JP5189366B2 - 細胞傷害性t細胞の誘導抑制剤 - Google Patents
細胞傷害性t細胞の誘導抑制剤 Download PDFInfo
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Description
Hirano, T. et al., Nature (1986) 324, 73-76 Akira, S. et al., Adv. in Immunology (1993) 54, 1-78 Lotz, M. et al., J. Exp. Med. (1988)167, 1253-1258 Taga, T. et al., J. Exp. Med. (1987) 166, 967-981 Yamasaki, K. et al., Science (1988) 241, 825-828 Taga, T. et al., Cell (1989) 58, 573-581 Novick, D. et al., Hybridoma (1991) 10, 137-146 Huang, Y. W. et al., Hybridoma (1993) 12, 621-630 Hirata, Y. et al., J. Immunol. (1989) 143, 2900-2906 Okada M. et al., J.Immunology 141:1543-1549, 1988 Kitahara M.et al, Jpn.J. Cancer Res.81:1032-1038.1990
さらに本発明は、IL-6阻害剤を対象に投与する工程を含む、移植後の拒絶反応を抑制する方法の提供も課題とする。
まず、本発明者らは、C57BL/6マウスに対し、P815肥満細胞腫細胞を腹腔内投与した。またはBALB/cマウスに対し、EL4リンパ腫細胞を免疫細胞(同種異系抗原)として腹腔内投与した。これらのマウスより脾臓を採取し、脾細胞(エフェクター細胞)を上記の免疫細胞を標的細胞とし、様々なエフェクター細胞/標的細胞(E/T)比にて培養し、各標的細胞に対するCTL活性(細胞傷害性T細胞活性)を測定した。次に、上記の同種抗原を保持したモデルマウスに、抗IL-6受容体抗体またはラットIgG(コントロール抗体)を投与し、同じ条件下でCTL活性を測定した。
〔1〕IL-6阻害剤を有効成分として含有する、細胞傷害性T細胞の誘導抑制剤。
〔2〕IL-6阻害剤がIL-6を認識する抗体であることを特徴とする〔1〕に記載の細胞傷害性T細胞の誘導抑制剤。
〔3〕IL-6阻害剤がIL-6受容体を認識する抗体であることを特徴とする〔1〕に記載の細胞傷害性T細胞の誘導抑制剤。
〔4〕抗体がモノクローナル抗体であることを特徴とする〔2〕または〔3〕に記載の細胞傷害性T細胞の誘導抑制剤。
〔5〕抗体がヒトIL-6またはヒトIL-6受容体を認識する抗体であることを特徴とする〔2〕または〔3〕に記載の細胞傷害性T細胞の誘導抑制剤。
〔6〕抗体が組換え型抗体であることを特徴とする〔2〕または〔3〕に記載の細胞傷害性T細胞の誘導抑制剤。
〔7〕抗体がキメラ抗体、ヒト化抗体またはヒト抗体であることを特徴とする〔6〕に記載の細胞傷害性T細胞の誘導抑制剤。
〔8〕移植後の拒絶反応の抑制に用いられる〔1〕に記載の細胞傷害性T細胞の誘導抑制剤。
〔9〕IL-6阻害剤を有効成分として含有する、心移植における拒絶反応の抑制剤。
〔10〕IL-6阻害剤がIL-6を認識する抗体であることを特徴とする〔9〕に記載の心移植における拒絶反応の抑制剤。
〔11〕IL-6阻害剤がIL-6受容体を認識する抗体であることを特徴とする〔9〕に記載の心移植における拒絶反応の抑制剤。
〔12〕抗体がモノクローナル抗体であることを特徴とする〔10〕または〔11〕に記載の心移植における拒絶反応の抑制剤。
〔13〕抗体がヒトIL-6またはヒトIL-6受容体を認識する抗体であることを特徴とする〔10〕または〔11〕に記載の心移植における拒絶反応の抑制剤。
〔14〕抗体が組換え型抗体であることを特徴とする〔10〕または〔11〕に記載の心移植における拒絶反応の抑制剤。
〔15〕抗体がキメラ抗体、ヒト化抗体またはヒト抗体であることを特徴とする〔14〕に記載の心移植における拒絶反応の抑制剤。
〔16〕心移植における急性拒絶反応を抑制するための〔9〕に記載の抑制剤。
〔17〕IL-6阻害剤を対象に投与する工程を含む、細胞傷害性T細胞の誘導抑制方法。
〔18〕IL-6阻害剤がIL-6を認識する抗体であることを特徴とする〔17〕に記載の方法。
〔19〕IL-6阻害剤がIL-6受容体を認識する抗体であることを特徴とする〔17〕に記載の方法。
〔20〕抗体がモノクローナル抗体であることを特徴とする〔18〕または〔19〕に記載の方法。
〔21〕抗体がヒトIL-6またはヒトIL-6受容体を認識する抗体であることを特徴とする〔18〕または〔19〕記載の方法。
〔22〕抗体が組換え型抗体であることを特徴とする〔18〕または〔19〕に記載の方法。
〔23〕抗体がキメラ抗体、ヒト化抗体またはヒト抗体であることを特徴とする〔22〕に記載の方法。
〔24〕移植後の拒絶反応の抑制に用いられる、〔17〕に記載の方法。
〔25〕細胞傷害性T細胞の誘導抑制剤を製造するための、IL-6阻害剤の使用。
〔26〕IL-6阻害剤がIL-6を認識する抗体であることを特徴とする〔25〕に記載の使用。
〔27〕IL-6阻害剤がIL-6受容体を認識する抗体であることを特徴とする〔25〕に記載の使用。
〔28〕抗体がモノクローナル抗体であることを特徴とする〔26〕または〔27〕に記載の使用。
〔29〕抗体がヒトIL-6またはヒトIL-6受容体を認識する抗体であることを特徴とする〔26〕または〔27〕に記載の使用。
〔30〕抗体が組換え型抗体であることを特徴とする〔26〕または〔27〕に記載の使用。
〔31〕抗体がキメラ抗体、ヒト化抗体またはヒト抗体であることを特徴とする〔30〕に記載の使用。
〔32〕IL-6阻害剤を対象に投与する工程を含む、心移植において拒絶反応を抑制する方法。
〔33〕IL-6阻害剤がIL-6を認識する抗体であることを特徴とする〔32〕に記載の方法。
〔34〕IL-6阻害剤がIL-6受容体を認識する抗体であることを特徴とする〔32〕に記載の方法。
〔35〕抗体がモノクローナル抗体であることを特徴とする〔33〕または〔34〕に記載の方法。
〔36〕抗体がヒトIL-6またはヒトIL-6受容体を認識する抗体であることを特徴とする〔33〕または〔34〕記載の方法。
〔37〕抗体が組換え型抗体であることを特徴とする〔33〕または〔34〕に記載の方法。
〔38〕抗体がキメラ抗体、ヒト化抗体またはヒト抗体であることを特徴とする〔37〕に記載の方法。
〔39〕心移植における急性拒絶反応を抑制するための〔32〕に記載の方法。
〔40〕心移植における拒絶反応の抑制剤を製造するための、IL-6阻害剤の使用。
〔41〕IL-6阻害剤がIL-6を認識する抗体であることを特徴とする〔40〕に記載の使用。
〔42〕IL-6阻害剤がIL-6受容体を認識する抗体であることを特徴とする〔40〕に記載の使用。
〔43〕抗体がモノクローナル抗体であることを特徴とする〔41〕または〔42〕に記載の使用。
〔44〕抗体がヒトIL-6またはヒトIL-6受容体を認識する抗体であることを特徴とする〔41〕または〔42〕に記載の使用。
〔45〕抗体が組換え型抗体であることを特徴とする〔41〕または〔42〕に記載の使用。
〔46〕抗体がキメラ抗体、ヒト化抗体またはヒト抗体であることを特徴とする〔45〕に記載の使用。
本発明において「IL-6阻害剤」とは、IL-6によるシグナル伝達を遮断し、IL-6の生物学的活性を阻害する物質である。IL-6阻害剤は、好ましくはIL-6、IL-6受容体及びgp130のいずれかの結合に対する阻害作用を有する物質である。
本発明における抗体の由来は特に限定されるものではないが、好ましくは哺乳動物由来であり、より好ましくはヒト由来の抗体を挙げることが出来る。
このような抗体としては、AM64抗体(特開平3-219894)、4B11抗体および2H4抗体(US 5571513)B-S12抗体およびB-P8抗体(特開平8-291199)などが挙げられる。
これらの細胞に、目的とする抗体遺伝子を形質転換により導入し、形質転換された細胞をin vitroで培養することにより抗体が得られる。培養は、公知の方法に従い行う。例えば、培養液として、DMEM、MEM、RPMI1640、IMDMを使用することができ、牛胎児血清(FCS)等の血清補液を併用することもできる。また、抗体遺伝子を導入した細胞を動物の腹腔等へ移すことにより、in vivoにて抗体を産生してもよい。
哺乳類動物としては、ヤギ、ブタ、ヒツジ、マウス、ウシなどを用いることができる(Vicki Glaser, SPECTRUM Biotechnology Applications, 1993)。また、昆虫としては、カイコを用いることができる。植物を使用する場合、例えばタバコを用いることができる。
これら抗体の断片は、前記と同様にしてその遺伝子を取得し発現させ、宿主により産生させることができる。本発明でいう「抗体」にはこれらの抗体の断片も包含される。
また、本発明はIL-6阻害剤を有効成分として含有する、心移植における拒絶反応の抑制剤を提供する。
本発明の抑制剤が抑制する拒絶反応は、特に限定されないが好ましくは、実際の移植医療において問題となる急性拒絶反応(acute rejection)である。この拒絶反応とは、同種異系移植片(アログラフト)が、組織適合性を規定する主要組織適合遺伝子複合体 (major histocompatibility complex: MHC) の違いにより外来抗原として認識され、レシピエントの細胞傷害性T細胞とヘルパーT細胞の活性化によってアログラフトが攻撃される病態である。通常は移植後3ヶ月以内に出現するが、3ヶ月以降にアログラフト組織内への細胞浸潤として診断されることもある。
本発明の抑制剤が使用される臓器移植において、臓器移植は特に限定されるものではない。本発明が対象とする臓器移植の好ましい例としては、心臓、肝臓、腎臓、膵臓、肺、小腸などの実質臓器が挙げられ、さらに、心臓弁、血管、皮膚、骨、角膜などの組織移植へも応用可能である。
所望によりさらに希釈剤、溶解補助剤、pH調整剤、無痛化剤、含硫還元剤、酸化防止剤等を含有してもよい。
また、本発明は、IL-6阻害剤を対象に投与する工程を含む、心移植における拒絶反応を抑制する方法に関する。
本発明の方法により抑制する拒絶反応としては、特に限定されないが好ましくは、急性拒絶反応である。また、本発明の抑制剤が使用される臓器移植において、臓器移植は特に限定されるものではない。本発明が対象とする臓器移植の好ましい例としては、心臓、肝臓、腎臓、膵臓、肺、小腸などの実質臓器が挙げられ、さらに、心臓弁、血管、皮膚、骨、角膜などの組織移植へも応用可能である。
本発明の抑制剤の対象への投与は、臓器移植の前であってもよいし、臓器移植と同時、または臓器移植の後であってもよい。また抑制剤の投与は一回であってもよいし、連続して投与することもできる。
また、本発明において「接触」は、生物体の状態に応じて行う。例えば、生物体の一部への本抑制剤の散布、あるいは、生物体の一部の破砕物への本抑制剤の添加等を挙げることができるが、これらの方法に制限されない。生物体の一部が培養細胞の場合には、該細胞の培養液への本抑制剤の添加あるいは、本発明のオリゴヌクレオチドを含むDNAを、生物体の一部を構成する細胞へ導入することにより、上記「接触」を行うことも可能である。
なお本明細書において引用された全ての先行技術文献は、参照として本明細書に組み入れられる。
〔実施例1〕抗IL-6受容体抗体の投与による、P815肥満細胞腫細胞に対するCTL活性への影響の解析
まずC57BL/6マウスに対し、3×107個のP815肥満細胞腫細胞(免疫細胞)を腹腔内投与した。13日後にこれらのマウスより脾臓を採取し、脾細胞(エフェクター細胞)を51CrラベルP815細胞(標的細胞)と、様々なエフェクター細胞/標的細胞(E/T)比にて培養し、51CrラベルP815に対するCTL活性を測定した。
CTL活性の測定は、各細胞における細胞の溶解率を測定することにより行った。細胞の溶解率を〔(実験における51Cr放出量−自発的な51Cr放出量)/(全51Cr放出量−自発的な51Cr放出量)〕×100で示した。
なお、IL-6欠損C57BL/6マウスにP815細胞を接種したところ、インビボ(in vivo)におけるCTL誘導は著明に低下することが明らかとなった(データ示さず)。
同様に、BALB/cマウスに対し、3×107個のEL4リンパ腫細胞(免疫細胞)を腹腔内投与した。13日後にこれらのマウスより脾臓を摘出し、脾細胞(エフェクター細胞)を51CrラベルEL4細胞(標的細胞)と、様々なエフェクター細胞/標的細胞(E/T)比にて培養し、51CrラベルEL4に対するCTL活性を実施例1に記載の方法で測定した。
次に、実施例1と同様に抗IL-6受容体抗体を、同種抗原投与4日前に2000mg腹腔内投与、1日前に500mg 腹腔内投与し、同種抗原投与後4日後、9日後に500mg投与し、上記に記載の方法でCTL活性を測定した。また、ラットIgGをIL-6受容体抗体に対するコントロール抗体として同様の処理条件によってコントロールマウスに投与し、上記に記載の方法でCTL活性を測定した。
マウス心移植モデルを用いて移植後急性拒絶反応に対する抗IL-6受容体抗体(MR16-1)の投与効果を検討した。
実験に用いるマウスは、日本SLC株式会社から購入し、信州大学ヒト環境科学研究支援センター生命科学分野動物実験部門で飼育し、当施設の動物実験プロトコールに従って飼育した。BALB/cマウスをドナーとし、同種異系であるC57BL/6マウスをレシピエントに用いて、以下の手順で顕微鏡下手術によりマウス異所性心移植モデルを作成した。ドナーとレシピエントは4から8週齢の雄マウスを用いた。
ドナーとレシピエントのマウスはともに70 mg/kgのPentobarbital sodium (Nenbutal(R)) 70 mg/kgを腹腔内注射することにより麻酔した。移植心は、吻合に用いる上行大動脈と肺動脈の2本を残し、その他の血管は一括に結紮して摘出した。移植心は氷上の7.5%ヘパリン添加冷生理食塩水中で保存した。レシピエントは正中で開腹し、腸管を脱転して腹部大動脈と下大静脈を露出し、微小血管用マイクロクリップで血流を遮断した後に、それぞれの表面を約1 mm切開して吻合口を作成した。移植心の大動脈とレシピエントの腹部大動脈、移植心の肺動脈とレシピエントの下大静脈をそれぞれ10-0ナイロン糸の連続縫合により吻合した。マイクロクリップを徐々に解除し、血流を再開して移植心の拍動の再開を確認した。止血を確認した後に腹壁と皮膚を縫合して閉腹した。
1件の手術時間は約45分であり、成功率は95%以上であった。
治療群には、手術直後、3日後、6日後に、2 mg/マウス/回の投与量で抗IL-6受容体抗体を腹腔内に注射した。移植心の拍動は腹部の触診で毎日確認し、完全な拍動停止を拒絶とし、その時点でレシピエントを麻酔後に開腹して肉眼的に拍動の停止を確認した。拒絶までの日数を移植心の生着期間として比較検討した。
その結果、抗IL-6受容体抗体投与は移植心の急性拒絶反応を抑制し、移植心の生着期間を統計的に有意に延長した(図5)。(p=0.0001)
無治療群:7, 7, 7, 7, 7, 7, 8, 9, 9, 9, 10 (日). (11例, 生着期間の中央値: 7日)。
抗IL-6受容体抗体治療群:11, 13, 16, 17, 20, 21 (日). (6例, 生着期間の中央値: 16.5日)。
移植5日後の移植心の凍結組織標本を用いて病理組織切片を作成し、ヘマトキシリン・エオジン染色を行った。無治療群では広範な炎症細胞浸潤と、心筋壊死の所見を認めた。抗IL-6受容体抗体治療群では、炎症細胞浸潤は軽度にとどまり、心筋細胞の構築は比較的保たれていた(図6)。
この組織学的解析結果を、「0:拒絶を認めない〜4:高度な拒絶」の5段階の基準(Rodriguez, E.R. The pathology of heart transplant biopsy specimens: revisiting the 1990 ISHLT working formulation. J Heart Lung Transplant. (2003) 22, 3-15、Billingham, M.E. et al., A working formulation for the standardization of nomenclature in the diagnosis of heart and lung rejection: Heart Rejection Study Group. The International Society for Heart Transplantation. J Heart Transplant. (1990) 9, 587-93)に従って点数(スコア)化したところ、抗IL-6受容体抗体投与群の拒絶スコアは、無治療群に比し、統計的に有意な抑制を認めた(図7)。(p=0.0006)
また、抗IL-6受容体抗体を投与することにより、移植後の免疫拒絶反応を抑制できることが示された。
Claims (6)
- IL-6受容体を認識する抗体を有効成分として含有する、心移植における拒絶反応の抑制剤。
- 抗体がモノクローナル抗体であることを特徴とする請求項1に記載の心移植における拒絶反応の抑制剤。
- 抗体がヒトIL-6受容体を認識する抗体であることを特徴とする請求項1に記載の心移植における拒絶反応の抑制剤。
- 抗体が組換え型抗体であることを特徴とする請求項1に記載の心移植における拒絶反応の抑制剤。
- 抗体がキメラ抗体、ヒト化抗体またはヒト抗体であることを特徴とする請求項4に記載の心移植における拒絶反応の抑制剤。
- 心移植における急性拒絶反応を抑制するための請求項1に記載の抑制剤。
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Publication number | Publication date |
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EP1967207A4 (en) | 2010-01-06 |
KR20080070855A (ko) | 2008-07-31 |
TW200803893A (en) | 2008-01-16 |
JPWO2007058194A1 (ja) | 2009-04-30 |
TWI441647B (zh) | 2014-06-21 |
US20090263384A1 (en) | 2009-10-22 |
AR057582A1 (es) | 2007-12-05 |
WO2007058194A1 (ja) | 2007-05-24 |
US8623355B2 (en) | 2014-01-07 |
JP2013056914A (ja) | 2013-03-28 |
KR101457709B1 (ko) | 2014-11-03 |
EP1967207B1 (en) | 2016-06-22 |
EP1967207A1 (en) | 2008-09-10 |
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