JP2014059299A - Method of testing blast crisis easiness from chronic type adult human t-cell leukemia (atl) to acute type atl - Google Patents
Method of testing blast crisis easiness from chronic type adult human t-cell leukemia (atl) to acute type atl Download PDFInfo
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Abstract
Description
本発明は、慢性型の成人Ｔ細胞白血病（以下、ＡＴＬという）患者の急性転化のし易さを試験する方法、及び、当該方法のためのキットに関する。 The present invention relates to a method for testing the susceptibility of patients with chronic type adult T-cell leukemia (hereinafter referred to as ATL) to an acute transformation, and a kit for the method.
ヒトＴリンパ球向性ウィルス（以下、ＨＴＬＶという）は、レトロウィルスの１種であり、１型と２型の２つの型が存在する。このうち、１型、すなわち、ＨＴＬＶ−１は、日沼らによって成人Ｔ細胞白血病／リンパ腫の原因ウィルスとして同定されている（非特許文献１、２、３参照）。 Human T lymphotropic virus (hereinafter referred to as HTLV) is a type of retrovirus, and there are two types, type 1 and type 2. Of these, type 1, ie, HTLV-1, has been identified as a causative virus for adult T-cell leukemia / lymphoma by Hinuma et al. (See Non-Patent Documents 1, 2, and 3).
ヒトにおけるＨＴＬＶ−１感染は、主に母から子への垂直感染ならびに夫から妻への水平感染であるが、輸血による医原性感染も知られている。輸血による医原性感染は、１９８６年から開始された抗ＨＴＬＶ−１（または２）抗体を検査することにより防止されてきた。輸血による医原性感染の疫学的研究から、ＨＴＬＶ−１感染は血球細胞成分が介在していることが知られている。ＨＴＬＶ−１に感染すると、生体中に抗ＨＴＬＶ−１抗体が生成してくるので、抗ＨＴＬＶ−１抗体を測定することにより、ＨＴＬＶ−１の感染を知ることができる。 HTLV-1 infection in humans is mainly vertical transmission from mother to child and horizontal transmission from husband to wife, but iatrogenic infection by blood transfusion is also known. Iatrogenic infections from blood transfusions have been prevented by examining anti-HTLV-1 (or 2) antibodies, started in 1986. From epidemiological studies of iatrogenic infection by blood transfusion, it is known that HTLV-1 infection is mediated by blood cell components. When infected with HTLV-1, an anti-HTLV-1 antibody is produced in the living body. Therefore, by measuring the anti-HTLV-1 antibody, infection of HTLV-1 can be known.
抗ＨＴＬＶ−１抗体を測定する方法としては、免疫学的手法を用いた測定方法が知られており、ゼラチン粒子凝集法（PA法）、蛍光抗体法（FA法）、間接蛍光抗体法（IF法、化学発光酵素免疫測定法（ＣＬＥＩＡ法）、ウェスタンブロット法（ＷＢ法）などが知られている。ＨＴＬＶ−１キャリア 指導の手引き（厚生労働省研究班「本邦におけるHTLV-１感染及び関連疾患の実態調査と総合対策」、２０１１年）によると、一般医療機関ではスクリーニング検査としてＰＡ法やＣＬＥＩＡ法が用いられる。スクリーニング検査で陽性と判断された場合であっても、ＷＢ法による確認検査が実施される。さらに、ＷＢ法による確認検査で判定保留となった場合、ＨＴＬＶ−１プロウイルスを検出するＰＣＲ法（ポリメラーゼ連鎖反応法）による検査を実施することがある。 As a method for measuring an anti-HTLV-1 antibody, a measurement method using an immunological technique is known. Gelatin particle aggregation method (PA method), fluorescent antibody method (FA method), indirect fluorescent antibody method (IF Method, chemiluminescent enzyme immunoassay (CLEIA method), Western blot method (WB method), etc. HTLV-1 Carrier Guidance Guide (Ministry of Health, Labor and Welfare, Research Team “HTLV-1 infection and related diseases in Japan” According to the “Fact-finding survey and comprehensive measures”, 2011), PA and CLEIA methods are used as screening tests in general medical institutions. Furthermore, if the determination is suspended in the confirmation test by the WB method, the test by the PCR method (polymerase chain reaction method) is used to detect the HTLV-1 provirus. There is be carried out.
ＨＴＬＶ−１が引き起こす疾患としては、例えば血流内やリンパ器官内で発症する成人Ｔ細胞性白血病／リンパ腫、脊髄内で発症するＨＴＬＶ−１関連脊髄症（ＨＡＭ／ＴＳＰ）、眼球内で発症したブドウ膜炎（ＨＵ）等が知られている。 Diseases caused by HTLV-1 include, for example, adult T-cell leukemia / lymphoma that develops in the bloodstream and lymphoid organs, HTLV-1-related myelopathy that develops in the spinal cord (HAM / TSP), and in the eyeball Uveitis (HU) and the like are known.
ＡＴＬは、ＨＴＬＶ−１の感染が原因となって起こる独立した疾患である。ＨＴＬＶ−１キャリア（ＨＴＬＶ−１に感染した者で、上記のＨＴＬＶ−１が引き起こす疾患を発症していない者）は、２００８年の段階で、日本国内で約１０８万人と推定されている。年間ＨＴＬＶ−１キャリア１０００人に１人の割合でＡＴＬを発症し、また、ＡＴＬ生涯発症率はＨＴＬＶ−１キャリアの約５％と言われている。発症率は非常に低いがひとたび発症するときわめて短期間で重篤な結果もたらすと言われている。 ATL is an independent disease caused by HTLV-1 infection. The number of HTLV-1 carriers (those who have been infected with HTLV-1 and who have not developed the disease caused by HTLV-1) is estimated to be about 1.08 million in Japan in 2008. ATL develops at a rate of 1 in 1000 HTLV-1 carriers per year, and the ATL lifetime incidence is said to be about 5% of HTLV-1 carriers. Although the incidence is very low, once it develops, it is said to have very short and severe consequences.
ＡＴＬは、急性型、リンパ腫型、慢性型、くすぶり型の４種類の臨床病型に分類され、この臨床病型は化学療法を含めた治療方針の決定に広く使用されている。１９９０〜１９９５年の本邦全国ＡＴＬ実態調査によると、ＡＴＬ２１２３例中、急性型は１３２８例（６２．６％）、リンパ腫型は５０５例（２３．８％）、慢性型は１７６例（８．３％）、くすぶり型は１１４例（５．４％）であった。 ATLs are classified into four types of clinical disease types, acute type, lymphoma type, chronic type, and smoldering type, and this clinical type is widely used in determining treatment strategies including chemotherapy. According to the ATL survey in Japan from 1990 to 1995, among the ATL2123 cases, the acute type was 1328 cases (62.6%), the lymphoma type was 505 cases (23.8%), and the chronic type was 176 cases (8.3). %) And smoldering type was 114 cases (5.4%).
リンパ腫型や急性型は高悪性度ＡＴＬと定義され、予後（生存率）が悪く早急な治療が必要となる。一方、くすぶり型や慢性型は低悪性度ＡＴＬと定義され、無治療で経過を観察することが一般的に行われている。このように、急性型、リンパ腫型に比べると、慢性型やくすぶり型は生存率が高いと言われている。 Lymphoma types and acute types are defined as high-grade ATL, and have a poor prognosis (survival rate) and require immediate treatment. On the other hand, the smoldering type and the chronic type are defined as low-grade ATL, and it is a common practice to observe the course without treatment. As described above, it is said that the chronic type and the smoldering type have a higher survival rate than the acute type and the lymphoma type.
しかしながら、慢性型やくすぶり型から、急性型やリンパ腫型の病状へと急性転化する場合があると言われている。くすぶり型ＡＴＬ、慢性型ＡＴＬ患者の長期追跡結果によるとくすぶり型ＡＴＬの３割は急性転化し、慢性型ＡＴＬの８割が経過中に急性転化していたと報告されている。急性転化した場合は、急性型やリンパ腫型と同様に、早急に治療を開始する必要がある。現在、血清中の乳酸デヒドロゲナーゼ活性（以下、ＬＤＨ活性と記す）や可溶型インターロイキン−２受容体（以下、ｓＩＬ−２Ｒと記す）濃度、白血球数、末梢血ＡＴＬ細胞数、カルシウム濃度などを検査し、異常がみられた場合には、リンパ節腫脹の有無と数、皮膚病変の有無、肺病変の有無、肝脾腫の有無、その他の病変の有無、画像診断としてのＣＴ（Computed Tomography）検査ならびにガリウムシンチグラフィ検査あるいはＰＥＴ（陽電子放射断層撮影）検査を行い、急性型やリンパ腫型への急性転化の確定診断を行っているが、急性転化を早期に予知することは困難である。 However, it is said that there is a case where acute type or smoldering type changes into acute type or lymphoma type medical condition. According to the long-term follow-up results of patients with smoldering ATL and chronic ATL, it has been reported that 30% of smoldering ATL was acutely changed and 80% of chronic ATL was acutely changed during the course. In the case of an acute change, it is necessary to start treatment as soon as the acute type and lymphoma type. Currently, serum lactate dehydrogenase activity (hereinafter referred to as LDH activity), soluble interleukin-2 receptor (hereinafter referred to as sIL-2R) concentration, white blood cell count, peripheral blood ATL cell count, calcium concentration, etc. If abnormalities are detected, the presence and number of lymphadenopathy, presence or absence of skin lesions, presence or absence of lung lesions, presence or absence of hepatosplenomegaly, presence or absence of other lesions, CT (Computed Tomography) as diagnostic imaging Examinations and gallium scintigraphy examinations or PET (positron emission tomography) examinations are performed to make a definitive diagnosis of acute transformation to acute type or lymphoma type, but it is difficult to predict acute transformation at an early stage.
また、慢性型からの急性転化を判定する方法として、慢性型ＡＴＬ患者より採取した試料中ｓＣＤ３０濃度を測定する方法が知られている（特許文献１）。 In addition, as a method for determining the acute conversion from the chronic type, a method of measuring the sCD30 concentration in a sample collected from a chronic ATL patient is known (Patent Document 1).
ＡＴＬの予後は極めて不良と言われている。現在のところ、ｍＬＳＧ１５と呼ばれる多剤併用療法で最も良好な生存率が得られているが、生存期間の中央値は約１３ヵ月、３年生存割合は約２４％と依然極めて不良である。最近、ＣＣＲ４（ケモカイン受容体４）をターゲットとした抗体医薬であるポテリジオ（登録商標）が承認され、第２相試験で再発高悪性度ＡＴＬに対する奏功率が５０％であった事が報告されている。化学療法で十分な効果が期待できない場合は、骨髄移植（同種造血幹細胞移植）が積極的に行われるようになり、一部の患者では治癒も期待できるようになってきた（非特許文献４参照）。 The prognosis of ATL is said to be extremely poor. Currently, multi-drug combination therapy called mLSG15 has achieved the best survival, but the median survival is about 13 months and the 3-year survival rate is still about 24%, which is still very poor. Recently, Poterigio (registered trademark), an antibody drug targeting CCR4 (chemokine receptor 4), was approved, and it was reported that the response rate for relapsed high-grade ATL was 50% in a phase 2 study. Yes. When a sufficient effect cannot be expected with chemotherapy, bone marrow transplantation (allogeneic hematopoietic stem cell transplantation) has been actively performed, and some patients can also be expected to be cured (see Non-Patent Document 4). ).
インターロイキン−２受容体（以下、ＩＬ−２Ｒという）はα鎖（ＣＤ２５）、β鎖（ＣＤ１２２）、γ鎖（ＣＤ１３２）の３つの細胞膜表面タンパク質から構成され、α鎖はプロテアーゼによって切断され、ｓＩＬ−２Ｒとして血中に遊離することが報告されている（一般的に、ｓＩＬ−２Ｒとはプロテアーゼにより切断されたα鎖のことを指す）。ＡＴＬ細胞は制御性Ｔ細胞の表面形質を有しており、表面にＣＤ２５（ＩＬ−２Ｒα鎖）を発現しているため、ｓＩＬ−２ＲはＡＴＬの病態モニタリングや予後予測の有用な指標として活用されている。 Interleukin-2 receptor (hereinafter referred to as IL-2R) is composed of three cell membrane surface proteins of α chain (CD25), β chain (CD122), and γ chain (CD132), which is cleaved by proteases, It is reported that it is released into the blood as sIL-2R (generally, sIL-2R refers to an α chain cleaved by a protease). Since ATL cells have the surface traits of regulatory T cells and express CD25 (IL-2Rα chain) on the surface, sIL-2R is used as a useful indicator for ATL disease state monitoring and prognosis prediction. ing.
ＣＤ３０は、ＴＮＦＲスーパーファミリーに属する受容体で、ホジキン病細胞、ステルンベルグ−リード（Sternberg-Reed）細胞、未分化大細胞リンパ腫(ALCL)細胞、ＡＴＬ細胞で発現していることが報告されている（非特許文献５、６参照）。その後、ＣＤ３０の細胞外部分が切断された可溶型ＣＤ３０（以下、ｓＣＤ３０と記す）が血中に存在すること事が報告されている。ＡＴＬ患者とｓＣＤ３０との関連については、健常人と比べＡＴＬ患者血液中のｓＣＤ３０量が多いこと、すでに増悪化した急性型ＡＴＬおよびリンパ腫型ＡＴＬにおいて、化学療法により寛解となるとｓＣＤ３０量が低下すること、寛解した後に再発した際にｓＣＤ３０量が増加することが報告されている（非特許文献７参照）。 CD30 is a receptor belonging to the TNFR superfamily and has been reported to be expressed in Hodgkin's disease cells, Sternberg-Reed cells, anaplastic large cell lymphoma (ALCL) cells, and ATL cells. (See Non-Patent Documents 5 and 6). Thereafter, it has been reported that soluble CD30 (hereinafter referred to as sCD30) obtained by cleaving the extracellular portion of CD30 is present in the blood. Regarding the relationship between ATL patients and sCD30, the amount of sCD30 in the blood of ATL patients is higher than that in healthy individuals, and the amount of sCD30 decreases in acute ATL and lymphoma type ATL that have already been exacerbated when chemotherapy is ameliorated. It has been reported that the amount of sCD30 increases when relapse occurs after remission (see Non-Patent Document 7).
本発明の課題は、慢性型ＡＴＬ患者における急性転化の早期診断による慢性型ＡＴＬ患者のＱＯＬ向上を指向し、慢性型のＡＴＬ患者における急性転化し易さを試験する方法、及び、当該方法のためのキットを提供することにある。 An object of the present invention is to improve QOL of chronic ATL patients by early diagnosis of acute transformation in chronic ATL patients, and to test the ease of acute transformation in chronic ATL patients, and for the method Is to provide a kit.
発明者らは、本課題の解決のために鋭意検討し、慢性型のＡＴＬ患者の試料中ｓＣＤ３０およびｓＩＬ−２Ｒを測定し、ｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上となり、ｓＩＬ−２Ｒ濃度／ｓＣＤ３０濃度が時間経過とともに減少しながら１０に近づく場合、又は、ｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上となり、ｓＩＬ−２Ｒ濃度／ｓＣＤ３０濃度が１０以下である場合、急性転化しやすいという、という知見を見いだし、本発明を完成させた。 The inventors have intensively studied to solve this problem, measured sCD30 and sIL-2R in a sample of a chronic ATL patient, and the sIL-2R concentration became 2500 U / mL or more, and sIL-2R concentration / sCD30. The finding that when the concentration approaches 10 while decreasing over time, or when the sIL-2R concentration is 2500 U / mL or more and the sIL-2R concentration / sCD30 concentration is 10 or less, it is found that acute conversion is likely to occur. The present invention has been completed.
すなわち、本発明は、［１］慢性型のＡＴＬ患者より採取された試料中のｓＣＤ３０とｓＩＬ−２Ｒとを測定し、ｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上となり、ｓＩＬ−２Ｒ濃度／ｓＣＤ３０濃度が（Ａ）時間経過とともに減少しながら１０に近づく場合、又は、（Ｂ）１０以下である場合には、急性転化しやすいという基準と比較することにより、慢性型のＡＴＬ患者の急性転化のし易さを試験する方法に関する。この発明の他の態様としては、慢性型のＡＴＬ患者より採取された試料中のｓＣＤ３０とｓＩＬ−２Ｒとを測定し、ｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上となり、ｓＩＬ−２Ｒ濃度／ｓＣＤ３０濃度が（Ａ）時間経過とともに減少しながら１０に近づく場合、又は（Ｂ）１０以下である場合には、急性転化しやすいという基準と比較することにより、慢性型のＡＴＬ患者の急性転化のし易さを試験するためのデータの収集方法等を挙げることができる。 That is, the present invention measures [1] sCD30 and sIL-2R in a sample collected from a chronic ATL patient, the sIL-2R concentration is 2500 U / mL or more, and the sIL-2R concentration / sCD30 concentration is (A) When it approaches 10 while decreasing with time, or (B) When it is 10 or less, it is easy to make acute change of chronic type ATL patients by comparing with the standard of being easy to change acutely. It relates to a method for testing the thickness. In another embodiment of the present invention, sCD30 and sIL-2R in a sample collected from a chronic ATL patient are measured, and the sIL-2R concentration is 2500 U / mL or more, and the sIL-2R concentration / sCD30 concentration is (A) When approaching 10 while decreasing over time, or (B) When it is 10 or less, by comparing with the standard that it is easily converted into acute, it is easy for acute type ATL patients to undergo acute conversion The data collection method for testing can be mentioned.
また本発明は、［２］ｓＩＬ−２Ｒ測定用試薬とｓＣＤ３０測定用試薬を含有することを特徴とする、慢性型のＡＴＬ患者の急性転化のし易さを試験するキットに関する。この発明の他の態様としては、ｓＩＬ−２Ｒ測定用試薬とｓＣＤ３０測定用試薬に加えて、試料中のｓＣＤ３０とｓＩＬ−２Ｒとの測定の結果、ｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上となり、ｓＩＬ−２Ｒ濃度／ｓＣＤ３０濃度が（Ａ）時間経過とともに減少しながら１０に近づく場合、又は（Ｂ）１０以下である場合には、急性転化しやすい、という慢性型のＡＴＬ患者の急性転化のし易さについての記載を含む添付文書を含有することを特徴とする、慢性型のＡＴＬ患者の急性転化のし易さを試験するためのキットを挙げることができる。 The present invention also relates to a kit for testing easiness of acute conversion of chronic ATL patients, comprising [2] a reagent for measuring sIL-2R and a reagent for measuring sCD30. As another aspect of the present invention, in addition to the reagent for measuring sIL-2R and the reagent for measuring sCD30, as a result of the measurement of sCD30 and sIL-2R in the sample, the sIL-2R concentration is 2500 U / mL or more. -2R concentration / sCD30 concentration is (A) approaching 10 while decreasing over time, or (B) When it is 10 or less, it is easy for acute type ATL patients to be acutely converted. There may be mentioned a kit for testing the susceptibility of patients with chronic type ATL, which is characterized by containing a package insert including a description of the above.
本発明により、慢性型のＡＴＬ患者の急性転化のし易さを試験する方法、及び当該方法のためのキットが提供され、慢性型のＡＴＬ患者の急性転化の早期診断が可能となり、慢性型ＡＴＬ患者のＱＯＬが向上し得る。 INDUSTRIAL APPLICABILITY According to the present invention, a method for testing the easiness of acute conversion of chronic ATL patients and a kit for the method are provided, which enables early diagnosis of acute conversion of chronic ATL patients, and chronic ATL The patient's QOL can be improved.
本発明において、慢性型のＡＴＬとは、ＡＴＬの分類基準によって４種類の臨床病型に分類されるＡＴＬのうちの１つであり、早急な治療を必要とせず、主として経過観察が行われる状態のＡＴＬである。本発明において、急性転化とは、慢性型のＡＴＬより急性型のＡＴＬへ移行することを意味する。急性転化により慢性型のＡＴＬより急性型のＡＴＬへ移行すると、早急な治療が必要となる。 In the present invention, the chronic type ATL is one of ATLs classified into four types of clinical disease types according to ATL classification criteria, and does not require immediate treatment and is mainly a follow-up ATL. In the present invention, the acute change means a transition from a chronic ATL to an acute ATL. When a transition from chronic ATL to acute ATL occurs due to acute transformation, immediate treatment is required.
本発明において、慢性型のＡＴＬ患者より採取された試料としては、当該患者から採取された試料であって、ｓＩＬ−２Ｒ及びｓＣＤ３０が測定され得る試料であれば特に制限はなく、例えば血漿、血清等が挙げられる。 In the present invention, the sample collected from a chronic ATL patient is not particularly limited as long as it is a sample collected from the patient and can measure sIL-2R and sCD30. Etc.
本発明において、慢性型のＡＴＬ患者の急性転化のし易さの試験は、例えば以下の工程（１）〜（８）を含有する方法により行うことができる。
（１）慢性型のＡＴＬ患者より試料を採取する工程；
（２）工程（１）で採取された試料を用いて、当該試料中のｓＩＬ−２Ｒを測定する工程；
（３）予め作成したｓＩＬ−２Ｒ濃度とｓＩＬ−２Ｒの測定値との関係を表す検量線と、工程（２）でのｓＩＬ−２Ｒの測定値とから、当該試料中のｓＩＬ−２Ｒ濃度を決定する工程；
（４）工程（１）で採取された試料を用いて、当該試料中のｓＣＤ３０を測定する工程；
（５）予め作成したｓＣＤ３０濃度とｓＣＤ３０の測定値との関係を表す検量線と、工程（４）でのｓＣＤ３０の測定値とから、当該試料中のｓＣＤ３０濃度を決定する工程；
（６）工程（３）で決定されたｓＩＬ−２Ｒ濃度と、工程（５）で決定されたｓＣＤ３０濃度とから、ｓＣＤ３０濃度に対するｓＩＬ−２Ｒ濃度の比、すなわち、ｓＩＬ−２Ｒ濃度／ｓＣＤ３０濃度（以下、ｓＩＬ−２Ｒ／ｓＣＤ３０と記す）を決定する工程；
（７）工程（１）〜工程（６）を複数の時点で行い、それぞれの時点でのｓＩＬ−２Ｒ濃度、及び、ｓＩＬ−２Ｒ／ｓＣＤ３０を比較し、ｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上であり、ｓＩＬ−２Ｒ／ｓＣＤ３０が時間経過とともに減少しながら１０に近づく場合に、当該患者は急性転化し易い、という基準と比較する工程；
（８）工程（７）における基準との比較から、当該患者の急性転化のし易さを判定する工程。
In the present invention, the test for the ease of acute conversion of a chronic ATL patient can be performed, for example, by a method comprising the following steps (1) to (8).
(1) collecting a sample from a chronic ATL patient;
(2) A step of measuring sIL-2R in the sample using the sample collected in step (1);
(3) From the calibration curve showing the relationship between the sIL-2R concentration prepared in advance and the measured value of sIL-2R, and the measured value of sIL-2R in step (2), the sIL-2R concentration in the sample is calculated. Determining step;
(4) A step of measuring sCD30 in the sample using the sample collected in step (1);
(5) A step of determining the sCD30 concentration in the sample from a calibration curve representing the relationship between the sCD30 concentration prepared in advance and the measured value of sCD30, and the measured value of sCD30 in step (4);
(6) From the sIL-2R concentration determined in step (3) and the sCD30 concentration determined in step (5), the ratio of sIL-2R concentration to sCD30 concentration, ie, sIL-2R concentration / sCD30 concentration ( Hereinafter, referred to as sIL-2R / sCD30);
(7) Steps (1) to (6) are performed at a plurality of time points, and the sIL-2R concentration and sIL-2R / sCD30 at each time point are compared, and the sIL-2R concentration is 2500 U / mL or more. Yes, when the sIL-2R / sCD30 is close to 10 while decreasing over time, comparing to the criteria that the patient is prone to acute transformation;
(8) The process of determining the ease of the patient's acute transformation from the comparison with the reference | standard in process (7).
また、上記工程（７）において、「ｓＩＬ−２Ｒ／ｓＣＤ３０が時間経過とともに減少しながら１０に近づく」とは、具体的には、複数の異なる時点で算出したｓＩＬ−２Ｒ／ｓＣＤ３０のうち、遅い（晩い）時点で算出したｓＩＬ−２Ｒ／ｓＣＤ３０の値の方が早い時点で算出したｓＩＬ−２Ｒ／ｓＣＤ３０の値よりも１０に近いことをいう。なお、３つ以上の異なる時点でｓＩＬ−２Ｒ／ｓＣＤ３０を算出した場合、近似曲線を作成するなどしてｓＩＬ−２Ｒ／ｓＣＤ３０が時間の経過とともに、減少しながら１０に近づくことを確認してもよい。 Moreover, in the said process (7), "sIL-2R / sCD30 approaches 10 while decreasing with time passage", specifically, it is late among sIL-2R / sCD30 calculated in several different time points. It means that the value of sIL-2R / sCD30 calculated at the (late) time point is closer to 10 than the value of sIL-2R / sCD30 calculated at the earlier time point. In addition, when sIL-2R / sCD30 is calculated at three or more different time points, it is confirmed that sIL-2R / sCD30 approaches 10 while decreasing as time passes by creating an approximate curve or the like Good.
また、本発明において、慢性型のＡＴＬ患者の急性転化のし易さの試験は、例えば以下の工程（１）〜（８）を含有する方法により行うこともできる。
（１）慢性型のＡＴＬ患者より試料を採取する工程；
（２）工程（１）で採取された試料を用いて、当該試料中のｓＩＬ−２Ｒを測定する工程；
（３）予め作成したｓＩＬ−２Ｒ濃度とｓＩＬ−２Ｒの測定値との関係を表す検量線と、工程（２）でのｓＩＬ−２Ｒの測定値とから、当該試料中のｓＩＬ−２Ｒ濃度を決定する工程；
（４）工程（１）で採取された試料を用いて、当該試料中のｓＣＤ３０を測定する工程；
（５）予め作成したｓＣＤ３０濃度とｓＣＤ３０の測定値との関係を表す検量線と、工程（４）でのｓＣＤ３０の測定値とから、当該試料中のｓＣＤ３０濃度を決定する工程；
（６）工程（３）で決定されたｓＩＬ−２Ｒ濃度と、工程（５）で決定されたｓＣＤ３０濃度とから、ｓＩＬ−２Ｒ／ｓＣＤ３０を決定する工程；
（７）ｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上であり、ｓＩＬ−２Ｒ／ｓＣＤ３０が１０以下である場合に、当該患者は急性転化し易い、という基準と比較する工程；
（８）工程（７）における基準との比較から、当該患者の急性転化のし易さを判定する工程。
Moreover, in this invention, the test of the easiness of the acute conversion of a chronic type ATL patient can also be performed, for example by the method containing the following processes (1)-(8).
(1) collecting a sample from a chronic ATL patient;
(2) A step of measuring sIL-2R in the sample using the sample collected in step (1);
(3) From the calibration curve showing the relationship between the sIL-2R concentration prepared in advance and the measured value of sIL-2R, and the measured value of sIL-2R in step (2), the sIL-2R concentration in the sample is calculated. Determining step;
(4) A step of measuring sCD30 in the sample using the sample collected in step (1);
(5) A step of determining the sCD30 concentration in the sample from a calibration curve representing the relationship between the sCD30 concentration prepared in advance and the measured value of sCD30, and the measured value of sCD30 in step (4);
(6) determining sIL-2R / sCD30 from the sIL-2R concentration determined in step (3) and the sCD30 concentration determined in step (5);
(7) a step of comparing with a criterion that when the sIL-2R concentration is 2500 U / mL or more and the sIL-2R / sCD30 is 10 or less, the patient is likely to undergo acute transformation;
(8) The process of determining the ease of the patient's acute transformation from the comparison with the reference | standard in process (7).
また、上記工程（７）において、「ｓＩＬ−２Ｒ／ｓＣＤ３０が１０以下である場合」のｓＩＬ−２Ｒ／ｓＣＤ３０の値としては、１０以下であれば特に制限されず、例えば８．５以下、８．０以下、７．５以下、７．０以下、６．５以下、６．０以下、５．５以下、５．０以下、４．５以下、４．０以下、３．５以下、３．０以下、２．５以下、２．０以下、１．７以下等を挙げることができる。 In the above step (7), the value of sIL-2R / sCD30 when “sIL-2R / sCD30 is 10 or less” is not particularly limited as long as it is 10 or less. For example, 8.5 or less, 8 0.0 or less, 7.5 or less, 7.0 or less, 6.5 or less, 6.0 or less, 5.5 or less, 5.0 or less, 4.5 or less, 4.0 or less, 3.5 or less, 3 or less 0.0 or less, 2.5 or less, 2.0 or less, 1.7 or less.
本発明において、慢性型のＡＴＬ患者より採取された試料中のｓＩＬ−２Ｒの測定は、公知の生体試料中のｓＩＬ−２Ｒ濃度の測定方法及びキットを用いることにより行うことができる。当該方法としては、生体試料中のｓＩＬ−２Ｒを測定可能とする方法であれば特に制限はないが、例えば免疫学的測定法が挙げられる。 In the present invention, sIL-2R in a sample collected from a chronic ATL patient can be measured by using a known method and kit for measuring sIL-2R concentration in a biological sample. The method is not particularly limited as long as it can measure sIL-2R in a biological sample, and examples thereof include an immunological measurement method.
本発明において、慢性型のＡＴＬ患者より採取された試料中のｓＣＤ３０の測定は、公知の生体試料中のｓＣＤ３０濃度の測定方法及びキットを用いることにより行うことができる。当該方法としては、生体試料中のｓＣＤ３０を測定可能とする方法であれば特に制限はないが、例えば免疫学的測定法が挙げられる。 In the present invention, sCD30 in a sample collected from a chronic ATL patient can be measured by using a known method and kit for measuring sCD30 concentration in a biological sample. The method is not particularly limited as long as sCD30 in a biological sample can be measured, and examples thereof include an immunological measurement method.
免疫学的測定法としては、任意の公知の免疫学的測定方法があげられ、例えば放射免疫測定法（ＲＩＡ）、酵素免疫測定法（ＥＩＡまたはＥＬＩＳＡ）、蛍光免疫測定法（ＦＩＡ）、間接蛍光抗体法（Indirect Fluorescence assay）、発光免疫測定法（Luminescentimmunoassay）、物理化学的測定法［比濁免疫測定法（ＴＩＡ）、ラテックス凝集法（ＬＡＰＩＡ）、微粒子計数免疫凝集測定法（ＰＣＩＡ）］、ウェスタンブロッティング法等が挙げられるが、ＥＬＩＳＡ法が好ましく用いられる[単クローン抗体実験マニュアル（講談社サイエンティフィック、1987）、続生化学実験講座５免疫生化学研究法（東京化学同人、1986）]。 Examples of the immunoassay include any known immunoassay, such as radioimmunoassay (RIA), enzyme immunoassay (EIA or ELISA), fluorescent immunoassay (FIA), indirect fluorescence. Antibody method (Indirect Fluorescence assay), Luminescent immunoassay, Physicochemical assay [turbidimetric immunoassay (TIA), latex agglutination (LAPIA), microparticle counting immunoagglutination (PCIA)], Western Although the blotting method etc. are mentioned, the ELISA method is preferably used [Monoclonal antibody experiment manual (Kodansha Scientific, 1987), Secondary Biochemistry Experiment Course 5 Immunobiochemistry Research Method (Tokyo Kagaku Dojin, 1986)].
免疫学的測定法においては、サンドイッチ法、競合法等を用いることができ、また、ホモジアニス法、ヘテロジニアス法等も用いることができる。 In the immunological measurement method, a sandwich method, a competitive method, or the like can be used, and a homogenis method, a heterogeneous method, or the like can also be used.
本発明において、試料中のｓＩＬ−２Ｒは、ｓＩＬ−２Ｒ測定用試薬を用いて測定することができる。ｓＩＬ−２Ｒ測定用試薬としては、例えばｓＩＬ−２Ｒに特異的に結合する第１の抗体が結合した固相、及びｓＩＬ−２Ｒに特異的に結合する第２の抗体に標識が結合した標識化第２抗体を含む試薬を例示することができる。第１の抗体におけるｓＩＬ−２Ｒの抗原決定部位と、第２の抗体におけるｓＩＬ−２Ｒの抗原決定部位とは同じであっても異なっていてもよい。 In the present invention, sIL-2R in a sample can be measured using a sIL-2R measurement reagent. Examples of the reagent for measuring sIL-2R include a solid phase in which a first antibody that specifically binds to sIL-2R is bound, and a label in which a label is bound to a second antibody that specifically binds to sIL-2R A reagent containing the second antibody can be exemplified. The antigen determining site of sIL-2R in the first antibody and the antigen determining site of sIL-2R in the second antibody may be the same or different.
標識化第２抗体における標識としては、例えば酵素や放射性物質等が挙げられる。酵素としては、例えばペルオキシダーゼ、アルカリ性ホスファターゼ等が挙げられる。放射性物質としては、例えば１２５Ｉ等が挙げられる。 Examples of the label in the labeled second antibody include an enzyme and a radioactive substance. Examples of the enzyme include peroxidase and alkaline phosphatase. Examples of the radioactive substance include 125 I.
第１の抗体が結合した固相における該抗体と固相との結合としては、例えば非共有結合、共有結合等が挙げられる。非共有結合としては、例えば物理吸着等が挙げられる。共有結合としては、例えば該抗体と固相との直接的な結合や、リンカー等を介した該抗体と固相との間接的な結合等が挙げられる。 Examples of the bond between the antibody and the solid phase in the solid phase to which the first antibody is bound include non-covalent bonds and covalent bonds. Examples of non-covalent bonds include physical adsorption. Examples of the covalent bond include a direct bond between the antibody and the solid phase and an indirect bond between the antibody and the solid phase via a linker or the like.
固相としては、第１の抗体を固定化し、ｓＩＬ−２Ｒの免疫学的測定法を可能にする固相であれば特に制限はなく、例えばマイクロタイタープレートなどのポリスチレンプレート、ガラス製または合成樹脂製の粒子物（ビーズ）、ガラス製または合成樹脂製の球状物（ボール）、ラテックス、磁性粒子、ニトロセルロース膜などの各種メンブレン、合成樹脂製の試験管等が挙げられる。 The solid phase is not particularly limited as long as the first antibody is immobilized and the solid phase enabling immunoassay of sIL-2R is used. For example, a polystyrene plate such as a microtiter plate, glass or synthetic resin Examples thereof include particles (beads) made of glass, spheres (balls) made of glass or synthetic resin, latex, magnetic particles, various membranes such as nitrocellulose membrane, test tubes made of synthetic resin, and the like.
第１の抗体が結合した固相を用いることにより、検体中のｓＩＬ−２Ｒと、該固相上の該抗体との反応後、固相を洗浄することにより、未反応の物質を固相から除去することができるので好ましい。このｓＩＬ−２Ｒ測定用試薬を用いることにより、試料中のｓＩＬ−２Ｒを測定することができる。試料中のｓＩＬ−２Ｒ濃度は、例えば以下の工程［１］〜［５］を含む方法により決定することが出来る。
［１］固相上に結合した第１の抗体と試料中のｓＩＬ−２Ｒとを反応させて、固相上に第１の抗体とｓＩＬ−２Ｒの複合体を形成させる工程；
［２］工程［１］で生成した複合体と標識化第２抗体とを反応させて、固相上に第１の抗体、ｓＩＬ−２Ｒ及び標識化第２抗体の複合体を形成させる工程；
［３］工程［２］での固相を洗浄し、未反応の物質を固相上から除去する工程；
［４］工程［３］の後、固相上に生成した第１の抗体、ｓＩＬ−２Ｒ及び標識化第２抗体の複合体中の標識量を測定する工程；
［５］工程［４］での測定値と、予め作成したｓＩＬ−２Ｒ濃度と標識量との関係を表す検量線とから、該試料中のｓＩＬ−２Ｒ濃度を決定する工程。
By using the solid phase to which the first antibody is bound, the unreacted substance is removed from the solid phase by washing the solid phase after the reaction between sIL-2R in the specimen and the antibody on the solid phase. This is preferable because it can be removed. By using this sIL-2R measurement reagent, sIL-2R in a sample can be measured. The sIL-2R concentration in the sample can be determined, for example, by a method including the following steps [1] to [5].
[1] reacting the first antibody bound on the solid phase with sIL-2R in the sample to form a complex of the first antibody and sIL-2R on the solid phase;
[2] A step of reacting the complex produced in step [1] with the labeled second antibody to form a complex of the first antibody, sIL-2R and the labeled second antibody on the solid phase;
[3] A step of washing the solid phase in step [2] and removing unreacted substances from the solid phase;
[4] A step of measuring the amount of label in the complex of the first antibody, sIL-2R and labeled second antibody produced on the solid phase after the step [3];
[5] A step of determining the sIL-2R concentration in the sample from the measurement value in the step [4] and a calibration curve representing the relationship between the sIL-2R concentration and the labeled amount prepared in advance.
尚、上記［１］工程と［２］工程との間に洗浄工程を挿入してもよい。 In addition, you may insert a washing | cleaning process between the said [1] process and [2] process.
試料中のｓＩＬ−２Ｒ濃度を決定する際に使用する検量線は、既知濃度のｓＩＬ−２Ｒを用いて作成することができる。すなわち、既知濃度のｓＩＬ−２Ｒを含む試料を、例えば上記の測定法に供し、得られる情報量とｓＩＬ−２Ｒ濃度とを関係付けることにより検量線を作成することができる。ここで、情報量としては、例えば吸光度、蛍光強度、発光強度、放射活性、濁度等が挙げられる。作成した検量線と測定値とから、測定に使用した試料中のｓＩＬ−２Ｒ濃度を決定することができる。 A calibration curve used in determining the sIL-2R concentration in the sample can be prepared using a known concentration of sIL-2R. That is, a sample containing a known concentration of sIL-2R is subjected to, for example, the above-described measurement method, and a calibration curve can be created by associating the obtained information amount with the sIL-2R concentration. Here, examples of the information amount include absorbance, fluorescence intensity, emission intensity, radioactivity, and turbidity. From the prepared calibration curve and the measured value, the sIL-2R concentration in the sample used for the measurement can be determined.
検量線作成および試料中のｓＩＬ−２Ｒの測定においては、市販のｓＩＬ−２Ｒ測定用キットを用いることもできる。市販のｓＩＬ−２Ｒ測定用キットとしては、例えばセルフリーＮ ＩＬ−２Ｒ（協和メデックス社製）、デタミナーＣＬ ＩＬ−２Ｒ（協和メデックス社製）、シーメンス・イムライズ ＩＬ−２Ｒ ＩＩ（シーメンス社製）やシーメンス・イムライズＩＬ−２Ｒ ＩＩ ２０００（シーメンス社製）、ＩＬ−２Ｒテスト・ＢＭＬ（ビー・エム・エル社製）等が挙げられる。 In preparing a calibration curve and measuring sIL-2R in a sample, a commercially available sIL-2R measurement kit can also be used. Examples of commercially available kits for measuring sIL-2R include cell-free N IL-2R (manufactured by Kyowa Medex), determiner CL IL-2R (manufactured by Kyowa Medex), Siemens Imrise IL-2R II (manufactured by Siemens) and Siemens Imrise IL-2R II 2000 (manufactured by Siemens), IL-2R test BML (manufactured by BML) and the like.
本発明において、試料中のｓＣＤ３０は、ｓＣＤ３０測定用試薬を用いて測定することができる。ｓＣＤ３０測定用試薬としては、ｓＣＤ３０に特異的に結合する第１の抗体が結合した固相、及びｓＣＤ３０に特異的に結合する第２の抗体に標識が結合した標識化第２抗体を含む試薬を例示することができる。第１の抗体におけるｓＣＤ３０の抗原決定部位と、第２の抗体におけるｓＣＤ３０の抗原決定部位とは同じであっても異なっていてもよい。標識化第２抗体における標識としては、例えば前述の標識等が挙げられる。 In the present invention, sCD30 in a sample can be measured using a reagent for measuring sCD30. As a reagent for measuring sCD30, a reagent comprising a solid phase bound to a first antibody that specifically binds to sCD30, and a labeled second antibody bound to a second antibody that specifically binds to sCD30. It can be illustrated. The antigen determining site of sCD30 in the first antibody and the antigen determining site of sCD30 in the second antibody may be the same or different. Examples of the label in the labeled second antibody include the aforementioned labels.
第１の抗体が結合した固相における該抗体と固相との結合としては、例えば前述の結合等が挙げられる。 Examples of the binding between the antibody and the solid phase in the solid phase to which the first antibody is bound include the aforementioned binding.
固相としては、第１の抗体を固定化し、ｓＣＤ３０の免疫学的測定法を可能にする固相であれば特に制限はなく、例えば前述の固相等が挙げられる。 The solid phase is not particularly limited as long as it immobilizes the first antibody and enables immunological measurement of sCD30, and examples thereof include the aforementioned solid phase.
第１の抗体が結合した固相を用いることにより、検体中のｓＣＤ３０と、該固相上の該抗体との反応後、固相を洗浄することにより、未反応の物質を固相から除去することができるので好ましい。このｓＣＤ３０測定用試薬を用いることにより、試料中のｓＣＤ３０を測定することができる。試料中のｓＣＤ３０濃度は、例えば上記のｓＩＬ−２Ｒ濃度測定方法と同様の方法で決定することができる。 By using the solid phase to which the first antibody is bound, the unreacted substance is removed from the solid phase by washing the solid phase after the reaction between the sCD30 in the sample and the antibody on the solid phase. This is preferable. By using this sCD30 measurement reagent, sCD30 in a sample can be measured. The sCD30 concentration in the sample can be determined, for example, by the same method as the sIL-2R concentration measurement method described above.
試料中のｓＣＤ３０濃度を決定するに際して使用する検量線は、既知濃度のｓＣＤ３０を用いて作成することができる。すなわち、既知濃度のｓＣＤ３０を含む試料を、例えば上記の測定法に供し、得られる情報量とｓＣＤ３０濃度とを関係付けることにより検量線を作成することができる。ここで、情報量としては、例えば吸光度、蛍光強度、発光強度、放射活性、濁度等が挙げられる。作成した検量線と測定値とから、測定に使用した試料中のｓＣＤ３０濃度を決定することができる。 A calibration curve used in determining the sCD30 concentration in the sample can be prepared using a known concentration of sCD30. That is, a calibration curve can be created by subjecting a sample containing a known concentration of sCD30 to, for example, the above-described measurement method, and relating the obtained information amount to the sCD30 concentration. Here, examples of the information amount include absorbance, fluorescence intensity, emission intensity, radioactivity, and turbidity. The sCD30 concentration in the sample used for the measurement can be determined from the prepared calibration curve and the measured value.
検量線作成および試料中のｓＣＤ３０の測定においては、市販のｓＣＤ３０測定用キットを用いることもできる。市販のｓＣＤ３０測定用キットとしては、例えばHuman sCD30 Platinum ELISA (eBioscience社製)等を挙げることができる。 In preparing a calibration curve and measuring sCD30 in a sample, a commercially available sCD30 measurement kit can also be used. Examples of commercially available sCD30 measurement kits include Human sCD30 Platinum ELISA (manufactured by eBioscience).
本発明におけるｓＩＬ−２Ｒ濃度の２５００Ｕ／ｍＬは、セルフリーＮ ＩＬ−２Ｒ（協和メデックス社製）の添付文書に記載された方法、すなわち、１０％(W/V)インターロイキン２（ＩＬ−２）で４日間刺激した正常ヒトＩＬ−２依存性Ｔ細胞の無細胞培養上清（無希釈）中に含まれるｓＩＬ−２Ｒ濃度を１０００Ｕ／ｍＬとする方法により決定される濃度、又は、セルフリーＮ ＩＬ−２Ｒでの測定と相関関係が認められる、他の測定により決定される濃度である。かかる他の測定により決定される濃度としては、セルフリーＮ ＩＬ−２Ｒを用いた測定により決定されるｓＩＬ−２Ｒ濃度に換算したときに、当該ｓＩＬ−２Ｒ濃度と、少なくとも９０％、好ましくは少なくとも９５％、より好ましくは１００％同一を示す濃度を挙げることができる。 In the present invention, the sIL-2R concentration of 2500 U / mL was determined by the method described in the package insert of Cell Free N IL-2R (manufactured by Kyowa Medex), that is, 10% (W / V) interleukin 2 (IL-2 The concentration determined by the method of setting the sIL-2R concentration in the cell-free culture supernatant (undiluted) of normal human IL-2-dependent T cells stimulated for 4 days to 1000 U / mL, or cell-free It is the concentration determined by other measurements that correlate with the measurement with NIL-2R. As the concentration determined by such other measurement, when converted to the sIL-2R concentration determined by the measurement using cell-free N IL-2R, the sIL-2R concentration is at least 90%, preferably at least A concentration showing 95%, more preferably 100% identity can be mentioned.
本発明におけるｓＣＤ３０濃度は、Human sCD30 Platinum ELISA(eBioscience社製)の添付文書に記載された方法により決定される濃度、又は、Human sCD30 Platinum ELISAでの測定と相関関係が認められる、他の測定により決定される濃度である。かかる他の測定により決定される濃度としては、Human sCD30 Platinum ELISA(eBioscience社製)を用いた測定により決定されるｓＣＤ３０濃度に換算したときに、当該ｓＣＤ３０濃度と、少なくとも９０％、好ましくは少なくとも９５％、より好ましくは１００％同一を示す濃度を挙げることができる。なお、Human sCD30 Platinum ELISA(eBioscience社製)の添付文書に記載された濃度単位「ｎｇ／ｍＬ」と本発明における濃度単位「Ｕ／ｍＬ」とは同一である。 The sCD30 concentration in the present invention is determined by the method described in the package insert of the Human sCD30 Platinum ELISA (manufactured by eBioscience), or by other measurement that is correlated with the measurement by the Human sCD30 Platinum ELISA. The concentration to be determined. The concentration determined by such other measurement is at least 90%, preferably at least 95%, when converted to sCD30 concentration determined by measurement using Human sCD30 Platinum ELISA (manufactured by eBioscience). %, More preferably 100%. The concentration unit “ng / mL” described in the package insert of Human sCD30 Platinum ELISA (manufactured by eBioscience) is the same as the concentration unit “U / mL” in the present invention.
本発明は、また、ｓＩＬ−２Ｒ測定用試薬とｓＣＤ３０測定用試薬を含有することを特徴とする、慢性型のＡＴＬ患者の急性転化のし易さを試験するキットに関する。本発明のキットに用いられるｓＩＬ−２Ｒ測定用試薬としては、例えば前述のｓＩＬ−２Ｒ測定用試薬等が挙げることができ、ｓＣＤ３０測定用試薬としては、例えば前述のｓＣＤ３０測定用試薬等が挙げることができる。上記キットには、ｓＩＬ−２Ｒ測定用試薬やｓＣＤ３０測定用試薬の他、慢性型のＡＴＬ患者の急性転化のし易さ（リスク）を判断するための指標、例えば、慢性型のＡＴＬ患者より採取された試料中のｓＣＤ３０とｓＩＬ−２Ｒとを測定し、ｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上となり、ｓＩＬ−２Ｒ濃度／ｓＣＤ３０濃度が（Ａ）時間経過とともに減少しながら１０に近づく場合、又は（Ｂ）１０以下である場合には、急性転化しやすいという基準と比較する旨が記載された添付文書を含むものが好ましい。 The present invention also relates to a kit for testing the easiness of chronological change of chronic ATL patients, comprising a reagent for measuring sIL-2R and a reagent for measuring sCD30. Examples of the sIL-2R measurement reagent used in the kit of the present invention include the aforementioned sIL-2R measurement reagent, and examples of the sCD30 measurement reagent include the aforementioned sCD30 measurement reagent. Can do. In the above-mentioned kit, in addition to the reagent for measuring sIL-2R and the reagent for measuring sCD30, an index for determining the ease (risk) of chronic ATL patient's acute transformation, for example, collected from a chronic ATL patient When sCD30 and sIL-2R in the prepared sample are measured, the sIL-2R concentration becomes 2500 U / mL or more, and the sIL-2R concentration / sCD30 concentration approaches 10 while decreasing with time (A), or ( B) In the case of 10 or less, it is preferable to include a package insert that describes the comparison with the standard of being easily converted into an acute state.
以下、実施例により本発明を説明するが、本発明はこの実施例に限定されるものではない。 EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to this Example.
急性転化した６症例のｓＣＤ３０濃度とｓＩＬ-２Ｒ濃度
慢性型から急性型へ急性転化した６症例（インフォームドコンセントを取得）のそれぞれの症例について、ｓＩＬ−２Ｒ濃度、ｓＣＤ３０濃度、及び、ｓＩＬ−２Ｒ／ｓＣＤ３０を決定した。その結果を表１に示す。ｓＣＤ３０濃度はｓＣＤ３０測定用キット［Human sCD30 Platinum ELISA (eBioscience社製)］を用いて、ｓＩＬ−２Ｒ濃度はｓＩＬ−２Ｒ測定キット[セルフリーＮ ＩＬ−２Ｒメデックス（協和メデックス社製）]を用いて測定した。
SCD30 concentration and sIL-2R concentration of 6 cases that were acutely changed For each case of 6 cases (obtained informed consent) that were acutely changed from chronic type to acute type, sIL-2R concentration, sCD30 concentration, and sIL-2R / SCD30 was determined. The results are shown in Table 1. The sCD30 concentration was determined using an sCD30 measurement kit [Human sCD30 Platinum ELISA (manufactured by eBioscience)], and the sIL-2R concentration was determined using an sIL-2R measurement kit [Cell-free N IL-2R Medex (manufactured by Kyowa Medex)]. It was measured.
尚、表１中の急性転化前観察期間とは、慢性型のＡＴＬ症例として観察を開始した日、すなわち、慢性型のＡＴＬ患者より採取した血液から得られた血清を用いて、当該血清中のｓＩＬ−２Ｒ濃度とｓＣＤ３０濃度を測定した日を基準とし、急性転化と診断されるまでの期間（日）を示している。 It should be noted that the observation period before acute change in Table 1 refers to the day when observation was started as a chronic ATL case, that is, using serum obtained from blood collected from a chronic ATL patient, The period (day) until diagnosis of blast crisis is shown with reference to the day on which the sIL-2R concentration and sCD30 concentration were measured.
症例１は、胸水に腫瘍病変が確認されたため急性型（急性転化）と診断された。症例２、症例３、症例５、症例６は、ＬＤＨ活性が正常値上限の２倍を超えたため急性型（急性転化）と診断された。症例４は、高カルシウム血症となったため急性型（急性転化）と診断された。 Case 1 was diagnosed as acute (acute inversion) because a tumor lesion was confirmed in pleural effusion. Case 2, case 3, case 5, and case 6 were diagnosed as acute (acute transformation) because LDH activity exceeded twice the upper limit of the normal value. Case 4 was diagnosed as acute (acute change) because of hypercalcemia.
症例１は、慢性型として観察を開始した時点で、ｓＩＬ−２Ｒ濃度が２６９１Ｕ／ｍＬ、ｓＩＬ−２Ｒ／ｓＣＤ３０は８．６であった。この時点で急性転化しやすい状態であり、観察開始から１６８日目で急性転化と診断された。急性転化と診断された時点で、ｓＩＬ−２Ｒは３１２６Ｕ／ｍＬにまで上昇し、ｓＩＬ−２Ｒ／ｓＣＤ３０比は１．６まで低下していた。 Case 1 had a sIL-2R concentration of 2691 U / mL and sIL-2R / sCD30 of 8.6 when observation was started as a chronic type. At this time, it was in a state of being easily converted into an acute state, and it was diagnosed as an acute change on the 168th day from the start of observation. At the time of diagnosis of blast crisis, sIL-2R increased to 3126 U / mL and the sIL-2R / sCD30 ratio had decreased to 1.6.
症例２は、慢性型として観察を開始した時のｓＩＬ−２Ｒ濃度が２９２９Ｕ／ｍＬ、ｓＩＬ−２Ｒ／ｓＣＤ３０比は１１．４であった。観察開始から５１日目に急性転化と診断されたが、この時点でのｓＩＬ−２Ｒ濃度は１１７５０Ｕ／ｍＬにまで上昇し、ｓＩＬ−２Ｒ／ｓＣＤ３０は７．６まで低下していた。 Case 2 had a sIL-2R concentration of 2929 U / mL and an sIL-2R / sCD30 ratio of 11.4 when observation was started as a chronic type. Diagnosis was made on the 51st day from the start of observation. At this time, the sIL-2R concentration increased to 11750 U / mL, and sIL-2R / sCD30 decreased to 7.6.
症例３は、慢性型として観察を開始した時のｓＩＬ−２Ｒ濃度が２３３０Ｕ／ｍＬ、ｓＩＬ−２Ｒ／ｓＣＤ３０は１４．５であった。観察開始から２４４日目に急性転化と診断されたが、この時点でのｓＩＬ−２Ｒは５９５９Ｕ／ｍＬにまで上昇し、ｓＩＬ−２Ｒ／ｓＣＤ３０は１１．１まで低下していた。 Case 3 had a sIL-2R concentration of 2330 U / mL and sIL-2R / sCD30 of 14.5 when observation was started as a chronic type. Diagnosis was made on the 244th day after the start of observation, but sIL-2R at this time increased to 5959 U / mL, and sIL-2R / sCD30 decreased to 11.1.
症例４は、慢性型として観察を開始した時のｓＩＬ−２Ｒ濃度が３４７８Ｕ／ｍＬ、ｓＩＬ−２Ｒ／ｓＣＤ３０は１８．３であった。観察開始から９２２日目に急性転化と診断されたが、この時点でのｓＩＬ−２Ｒ濃度は２０９１２Ｕ／ｍＬにまで上昇し、ｓＩＬ−２Ｒ／ｓＣＤ３０は９．１まで低下していた。 Case 4 had a sIL-2R concentration of 3478 U / mL and a sIL-2R / sCD30 of 18.3 when observation was started as a chronic type. On the 922th day after the start of the observation, the patient was diagnosed with blast crisis. At this time, the sIL-2R concentration increased to 20912 U / mL, and the sIL-2R / sCD30 decreased to 9.1.
症例５は、慢性型として観察を開始した時のｓＩＬ−２Ｒ濃度が９０００Ｕ／ｍＬ、ｓＩＬ−２Ｒ／ｓＣＤ３０は２３．９であった。観察開始から２０２日目に急性転化と診断されたが、この時点でのｓＩＬ−２Ｒ濃度は３９９１６Ｕ／ｍＬにまで上昇し、ｓＩＬ−２Ｒ／ｓＣＤ３０は１１．５まで低下していた。 Case 5 had a sIL-2R concentration of 9000 U / mL and sIL-2R / sCD30 of 23.9 when observation was started as a chronic type. Diagnosis was made on the 202th day from the start of observation, but the sIL-2R concentration at this point increased to 39916 U / mL, and sIL-2R / sCD30 decreased to 11.5.
症例６は、慢性型として観察を開始した時のｓＩＬ−２Ｒ濃度が１０８４２Ｕ／ｍＬ、ｓＩＬ−２Ｒ／ｓＣＤ３０比は１３．０であった。観察開始から３１日目に急性転化と診断されたが、この時点でのｓＩＬ−２Ｒ濃度は１６２２８Ｕ／ｍＬにまで上昇し、ｓＩＬ−２Ｒ／ｓＣＤ３０は７．３まで低下していた。 Case 6 had a sIL-2R concentration of 10842 U / mL and an sIL-2R / sCD30 ratio of 13.0 when observation was started as a chronic type. Diagnosis was made on the 31st day from the start of observation, but the sIL-2R concentration at this point increased to 16228 U / mL, and sIL-2R / sCD30 decreased to 7.3.
これからの結果より、急性転化した６症例では、急性転化前でｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上で、急性転化した時点でのｓＩＬ−２Ｒ／ｓＣＤ３０が急性転化前に比べて減少しながら１０に近づいている（症例２〜６）か、又は、急性転化前でｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上で、かつ、ｓＩＬ−２Ｒ／ｓＣＤ３０が１０以下であり、急性転化した時点でのｓＩＬ−２Ｒ／ｓＣＤ３０が急性転化前に比べてさらに低い値に変化している（症例１）ことがわかる。従って、慢性型のＡＴＬ患者由来の試料中のｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上で、かつ、ｓＩＬ−２Ｒ／ｓＣＤ３０が時間経過とともに減少し１０に近づく場合、及び、慢性型のＡＴＬ患者由来の試料中のｓＩＬ−２Ｒ濃度が２５００Ｕ／ｍＬ以上で、かつ、ｓＩＬ−２Ｒ／ｓＣＤ３０が１０以下の場合は、当該患者は急性転化し易い、ということが分かった。 From these results, in the 6 cases that became acute, the sIL-2R concentration was 2500 U / mL or more before the acute change, and the sIL-2R / sCD30 at the time of the acute change decreased to 10 compared to before the acute change. SIL-2R when approaching (cases 2 to 6), or when sIL-2R concentration is 2500 U / mL or more before blast crisis and sIL-2R / sCD30 is 10 or less, and sIL-2R at the time of blast crisis It can be seen that / sCD30 is changed to a lower value (case 1) than before the blast crisis. Therefore, when the sIL-2R concentration in a sample derived from a chronic type ATL patient is 2500 U / mL or more and the sIL-2R / sCD30 decreases with time and approaches 10, and from a chronic type ATL patient It was found that when the sIL-2R concentration in the sample is 2500 U / mL or more and the sIL-2R / sCD30 is 10 or less, the patient is likely to undergo acute conversion.
このように、慢性型のＡＴＬ患者由来の試料中のｓＩＬ−２Ｒ濃度とｓＣＤ３０濃度をモニターすることで、急性転化のし易さを事前に予測することでき、早期に適切な治療を開始することができる。 Thus, by monitoring the sIL-2R concentration and sCD30 concentration in a sample derived from a chronic type ATL patient, it is possible to predict the ease of acute transformation in advance, and to start appropriate treatment at an early stage. Can do.
本発明により、慢性型のＡＴＬ患者における急性転化を試験する方法、及び、当該方法のためのキットが提供される。 According to the present invention, a method for testing blast crisis in a chronic ATL patient and a kit for the method are provided.
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