JP2015501835A - 中枢神経系の損傷の治療のためのヒト単球亜集団 - Google Patents
中枢神経系の損傷の治療のためのヒト単球亜集団 Download PDFInfo
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Abstract
Description
(i)動物:実験に使用した動物は、別に示されなければ、イスラエルのISO公認のSPF実験動物繁殖施設であるHarlan Laboratories及びWeizmann科学研究所の動物繁殖センター(イスラエル、レホヴォト)から供給された。動物はすべてWeizmann研究所の動物実験委員会によって編成された規則に従って取り扱った。
初めに、我々は、最少限の侵襲性の方法を用いて損傷した脊髄にて所望の表現型を持つ血液由来の単球の数を増やす臨床的に実現可能な方法を探していた。我々は、ラットにおける脊髄損傷に続く機能的欠陥を軽減することにおいて、腰椎穿刺(LP)によって皮膚活性化した血液由来の単球を脳脊髄液(CSF)に注入することの有効性を調べた。
さらに我々は、脳室内(ICV)を介してCSFに注入された非活性化の骨髄由来の単球が損傷した脊髄実質にホーミングするかどうかを調べた。野生型マウスを脊髄挫傷の対象とした(材料及び方法を参照)。3日後、損傷した動物に単離した緑色蛍光タンパク質(GFP)を発現する未感作の骨髄由来の単球(0.5×106個のCx3cr1GFP/+単球)をICV注入し、損傷の部位での注入した細胞の存在について解析した。注入の4日後の損傷部位の免疫組織化学的な解析は、病変部位の周辺に近接した損傷した実質にて注入したGFPを発現する細胞の存在を明らかにした(示さず、[図面の短い記載での説明を参照])。同様に治療した動物を運動スケール(BMS)によって評価される自発運動活動度について観察した:単球プールの増強は、マウスにおける自発運動での有意な改善から理解できるように、自然発生的な回復レベルを超える回復を生じた(図2)。
ヒトでは、CD14及びCD16の発現、すなわち、CD14+CD16−、CD14+CD16+及びCD14低CD16+によって単球の3つの集団が定義される。CD14+CD16−の単球は血中単球の80%〜90%を表し、高レベルのケモカイン受容体CCR2及び低レベルのケモカイン受容体CX3CR1(フラクタルカインの受容体)を発現する。この主要なサブセットとは対照的に、ヒトCD16+単球は高レベルのCX3CR1及び低レベルのCCR2を発現する(Cros et al., 2010)。Crosら、2010によれば、遺伝子発現の解析は、ヒトのCD14低CD16+とマウスのパトロールGr1低の間で類似性を示した。CD14低CD16+細胞は組織の先天性局所監視及び自己免疫疾患の病態形成に関与する真正の単球である。
スキーム1
(i)ヒト末梢血からの単核細胞の単離:健常な供血者から採取した新鮮血(8ml)をPBS中2.5%のFCSで1:1に希釈し、Ficoll勾配(Ficoll−Paque plus,Amersham Biosciences)に負荷した。試験管を1000gにて20℃で20分間遠心した。単核細胞相を回収し、PBSで2回洗浄した。
生細胞集団のうちで単球の集団を解析し(図3A)、CD45+細胞の側方散乱分布を用いて特定した(図3B、細い黒線よって示す)。単球の亜集団の分布はそのCD14抗原及びCD16抗原の発現によって提示される(図3C)。FACSによるCD14及びCD16の染色に従った健常供血者のPBMCからの単球の亜集団の解析は以下の亜集団の分布を明らかにする:CD14+CD16−(80.5%)、CD14+CD16+(4.8%)及びCD14低CD16+(3.5%)、図3A〜C。興味深いことに、CD14低CD16+の亜集団は、CSF−1受容体に属し、骨髄由来の単球を特徴付けるマーカーCD115によっても染まった(図3D)。
上記の所見の観点から、我々はMACSによる負の選択の手順を用いたCD16−単球を単離する手順を開発した。CD3、CD19、及びCD56に結合したマイクロビーズでPBMCを標識し、T細胞、B細胞及びNK細胞を除去した。磁気カラムを通過した非標識の細胞を回収した。この分画をCD16マイクロビーズで標識し、再び磁気カラムに負荷した。カラムを通過した細胞を回収し、FACSによる解析のためにCD14及びCD16の蛍光抗体で染色した。左の図は単離前のPBMCを表し(図8A)、右の図は上述のような負の選択の後の最終産物を表す(図8B)。PBMCでは、生細胞全体の19%が単球である(CD14+)。単球のうち、約10%がCD16+である。最終産物では、生細胞の約90%が単球であり、そのうちでCD16+は0.1%未満である。
Bomstein Y, Marder J. B., Vitner K, Smirnov I, Lisaey G, Butovsky O, Fulga V, Yoles E. (2003) Features of skin-coincubated macrophages that promote recovery from spinal cord injury. Journal of Neuroimmunology 142: 10-16
Cros J, Cagnard N, Woollard K, Patey N, Zhang SY, Senechal B, Puel A, Biswas SK, Moshous D, Picard C, Jais JP, D'Cruz D, Casanova JL, Trouillet C, Geissmann F. Human CD14dim monocytes patrol and sense nucleic acids and viruses via TLR7 and TLR8 receptors. Immunity. 2010 Sep 24;33(3):375-86
Knoller N, Auerbach G, Fulga V, Zelig G, Attias J, Bakimer R, Marder J.B., Yoles E, Belkin M, Schwartz M, and Hadani M (2005) Clinical experience using incubated autologous macrophages as a treatment for complete spinal cord injury: Phase I study results J Neurosurg Spine 3: 173-181.
Shechter R, London A, Varol C, Raposo C, Cusimano M, Yovel G, Rolls A, Mack M, Pluchino S, Martino G, Jung S, Schwartz M. (2009) Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. 6(7)
Claims (28)
- 中枢神経系(CNS)の損傷の治療に使用するための、CD3+細胞、CD19+細胞及びCD56+細胞を実質的に欠く末梢血単核細胞(PBMC)の亜集団。
- CD16+細胞をさらに実質的に欠く請求項1に記載のPBMCの亜集団。
- CNSの損傷の治療に使用するための、CD3+細胞、CD19+細胞、CD56+細胞及びCD16+細胞を実質的に欠く末梢血単核細胞(PBMC)の亜集団。
- CD14+細胞が実質的に濃縮される請求項1又は3に記載のPBMCの亜集団。
- 前記CNSの損傷が原因で生じるニューロンの変性の治療に使用するための請求項1〜4のいずれか1項に記載のPBMCの亜集団。
- 脊髄損傷の治療に使用するための請求項1〜4のいずれか1項に記載のPBMCの亜集団。
- 前記治療が、脊髄組織の復元の促進、機能回復又はその双方である請求項5又は6に記載のPBMCの亜集団。
- 前記CNSの損傷が、たとえば、鈍的外傷、浸透外傷、脳の衝撃又は反衝、神経外科手術若しくは他の処置の間に持続する外傷のような外傷、又は出血性脳卒中若しくは虚血性脳卒中のような脳卒中である請求項1〜5のいずれか1項に記載のPBMCの亜集団。
- 自己PBMCである請求項1〜8のいずれか1項に記載のPBMCの亜集団。
- 同種PBMCである請求項1〜8のいずれか1項に記載のPBMCの亜集団。
- 注入用に製剤化される請求項9又は10に記載のPBMCの亜集団。
- 脳脊髄液(CSF)に注入するために製剤化される請求項11に記載のPBMCの亜集団。
- CNSの損傷の治療に使用するための、CD3+細胞、CD19+細胞及びCD56+細胞を実質的に欠く末梢血単核細胞(PBMC)の亜集団を含む組成物。
- PBMCの前記亜集団がさらにCD16+細胞を実質的に欠く請求項13に記載の組成物。
- CNSの損傷の治療に使用するための、CD3+細胞、CD19+細胞、CD56+細胞及びCD16+細胞を実質的に欠く末梢血単核細胞(PBMC)の亜集団を含む組成物。
- PBMCの前記亜集団はCD14+細胞が実質的に濃縮される請求項13又は15に記載の組成物。
- 前記亜集団のPBMCが注入に適合する薬学上許容可能なキャリアに懸濁される請求項13又は15に記載の組成物。
- 注入がCSFへの投与である請求項17に記載の組成物。
- CSFへの投与が、クモ膜下注入、腰椎穿刺(LP)、大槽(CM)を介した注入、脳室内(ICV)注入又はそれらの組み合わせを介する請求項18に記載の組成物。
- 必要とする個人に有効量の、CD3+細胞、CD19+細胞及びCD56+細胞を実質的に欠く末梢血単核細胞(PBMC)の亜集団を投与することを含む、CNSの損傷を治療する方法。
- PBMCの前記亜集団がさらにCD16+細胞を実質的に欠く請求項20に記載の方法。
- 必要とする個人に有効量の、CD3+細胞、CD19+細胞、CD56+細胞及びCD16+細胞を実質的に欠く末梢血単核細胞(PBMC)の亜集団を投与することを含む、CNSの損傷を治療する方法。
- PBMCの前記亜集団はCD14+細胞が実質的に濃縮される請求項20又は22に記載の方法。
- PBMCの前記亜集団をCSFに注入することを含む請求項23に記載の方法。
- CD3+細胞、CD19+細胞及びCD56+細胞を実質的に欠く血液由来のヒト末梢血単核細胞(PMBC)の亜集団を単離する方法であって、
(i)血液から単核細胞を単離する工程と、
(ii)前記単核細胞を、それぞれがマイクロビーズに連結された抗CD3+抗体、抗CD19+抗体及び抗CD56+抗体に接触させ、それによって前記マイクロビーズに前記細胞を結合させ、マイクロビーズを取り除くことによって(i)の単核細胞からCD3+細胞、CD19+細胞及びCD56+細胞を取り除く工程を含み、それによってCD3+細胞、CD19+細胞及びCD56+細胞を実質的に欠く血液由来のヒト末梢血単核細胞(PMBC)の亜集団を得る、前記方法。 - CD3+細胞、CD19+細胞、CD56+細胞及びCD16+細胞を実質的に欠く血液由来のヒト末梢血単核細胞(PMBC)の亜集団を単離する方法であって、
(iii)血液から単核細胞を単離する工程と、
(iv)前記単核細胞を、それぞれがマイクロビーズに連結された抗CD3+抗体、抗CD19+抗体、抗CD56+抗体及び抗CD16+抗体に接触させ、それによって前記マイクロビーズに前記細胞を結合させ、マイクロビーズを取り除くことによって(iii)の単核細胞からCD3+細胞、CD19+細胞、CD56+細胞及びCD16+細胞を取り除く工程を含み、それによってCD3+細胞、CD19+細胞、CD56+細胞及びCD16+細胞を実質的に欠く血液由来のヒトPMBCの亜集団を得る、前記方法。 - 工程(iv)が、(i)の単核細胞からCD3+細胞、CD19+細胞及びCD56+細胞を取り除き、それによってCD3+細胞、CD19+細胞及びCD56+細胞を実質的に欠く、血液由来のヒトPMBCの亜集団を得る副工程(v)及び
(v)のPMBC集団からCD16+細胞を取り除き、それによってCD3+細胞、CD19+細胞、CD56+細胞及びCD16+細胞を実質的に欠く血液由来のヒトPMBCの亜集団を得る副工程(vi)を含む請求項26に記載の方法。 - 工程(iv)が単一工程で実施される請求項27に記載の方法。
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Patent Citations (3)
Publication number | Priority date | Publication date | Assignee | Title |
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WO1998005795A1 (en) * | 1996-08-02 | 1998-02-12 | The Center For Blood Research, Inc. | Enrichment of dendritic cells from blood |
WO2009120368A2 (en) * | 2008-03-28 | 2009-10-01 | Stemcyte, Inc. | Treatment of brain damage using umbilical cord blood cells |
JP2011515470A (ja) * | 2008-03-28 | 2011-05-19 | ステムサイト インコーポレーテッド | 臍帯血細胞を用いた脳損傷の処置 |
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MX2014007188A (es) | 2015-09-22 |
US20140363411A1 (en) | 2014-12-11 |
KR20140107439A (ko) | 2014-09-04 |
PL2790712T3 (pl) | 2017-04-28 |
BR112014014560A2 (pt) | 2017-06-13 |
AU2017254830A1 (en) | 2017-11-16 |
CN104159590A (zh) | 2014-11-19 |
PT2790712T (pt) | 2016-12-02 |
US9314483B2 (en) | 2016-04-19 |
IN2014MN01420A (ja) | 2015-04-03 |
WO2013088441A1 (en) | 2013-06-20 |
EP2790712B1 (en) | 2016-08-31 |
HUE032096T2 (en) | 2017-09-28 |
EP2790712A4 (en) | 2015-06-24 |
AU2012354057A1 (en) | 2014-07-31 |
AU2012354057B2 (en) | 2017-08-03 |
ES2604356T3 (es) | 2017-03-06 |
MX358589B (es) | 2018-08-27 |
BR112014014560A8 (pt) | 2017-07-04 |
EP2790712A1 (en) | 2014-10-22 |
JP6148679B2 (ja) | 2017-06-14 |
DK2790712T3 (en) | 2016-12-19 |
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