞においてリンパ球産生を促進する、請求項22〜47に記載の方法。
- 前記被験体が、幹細胞移植を受けたことがある、請求項22〜48に記載の方法。
- 前記被験体が、免疫無防備状態である、請求項22〜49に記載の方法。
- 前記リンパ系細胞および骨髄系細胞の1種または複数種が、CD4+、CD8+およびMac−1+/GR−1+である、請求項22〜50に記載の方法。
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