JP2006524484A - B細胞の増殖を増加させる方法 - Google Patents
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Abstract
Description
本発明はB細胞にPCDGFを投与することにより、非腫瘍性B細胞の増殖を増加させる方法を提供する。我々はPCDGFが正常(すなわち非腫瘍性)B細胞のオートクライン成長因子であることを発見した。そこで正常B細胞の増殖を促進するのにPCDGFを使用し、例えば初代造血細胞の培養の効率を改善することができる。初代B細胞の培養の効率と成長の改善は、例えば生物医学的な検討に使用するための細胞株の確立および維持(例えば幹細胞株)において大きな価値がある。
PCDGFは腫瘍細胞の強力な成長因子であり、乳房、卵巣、肺、腎臓、肝臓、造血および他の組織における広範囲の腫瘍の発癌剤である。腫瘍形成におけるPCDGFの重要な役割を考えると現在までのPCDGFの研究は、腫瘍細胞の成長を阻害するか又はそれに干渉するために、PCDGFを阻害および/または不活性化することに向けられていた。抗PCDGF抗体などのPCDGFアンタゴニストは、直接的にPCDGFと結合することにより、およびPCDGFが細胞成長のシグナルを標的細胞(例えば乳癌細胞)へ伝達することを防ぐことにより、PCDGFの生物学的な活性(例えば腫瘍形成活性)に干渉する。非腫瘍性B細胞で細胞増殖を増加させるために、PCDGFを使用することはこれまで行なわれていなかった。
我々は、マウスの正常B細胞のマイトジェンであるLPSで活性化することによるPCDGF発現を検討した。マウス脾臓リンパ球が10μg/mlのLPSにより活性化されたとき、ノザンブロット解析により示されるように、6時間という早期にPCDGFのmRNAの発現は劇的に増加した(図1)。マウス脾臓リンパ球を1.2×106細胞/mlで、10%FBSを含んでいるRPMI 1640の中で培養した。静止しているマウスB細胞を活性化するために、10μg/mlのLPSを使用した。0, 6, 12, 24および48時間にRNAを単離した。PCDGFのmRNAの発現をチェックするためにノサンブロット解析を行なった。上のパネルはPCDGFのmRNAの発現を示している。下のパネルは各レーンへ同じ量が搭載されていることを表すために、18Sと28S RNA のEB染色を示す。
我々が実験で使用した細胞であるマウス脾臓リンパ球は、マウスB細胞とT細胞の混合物である。PCDGF発現の増加がB細胞の活性化に特異的であるかをチェックするために、強力なTリンパ球活性化剤であるConAを使用し、マウス脾臓リンパ球のT細胞を刺激し、PCDGF発現を測定した。RT-PCR(図4)で示されたように、PCDGFのmRNAは6から48時間、LPSで刺激されたサンプルのみで検出され、コントロールとConA刺激されたサンプルで検出されなかった。マウス脾臓リンパ球を1.2×106細胞/mlで、10%FBSを含んでいるRPMI 1640の中で、10μg/mlのLPS、2.5μg/mlのConA、またはベヒクルと共に培養した。RNAを0, 6, 12, 24および48時間において単離し、PCDGFのmRNAの発現をチェックするためにRT-PCRを行なった(上のパネル)。マウスのβ-アクチンを内部標準として使用し、各レーンに同じ量が搭載されていることを示した(下のパネル)。
PCDGF陽性細胞はLPS刺激により増殖中のB細胞であることを証明するために、抗PCDGF抗体、抗BrdU抗体、および抗B220抗体を使用して免疫蛍光染色を行なった。BrdUはチミジンの類縁物質であり、DNA合成の間に特異的に取り込まれる。マウスリンパ球をBrdU-フルオレセイン抗体で染色すると、PCDGFに対して陽性に染色されたリンパ球はBrdUに対して陽性であり、PCDGFを発現した細胞は増殖中の細胞であることを示唆している(図7)。プロB細胞から成熟B細胞までの全ての段階において、Bリンパ球上にB220抗原は発現していた。B220はB細胞のマーカーとして一般的に使用されている。マウスリンパ球を抗B220-FITC抗体で染色すると、PCDGFについて染色が陽性であったリンパ球はB220についても陽性であり、PCDGFを発現した細胞はB細胞であることを示している(図8)。マウス脾臓リンパ球を1.2×106細胞/mlで、10%FBSを含んでいるRPMI 1640の中で、10μg/mlのLPS無し(A,B,C)または有り(D,E,F)で48時間培養した。細胞をパラフォルムアルデヒドの2%PBS溶液で固定化し、トライトンX100の0.2%PBS溶液で透水化し、B220-FITC(AおよびD)、ダピ(BとE)、または精製したウサギ抗ヒトPCDGF抗体で染色し、続いてテキサスレッドが結合したヤギ抗ウサギIgG二次抗体で染色した(CおよびF)。免疫蛍光染色を観察し、100Wの水銀ランプを装備したオリンパスBX40蛍光顕微鏡を用いて写真を撮影した。
休止中のB細胞の増殖を刺激できるのはPCDGF単独であるか、あるいは他のB細胞マイトジェンと共にであるかを検討することは重要である。我々はチミジンの取り込みを使用して、PCDGF、抗IgM、またはPCDGFと抗IgMを用いて、マウスの静止B細胞の増殖に対する影響を測定した。図9に見られるように、200ng/mlのPCDGF、10μg/mlの抗IgM、10μg/mlの抗IgMを含む200ng/mlのPCDGFは、処理の72時間後に、マウスの静止B細胞の増殖をそれぞれ2.7、3.7および4.6倍に刺激した。マウス脾臓リンパ球を5×106細胞/mlで72時間、200ng/mlのPCDGF、10μg/mlの抗IgM、または両者と共に、10%FBSを含んでいるRPMI 1640中で、最終容量0.2mlで平底96穴プレート中で培養した。最後の16時間、[3H]TdR(1μCi/ウェル)を培地に添加した。結果を平均±SD(標準偏差)で表現した。
Claims (7)
- PCDGF反応性の非腫瘍性細胞の増殖を増加させる方法であって、該方法は前記細胞へ有効量のPCDGFを投与することからなり、前記細胞の増殖は基礎レベルの細胞増殖を超えて増加している上記方法。
- 前記PCDGF反応性の細胞はB細胞、骨髄細胞、および形質細胞からなる群から選択される、請求項1記載の方法。
- 有効量のB細胞マイトジェンを更に投与することからなり、B細胞の増殖は細胞増殖の基礎レベルを超えて増加している、請求項1記載の方法。
- PCDGF反応性の非腫瘍性細胞のDNA合成を刺激する方法であって、該方法は前記細胞へ有効量のPCDGFを投与することからなり、DNA合成が基礎レベルの細胞のDNA合成を超えて増加している上記方法。
- 前記PCDGF反応性の細胞はB細胞、骨髄細胞、および形質細胞からなる群から選択される、請求項4記載の方法。
- 有効量のB細胞マイトジェンを投与することからなり、前記細胞におけるDNA合成は細胞増殖の基礎レベルを超えて増加している、請求項4記載の方法。
- 非腫瘍性細胞の集団中で増殖中のB細胞を同定する方法であって、前記細胞中のPCDGFレベルを測定することからなり、PCDGFを発現している細胞は増殖中のB細胞である上記方法。
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JP2010533660A (ja) * | 2007-07-16 | 2010-10-28 | ヨハン ウォルフガング ゲーテ−ウニベルジテート フランクフルト アム マイン | 慢性疼痛の治療又は予防のためのグラニュリン又はグラニュリン様化合物の使用 |
JP2017516496A (ja) * | 2014-05-19 | 2017-06-22 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | ヒツジb細胞を用いて抗体を産生するための方法およびその使用 |
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US20100111928A1 (en) * | 1997-05-23 | 2010-05-06 | A & G Pharmaceutical, Inc. | Methods and kits for diagnosis tumorgenicity |
US7411045B2 (en) * | 2002-11-19 | 2008-08-12 | A&G Pharmaceutical, Inc. | Autocrine growth factor receptor antibodies and methods |
CA2517140C (en) | 2003-02-26 | 2013-12-10 | A&G Pharmaceutical, Inc. | Use of pc-cell derived growth factor (pcdgf) for increasing the proliferation of b cells |
WO2005011590A2 (en) | 2003-08-01 | 2005-02-10 | A & G Pharmaceutical, Inc. | Compositions and methods for restoring sensitivity to treatment with her2 antagonists |
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EP2687223B1 (en) * | 2006-05-30 | 2017-07-12 | Mayo Foundation For Medical Education And Research | Detecting and treating dementia |
CA2653974A1 (en) | 2006-05-30 | 2008-02-14 | Mayo Foundation For Medical Education And Research | Detecting and treating dementia |
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WO1994016074A2 (en) * | 1993-01-15 | 1994-07-21 | Washington University, St. Louis | High molecular weight b-cell growth factor: interleukin-14 |
US7091047B2 (en) * | 1997-05-23 | 2006-08-15 | A&G Pharmaceutical, Inc. | Methods and kits for diagnosing tumorigenicity |
US20030215445A1 (en) * | 1997-05-23 | 2003-11-20 | Ginette Serrero | Methods and compositions for inhibiting the growth of hematopoietic malignant cells |
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CA2517140C (en) | 2003-02-26 | 2013-12-10 | A&G Pharmaceutical, Inc. | Use of pc-cell derived growth factor (pcdgf) for increasing the proliferation of b cells |
WO2005000207A2 (en) | 2003-05-30 | 2005-01-06 | Medimmune, Inc. | Pcdgf receptor antibodies and methods of use thereof |
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JP2017516496A (ja) * | 2014-05-19 | 2017-06-22 | エフ.ホフマン−ラ ロシュ アーゲーF. Hoffmann−La Roche Aktiengesellschaft | ヒツジb細胞を用いて抗体を産生するための方法およびその使用 |
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