JP5272115B2 - 経口免疫寛容を誘導するペプチド組成物及びその製造方法 - Google Patents
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Images
Description
例えば、β-ラクトグロブリンWPC水溶液にエンド型酵素を加え、基質濃度0.5〜15%、pH7〜8、温度40〜50℃、1時間〜6時間の範囲において処理する。さらに、より抗原性の高い高分子物質を除去するために平均分画分子量が10,000、5,000または1,000等の限外ろ過膜を用いて精製する事が望ましい。なお限外ろ過膜では、その膜材質や条件により分画できる分子量サイズが表示されている分画分子量サイズと前後することもあるため、平均分画分子量とし分子量サイズの異なる限外ろ過膜を組み合わせて使用することも可能である。さらには、組成物中のペプチドは、これら限界ろ過膜を組み合わせて用いて分子量1,000以上、5,000以下に分画された状態がより望ましい。
Glu-Pro-Glu-Gln-Ser-Leu-Val-Cys-Gln-Cys-Leu-Val-Arg [式2];以下ペプチド3という)の全て及び/または一部、ならびに106-122番目に相当するアミノ酸配列(Cys-Met-Glu-Asn-Ser-Ala-Glu-Pro-Glu-Gln-Ser-Leu-Val-Cys-Gln-Cys-Leu[式3];以下ペプチド4という)の全て及び/または一部を含むペプチドを同定した。
よって、合成ペプチド及び今回得られたペプチド組成物の結果から、β-ラクトグロブリン全162アミノ酸配列中の97-124番目の配列(Thr-Asp-Tyr-Lys-Lys-Tyr-Leu-Leu-Phe-Cys-Met-Glu-Asn-Ser-Ala-Glu-Pro-Glu-Gln-Ser-Leu-Val-Cys-Gln-Cys-Leu-Val-Arg[式1];以下ペプチド1という)の全て及び/または一部を含むことが重要である可能性が示された。
したがって、本発明のペプチド組成物は新しいアレルギー低減化及び予防と治療を目的とした食品素材あるいは経口免疫寛容誘導剤として有用である。
たんぱく質加水分解酵素は、ペプチド結合を加水分解する酵素を広く指し、プロテアーゼ、プロテイナーゼ、エンドペプチターゼ等を広く包含するものであり、植物由来、動物由来、微生物由来の各酵素が存在しているが、本発明に用いる酵素はエンド型酵素、特にトリプシン、キモトリプシン及びアルカリ性プロテアーゼが好ましい。
例えば、β-ラクトグロブリンWPC水溶液にエンド型酵素を加え、基質濃度0.5〜15%、pH7〜8、温度40〜50℃、1時間〜6時間の範囲において処理する。さらに、より抗原性の高い高分子物質を除去するために分子量が10,000、5,000または1,000の限外ろ過膜を用いて精製する事が望ましい。なお限外ろ過膜では、その膜材質や条件により分画できる分子量サイズが表示されている分画分子量サイズと前後することもあるため、平均分画分子量とし分子量サイズの異なる限外ろ過膜を組み合わせて使用することも可能である。さらには、組成物中のペプチドは、これら限界ろ過膜を組み合わせて用いて分子量1,000以上、5,000以下に分画された状態がより望ましい
ペプチド2画分を含むペプチド組成物を得るために、BLG‐WPC(たんぱく質含量80%、ドモ社)5gをイオン交換水1000mlに溶解し、基質濃度0.5%とした。水酸化ナトリウムにてpH8に調整した後、精製トリプシン(豚膵臓由来、トリプシン活性4,500USP Unit/mg以上、キモトリプシン活性50USP Unit/mg以下)100mg添加し酵素/基質比2.0%とし、40℃、6時間、酵素反応させた。反応終了後、100℃、10分間煮沸し、酵素活性を失活させ、酵素分解ペプチド組成物を得た。ペプチド組成物中には、β‐ラクトグロブリン全162アミノ酸配列中の102−124番目に相当するアミノ酸配列 Tyr‐Leu‐Leu‐Phe‐Cys‐Met‐Glu‐Asn‐Ser‐Ala‐Glu‐Pro‐Glu‐Gln‐Ser‐Leu‐Val‐Cys‐Gln‐Cys‐Leu‐Val‐Arg([式2];ペプチド3)のペプチドが確認された。
実施例1で得られたペプチド3含有組成物ならびに実施例2で得られたペプチド4含有組成物について、免疫寛容誘導効果を調べるためアレルギー患者から得たT細胞反応性をインターフェロンγ産生量およびリンパ球刺激試験にて評価した。その結果を、インターフェロンγ産生量の結果を図2に、リンパ球刺激性の結果を図3に示す。
インターフェロンγ産生量、リンパ球刺激性のいずれについても、基質のBLGと同様なT細胞反応性を示し、免疫寛容誘導効果が認められた。
実施例2で得られたペプチド4含有組成物ならびに実施例1で得られた合成ペプチドのペプチド2について、牛乳アレルギー患者の血清より樹立したT細胞クローンを用いて細胞増殖性を評価した。その結果を図4に示す。
ペプチド4含有組成物は、ペプチド2と同様なT細胞の反応性が認められた。
実施例1で得られたペプチド3含有組成物ならびに、実施例2および実施例3で得られたペプチド4含有組成物について、アナフィラキシーショックなど即時型のアレルギー症状を引き起こす可能性のあるB細胞反応性を競合エライザ法にて評価した。その結果を図5、6に示す。
B細胞反応性は、ペプチド3含有ならびにペプチド4含有のいずれの組成物ともに分解反応前の基質のBLGに比べて反応性の減弱が認められた。
Claims (2)
- 次の[式2]で表されるアミノ酸配列の全てを有し、かつ、経口免疫寛容誘導能を有するペプチドを有効成分とする経口免疫寛容誘導剤。
Tyr‐Leu‐Leu‐Phe‐Cys‐Met‐Glu‐Asn‐Ser‐Ala‐Glu‐Pro‐Glu‐Gln‐Ser‐Leu‐Val‐Cys‐Gln‐Cys‐Leu‐Val‐Arg [式2] - 次の[式3]で表されるアミノ酸配列の全てを有し、かつ、経口免疫寛容誘導能を有するペプチドを有効成分とする経口免疫寛容誘導剤。
Cys‐Met‐Glu‐Asn‐Ser‐Ala‐Glu‐Pro‐Glu‐Gln‐Ser‐Leu‐Val‐Cys‐Gln‐Cys‐Leu [式3]
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