JP2016501529A - 同種異系ドナーからの単球の共分化 - Google Patents
同種異系ドナーからの単球の共分化 Download PDFInfo
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- JP2016501529A JP2016501529A JP2015547082A JP2015547082A JP2016501529A JP 2016501529 A JP2016501529 A JP 2016501529A JP 2015547082 A JP2015547082 A JP 2015547082A JP 2015547082 A JP2015547082 A JP 2015547082A JP 2016501529 A JP2016501529 A JP 2016501529A
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Abstract
Description
NaCl、KC1、MgSO4、および/またはCa(NO3)2などの少なくとも1つの塩;
グルコースなどの少なくとも1つの糖類;
L−メチオニン、L−フェニルアラニン、L−プロリン、L−セリン、L−トレオニン、L−トリプトファン、L−チロシン、L−バリン、L−アルギニン、L−アスパラギン、L−アスパラギン酸、L−シスチン、L−グルタミン、L−グルタミン酸、グリシン、L−ヒスチジン、L−ヒドロキシプロリン、L−イソロイシン、L−ロイシンおよび/またはL−リジンなどの1つまたは複数のアミノ酸;
グルタチオン、ビオチン、ビタミンB12、D−Ca−パントテナート、塩化コリン、葉酸、ミオイノシトール、ニコチンアミド、パラアミノ安息香酸、ピリドキシン、リボフラビンおよび/またはチアミンなどの1つまたは複数のビタミンおよび他の必要不可欠な栄養素;および
リン酸塩(例えばNa2HPO4)および/または炭酸塩(例えばNaHCO3)などの少なくとも1つの緩衝液。
以下の実施例は単なる例であり、本発明の範囲を限定するように解釈されるべきでない。むしろ、本発明は、添付の請求項によってのみ限定される。
白血球除去フィルター(TACSIフィルター)から白血球を分離
白血球フィルター(血小板生成の間に4つの貯留された軟膜の通常の白血球除去のために使用されるTACSI白血球除去フィルター)を、Department of Transfusion Medicine, Sahlgrenska University HospitalのComponent Laboratoryで回収し、冷やして実験室(Department of Clinical Immunology,Sahlgrenska University Hospital)に運んだ。
健康な血液ドナーからの軟膜を輸血部で採取し、室温で実験室に運んだ。
健康なドナーの末梢血を輸血部で採取し、室温で実験室に運んだ。実験室において、血液を1:2の濃度で、Falcon管内で室温PBSと混合した。
健康なドナーの末梢血を輸血部で採取し、室温で実験室に運んだ。実験室において、血液を1:2の濃度で、Falcon管内で室温PBSと混合した。細胞懸濁液を、3mlのLymphoprep(Axis−Shield)を含有する10ml遠心分離管(Nunc)に静かに移した。各管に5〜6mlを移し、その後、室温で20分間、制動しないで2000rpmで遠心分離した。分離したPBMCを予め冷やした10ml管に移した。その管に冷PBSを満たすことにより細胞を2回洗い、その後、1450rpm、4℃で10分間、遠心分離した。上清を捨て、沈殿物を1mlの冷PBS内で再懸濁した。さらに9mlを各管に加えた。
5mlの溶出されたフィルター白血球/軟膜白血球または10〜20mlの全末梢血から分離されたPBMCを、1450rpm、4℃で10分間、管内で遠心分離した。上清を完全に除去し、細胞沈殿物を107細胞につき80μlのPBS/EDTA(Miltenyi)内で再懸濁した。107細胞につき、20μlのCD14ミクロビーズ(Miltenyi)を加えた。細胞を混合し、4℃で15分間培養し、その後、1〜2mlのPBS/EDTAを加えることによって洗い、次に300xgで10分間、遠心分離した。上清を完全に除去し、残りの細胞を500μlのPBS/EDTA内で再懸濁した。
TACSIフィルターで得られた白血球を、非ヒト血清を含まない培地のCellGro DC培地内で300000細胞/mlの濃度に再懸濁し、24ウェルプレート(1ウェルにつき1mL)に固定した(plate)。軟膜からの単球が豊富な白血球および末梢血をまず、CellGro培地において5x105単球/mLの濃度に再懸濁した。400μlのCellGro培地(細胞なし)をまず、24ウェルプレート内の12ウェル(Al−6、Bl−3、Cl−3)に加えた。ドナーAからの600μlの単球が豊富な細胞懸濁液(軟膜または末梢血のそれぞれ)をウェルAl−3に移した。ドナーBからの600μlの単球が豊富な細胞懸濁液をウェルCl−3(軟膜または末梢血)に移した。ドナーCからの600μlの単球が豊富な細胞懸濁液をウェルBl−3(軟膜または末梢血)に移した。ウェルA4−6において、200μlの単球が豊富な細胞懸濁液を全ての3人のドナーから移した(軟膜または末梢血)。全てのウェル内の最終細胞数は300000細胞であった(1ウェルにつき1mlのCellGro培地の容積につき)。
IL−4およびGM−CSFを添加したCellGro培地で5日間培養した後、未成熟DCの活性化/成熟は、20μg/mLのpolyI:C(Sigma,Steinheim,Germany)、ポリイノシン酸:ポリシチジル酸またはポリイノシン酸−ポリシチジル酸ナトリウムとしても知られるTLR−3受容体に特有の免疫賦活薬、2.5μg/mLのR848(Sigma,Steinheim,Germany)、レジキモドとしても知られるtoll様受容体7/8リガンド、および1000U/mlのインターフェロンガンマ(IFN−γ,R&D systems,Minneapolis,USA)を加えることによって誘導した。18時間の培養後、細胞を3回洗い、さらに24時間、新鮮なAIM−V培地で培養した(外因性活性化因子を添加しないで)。培養物の培養上清は、当業者が周知のプロトコルに従って回収した。
炎症誘発性ケモカインCCL3/MIP−1α、CCL4/MIP−1β、CCL5/RANTESおよびCXCL9/MIGならびに炎症誘発性サイトカインIL−12p70およびTNF−αを、酵素結合免疫吸着法(ELISA)で、米国ミネアポリスのR&D systemsのDuo Set ELISA Development Systemを用いて、その製造者説明書にしたがって測定した。
単球および単球由来DCを上述のとおり生成した。単球分離の後、CD14+単球の発生頻度を、細胞をFITC−抗ヒトCD14で染色することによって評価した。IL−4およびGM−CSFを添加したCellGro内で5日間培養した後、未成熟DCを洗い、その後、FITC抗ヒトCD83と組み合わせたPE抗ヒトCD86で染色した。その後、活性化因子を用いて18時間活性化した未成熟DCをまた、FITC抗ヒトCD83と組み合わせたPE抗ヒトCD86で染色した。FITCおよびPEで染色したマウスIgG1およびIgG2をアイソタイプ対照群として用いた(全て米国カリフォルニアのBD Biosciences製)。その試料をCell Quest software (BD Bioscience, California, USA)を用いて、フローサイトメトリー(FACS)で分析した。
以下に実験部分の結果をコメントする。
Claims (19)
- 少なくとも2人の異なる同種異系ドナーから得られた同種異系白血球の混合物を供給する工程と、
単球が豊富な同種異系白血球を供給するために前記同種異系白血球の混合物から同種異系単球を分離する工程と、
前記単球が豊富な同種異系白血球から非消耗未成熟樹状細胞(DC)を生成する工程と、
を含む非消耗未成熟DCの生成方法であって、
前記非消耗未成熟樹状細胞(DC)の生成は、前記単球が豊富な同種異系白血球を、非ヒト血清を含まない水性細胞培養培地で、2〜7日間共培養することによって行われ、前記培地に、インターロイキン4(IL−4)および顆粒球マクロファージコロニー刺激因子(GM−CSF)が添加される、非消耗未成熟樹状細胞(DC)の生成方法。 - 前記細胞培養培地が少なくともヒトポリペプチドを含む、請求項1記載の方法。
- 前記ヒトポリペプチドが、トランスフェリン、アルブミン、およびインシュリンからなる群から選択される、請求項2記載の方法。
- 前記単球が豊富な同種異系白血球が同種異系好中球を含む、請求項1〜3のいずれか1項に記載の方法。
- 前記同種異系白血球の混合物が、白血球を含む少なくとも2つの軟膜を貯留することによって供給され、前記貯留される軟膜が、少なくとも2人の異なる同種異系ドナーから得られる、請求項1〜4のいずれか1項に記載の方法。
- 前記貯留される軟膜が、血小板を含むか、血小板が除去されている、請求項5記載の方法。
- 前記同種異系白血球の混合物が、
少なくとも2つの白血球除去フィルターから白血球を溶出する工程であって、前記フィルターのそれぞれは、以前に全血から白血球を除去するのに使用され、前記全血は少なくとも2人の異なる同種異系ドナーから得られる、工程;および
前記同種異系白血球の混合物を得るために、得られた白血球を貯留する工程;または
1つの白血球除去フィルターから白血球を溶出する工程であって、前記フィルターは貯留された軟膜から白血球を除去するのに使用され、前記貯留された軟膜は少なくとも2人の異なる同種異系ドナーから得られる、工程、
によって供給される、請求項1〜4のいずれか1項に記載の方法。 - 前記同種異系単球が水簸、または抗体/ビーズ分離によって分離される、請求項1〜7のいずれか1項に記載の方法。
- 前記共培養が約5日間行われる、請求項1〜8のいずれか1項に記載の方法。
- 非消耗未成熟DCに抗原を負荷する工程をさらに含む、請求項1〜9のいずれか1項に記載の方法。
- 同種異系非消耗未成熟樹状細胞(DC)が請求項1〜10のいずれか1項に記載の方法によって得ることが可能な、少なくとも2人の異なる同種異系ドナーから得られる同種異系非消耗未成熟樹状細胞(DC)の混合物。
- 請求項1〜11のいずれか1項に記載の非消耗未成熟DCを供給する工程と、
炎症誘発性DCを得るために非消耗未成熟DCを活性化する工程と、
を含む、炎症誘発性DCの生成方法。 - 前記活性化が、活性化を誘導するToll様受容体3(TLR3)リガンドポリ−I:C、レシキモドなどのTLR7/8リガンドおよびインターフェロンガンマ(IFN−γ)を添加することによって行われる、請求項12記載の方法。
- 前記活性化が、活性化を誘導するTLR2−リガンド、TLR4−リガンド、TLR9−リガンド、インターフェロンアルファ(IFN−α)、インターロイキン1β(IL−1β)、および腫瘍壊死因子α(TNF−α)からなる群から選択される少なくとも1つの物質の添加をさらに含む、請求項13記載の方法。
- 前記活性化がプロスタグランジンE2(PGE2)の添加を含まない、請求項13または14記載の方法。
- 前記未成熟DCが活性化因子に8〜24時間さらされ、その後全ての前記活性化因子が実質的に洗い流される、請求項13〜15のいずれか1項に記載の方法。
- 同種異系炎症誘発性樹状細胞が請求項12〜16のいずれか1項による方法によって得ることが可能な、少なくとも2人の異なる同種異系ドナーから得られる、同種異系炎症誘発性樹状細胞の混合物。
- 請求項16による同種異系炎症誘発性樹状細胞の混合物および少なくとも1つの医薬上許容可能な担体を含む医薬組成物。
- 癌治療で使用するための請求項17による同種異系炎症誘発性樹状細胞の混合物、または請求項18による医薬組成物。
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