JP2013083671A - Method for determining treatment policy after blast crisis of smoldering or chronic adult t-cell leukemia patient - Google Patents
Method for determining treatment policy after blast crisis of smoldering or chronic adult t-cell leukemia patient Download PDFInfo
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Abstract
Description
本発明は、くすぶり型又は慢性型の成人Ｔ細胞白血病（以下、ＡＴＬと記す）患者より採取された試料中のＣＤ３０と、インターロイキン−２受容体（以下、ＩＬ−２Ｒと記す）及び／又は乳酸脱水素酵素（以下、ＬＤＨと記す）活性とを測定することを含む、当該患者の急性転化後の治療方針を決定するための方法や、この方法に用いるキットに関する。 The present invention relates to CD30 in a sample collected from a smoldering or chronic type adult T-cell leukemia (hereinafter referred to as ATL) patient, interleukin-2 receptor (hereinafter referred to as IL-2R) and / or The present invention relates to a method for determining a therapeutic policy after blast crisis of the patient, including measurement of lactate dehydrogenase (hereinafter referred to as LDH) activity, and a kit used in this method.
ヒトＴリンパ球向性ウィルスは、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 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）、酵素免疫法（ＥＬＩＳＡ法）、ウェスタンブロット法（ＷＢ法）などが知られている。 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), enzyme immunization (ELISA), Western blot (WB) and the like are known.
しかしながら、単独の方法でのＨＴＬＶ−１感染の判定は確実ではなく、一次スクリーニングで陽性と判断された場合でも、ＦＡ法、ＷＢ法といった二次スクリーニングを行う必要がある。さらに当該被験者がＨＴＬＶ−１に感染しているという診断を最終的に下すためには、末梢血またはリンパ節細胞のリンパ球ゲノムにＨＴＬＶ−１プロウィルスＤＮＡが組み込まれていることをサザンブロット法あるいはＰＣＲ法を用いて遺伝子的に証明する必要がある。 However, the determination of HTLV-1 infection by a single method is not reliable, and even when it is determined to be positive by the primary screening, it is necessary to perform secondary screening such as FA method and WB method. Furthermore, in order to finally make a diagnosis that the subject is infected with HTLV-1, Southern blotting shows that HTLV-1 proviral DNA is incorporated into the lymphocyte genome of peripheral blood or lymph node cells. Alternatively, it must be proved genetically using the PCR method.
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）は日本国内で１２０万人と推定されており、ＨＴＬＶ−１キャリアの１０００人に１人が感染から平均５０年後にＡＴＬを発症すると言われている。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. HTLV-1 carriers (those who have been infected with HTLV-1 and who have not developed the above-mentioned diseases caused by HTLV-1) are estimated to be 1.2 million in Japan, and 1000 of HTLV-1 carriers One person is said to develop ATL on average 50 years after infection. 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。リンパ腫型や急性型はがん細胞の増殖が早く、急速に症状が出現するために予後（生存率）が悪いと言われており、早急な治療が必要となる。一方、くすぶり型は血液中のがん細胞の数が少なく症状をあまり伴わないため、無治療で長期間変わらず経過することが多い。慢性型は、血液中のがん細胞の増殖が早くなく症状もあまり伴わないため、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。 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. Lymphoma type and acute type are said to have poor prognosis (survival rate) because cancer cells grow rapidly and symptoms appear rapidly, and prompt treatment is required. On the other hand, since the smoldering type has few cancer cells in the blood and is not accompanied by many symptoms, it often passes without treatment for a long time. In the chronic type, cancer cells in the blood do not grow quickly and are not accompanied by symptoms. Therefore, it is common 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ＬＤＨ活性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. If abnormalities are found by examining the LDH activity in serum, soluble interleukin-2 receptor (hereinafter referred to as sIL-2R) concentration, white blood cell count, peripheral blood ATL cell count, calcium concentration, etc. The presence and number of lymphadenopathy, the presence or absence of skin lesions, the presence or absence of lung lesions, the presence or absence of hepatosplenomegaly, the presence or absence of other lesions, CT (Computed Tomography) as diagnostic imaging, and gallium scintigraphy or PET ( (Positron emission tomography) examination is performed to make a definitive diagnosis of acute change to acute type or lymphoma type, but it is difficult to predict acute change at an early stage.
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。 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%).
ＡＴＬについては、化学療法のみの治療成績では完全寛解率は１６〜４１％、生存期間中央値は３〜１３ヵ月であり、その予後は極めて不良であることが報告されていたが、化学療法による着実な進歩が見られ、最近では生存期間中央値が１２ヶ月を越える治療法も報告されている。また、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）。 As for ATL, the complete remission rate was 16 to 41% and the median survival was 3 to 13 months in the treatment results of chemotherapy alone, and the prognosis was reported to be extremely poor. Steady progress has been made, and recently treatments with median survival exceeding 12 months have been reported. In addition, when a sufficient effect cannot be expected with chemotherapy, bone marrow transplantation (allogeneic hematopoietic stem cell transplantation) has been actively performed, and some patients have also been expected to be cured (Non-Patent Documents). 4).
ＡＴＬ発症を予測する方法がＪＳＰＦＡＤ(Joint Study of Predisposing Factors of ATL Development)により研究されているが、未だ有用な方法は報告されていない。 A method for predicting the onset of ATL has been studied by JSPFAD (Joint Study of Predisposing Factors of ATL Development), but no useful method has been reported yet.
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おり、ＡＴＬの発症予測因子として期待されている。しかしながら、ｓＩＬ−２Ｒは腫瘍細胞数を反映すると同時に生体内における免疫反応の活性化も反映していることや、慢性関節リウマチや間質性肺炎、Ｃ型肝炎患者では、ｓＩＬ−２Ｒ濃度が基準値を遙かに超えて数千Ｕ／ｍＬを示す事があることが報告されていることから、ＨＴＬＶ−１キャリアがこのような疾患に罹患していた場合、ＡＴＬの発症予測の指標としてｓＩＬ−２Ｒ濃度を用いることが適さない可能性がある。 sIL-2R is utilized as a useful index for ATL disease state monitoring and prognosis prediction, and is expected as a predictor of ATL onset. However, sIL-2R reflects the number of tumor cells as well as the activation of immune response in vivo, and in patients with rheumatoid arthritis, interstitial pneumonia, and hepatitis C, the sIL-2R concentration is the standard. Since it has been reported that the value may exceed several thousand U / mL, when HTLV-1 carrier suffers from such a disease, sIL is used as an index for predicting the onset of ATL. It may not be appropriate to use the -2R concentration.
ＬＤＨは、体内の組織中に広く分布し、嫌気的解糖系最終段階に働く酵素である。血清・血漿中のＬＤＨ活性は、急性肝炎、心筋梗塞、悪性貧血、白血病、悪性腫瘍などで上昇が見られることより、これらの疾患の診断および経過観察に有用である。ＡＴＬにおいて、ＬＤＨ活性は腫瘍量を反映し病勢とよく相関することから、診断基準の１つとして用いられている。 LDH is an enzyme that is widely distributed in tissues in the body and works in the final stage of anaerobic glycolysis. Since LDH activity in serum and plasma is increased in acute hepatitis, myocardial infarction, pernicious anemia, leukemia, malignant tumor, etc., it is useful for diagnosis and follow-up of these diseases. In ATL, LDH activity reflects tumor volume and correlates well with disease state, so it is used as one of the diagnostic criteria.
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ＣＤ３０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 is 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 CD30, 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).
本発明の目的は、ＨＴＬＶ−１キャリアにおけるＡＴＬ発症の早期診断によるＨＴＬＶ−１キャリアのＱＯＬの向上、ＡＴＬ患者、特にくすぶり型又は慢性型ＡＴＬ患者における急性転化の早期診断によるくすぶり型又は慢性型ＡＴＬ患者のＱＯＬの向上を指向し、ＨＴＬＶ−１キャリアにおけるＡＴＬ発症リスク、ＡＴＬ患者における骨髄移植後の予後、くすぶり型又は慢性型のＡＴＬ患者におけるＡＴＬの急性転化を判定する方法、及び、くすぶり型又は慢性型のＡＴＬ患者における治療時期決定のための優れた方法、並びにこれらの方法に用いるためのキットを提供することにある。 The object of the present invention is to improve QOL of HTLV-1 carrier by early diagnosis of ATL onset in HTLV-1 carrier, smoldering type or chronic type ATL by early diagnosis of acute transformation in ATL patients, particularly smoldering type or chronic type ATL patients. A method for determining QOL in patients, determining the risk of developing ATL in HTLV-1 carriers, prognosis after bone marrow transplantation in ATL patients, smoldering or chronic ATL transformation in chronic ATL patients, and smoldering or It is an object to provide an excellent method for determining the timing of treatment in chronic type ATL patients, and a kit for use in these methods.
発明者は、本課題の解決のために鋭意検討し、ＴＮＦスーパーファミリーに属する因子であるＣＤ３０を測定することにより、ＡＴＬ患者における骨髄移植後の予後、ＨＴＬＶ−１キャリアにおけるＡＴＬ発症リスク、及びくすぶり型又は慢性型のＡＴＬ患者におけるＡＴＬの急性転化の判定が可能となるという知見を見出し、さらに、ＣＤ３０と、ＩＬ−２Ｒ又はＬＤＨ活性とを測定することにより、くすぶり型又は慢性型のＡＴＬ患者における治療時期を決定できる、という知見を見出し、本発明を完成させた。 The inventor has intensively studied to solve this problem and measures the prognosis after bone marrow transplantation in ATL patients, the risk of developing ATL in HTLV-1 carriers, and smoldering by measuring CD30, a factor belonging to the TNF superfamily. Finding that it is possible to determine the blast crisis of ATL in patients with type or chronic ATL, and further measuring CD30 and IL-2R or LDH activity in smoldering or chronic type ATL patients The present inventors have found that the treatment time can be determined and have completed the present invention.
すなわち、本発明は、以下の［１］〜［１０］に関する。
［１］ ヒトＴリンパ球向性ウィルス１型キャリアより採取された試料中のＣＤ３０を測定し、得られる測定値により、当該キャリアにおける成人Ｔ細胞白血病発症リスクを判定する方法。
［２］ 成人Ｔ細胞白血病患者より採取された試料中のＣＤ３０を測定し、得られる測定値により、当該患者における骨髄移植後の予後を判定する方法。
［３］ くすぶり型又は慢性型の成人Ｔ細胞白血病患者より採取された試料中のＣＤ３０を測定し、得られる測定値により、当該患者における成人Ｔ細胞白血病の急性転化を判定する方法。
［４］ くすぶり型又は慢性型の成人Ｔ細胞白血病患者より採取された試料中のＣＤ３０と、インターロイキン−２受容体及び／又は乳酸脱水素酵素活性とを測定し、得られる測定値により、当該患者の急性転化後の治療方針を決定する方法。
［５］ ＣＤ３０が、可溶型である［１］〜［４］のいずれかに記載の方法。
［６］ ＣＤ３０測定用試薬を含有することを特徴とする、ヒトＴリンパ球向性ウィルス１型キャリアにおける成人Ｔ細胞白血病発症リスク判定用キット。
［７］ ＣＤ３０測定用試薬を含有することを特徴とする、成人Ｔ細胞白血病患者における骨髄移植後の予後判定用キット。
［８］ ＣＤ３０測定用試薬を含有することを特徴とする、くすぶり型又は慢性型の成人Ｔ細胞白血病（ＡＴＬ）患者におけるＡＴＬの急性転化判定用キット。
［９］ ＣＤ３０測定用試薬と、インターロイキン−２受容体測定用試薬及び／又は乳酸脱水素酵素活性測定用試薬とを含有することを特徴とする、くすぶり型又は慢性型の成人Ｔ細胞白血病患者の急性転化後の治療方針決定用キット。
［１０］ ＣＤ３０が、可溶型である［６］〜［９］のいずれかに記載のキット。
That is, the present invention relates to the following [1] to [10].
[1] A method of measuring CD30 in a sample collected from a human T lymphocyte-tropic virus type 1 carrier and determining the risk of developing adult T-cell leukemia in the carrier based on the obtained measurement value.
[2] A method for measuring CD30 in a sample collected from a patient with adult T-cell leukemia and determining the prognosis after bone marrow transplantation in the patient based on the obtained measurement value.
[3] A method of measuring CD30 in a sample collected from a smoldering or chronic adult T-cell leukemia patient and determining the acute conversion of adult T-cell leukemia in the patient based on the obtained measurement value.
[4] Measure CD30 and interleukin-2 receptor and / or lactate dehydrogenase activity in a sample collected from a smoldering or chronic adult T-cell leukemia patient. A method for determining the treatment strategy after blast crisis in a patient.
[5] The method according to any one of [1] to [4], wherein CD30 is a soluble type.
[6] A kit for determining the risk of developing adult T-cell leukemia in a human T lymphocyte-tropic virus type 1 carrier, comprising a reagent for measuring CD30.
[7] A kit for determining prognosis after bone marrow transplantation in an adult T-cell leukemia patient, comprising a reagent for measuring CD30.
[8] A kit for determining ATL inversion in a smoldering or chronic adult T cell leukemia (ATL) patient, comprising a reagent for measuring CD30.
[9] A smoldering or chronic adult T-cell leukemia patient, comprising a CD30 measurement reagent, an interleukin-2 receptor measurement reagent and / or a lactate dehydrogenase activity measurement reagent For determining treatment policy after blast crisis.
[10] The kit according to any one of [6] to [9], wherein CD30 is a soluble type.
本発明によると、ＨＴＬＶ−１キャリアにおけるＡＴＬ発症リスク、ＡＴＬ患者における骨髄移植後の予後、くすぶり型又は慢性型のＡＴＬ患者におけるＡＴＬの急性転化を判定することや、くすぶり型又は慢性型のＡＴＬ患者の急性転化後の治療方針を決定することができる。 According to the present invention, it is possible to determine the risk of ATL onset in HTLV-1 carriers, the prognosis after bone marrow transplantation in ATL patients, the acute conversion of ATL in smoldering or chronic ATL patients, and smoldering or chronic ATL patients The treatment policy after blast crisis can be determined.
本発明におけるＣＤ３０は、可溶型ＣＤ３０（ｓＣＤ３０）と非可溶型ＣＤ３０の両方を包含するが、可溶型ＣＤ３０（ｓＣＤ３０）が好ましい。また、本発明におけるＣＤ３０は、全長型のみならず一部が切れた断片型をも包含する。本発明におけるＩＬ−２Ｒは、可溶型ＩＬ−２Ｒ（ｓＩＬ−２Ｒ）と非可溶型ＩＬ−２Ｒの両方を含むが、可溶型ＩＬ−２Ｒ（ｓＩＬ−２Ｒ）が好ましい。 CD30 in the present invention includes both soluble CD30 (sCD30) and non-soluble CD30, preferably soluble CD30 (sCD30). Further, CD30 in the present invention includes not only the full-length type but also a fragment type in which a part is cut. IL-2R in the present invention includes both soluble IL-2R (sIL-2R) and non-soluble IL-2R, but soluble IL-2R (sIL-2R) is preferred.
［ＨＴＬＶ−１キャリアにおけるＡＴＬ発症リスク判定方法］
本発明において、ＨＴＬＶ−１キャリアにおけるＡＴＬ発症の判定は、例えば以下の工程を含有する方法により行うことが出来る。
（１）ＨＴＬＶ−１キャリアより採取された試料を用いて、当該試料中のＣＤ３０を測定する工程；
（２）予め作成したＣＤ３０濃度と情報量との関係を表す検量線と、（１）での測定値とから、当該生体試料中のＣＤ３０の濃度を決定する工程；
（３）（２）で決定した当該試料中のＣＤ３０濃度を基準値に照らし合わせて、ＣＤ３０濃度が当該基準値よりも高い場合、当該キャリアをＡＴＬ発症のリスクが高いと判定し、ＣＤ３０濃度が当該基準値よりも低い場合、当該キャリアをＡＴＬ発症のリスクが低いと判定する工程。
[Method for determining risk of developing ATL in HTLV-1 carrier]
In the present invention, the determination of the occurrence of ATL in the HTLV-1 carrier can be performed, for example, by a method including the following steps.
(1) A step of measuring CD30 in the sample using a sample collected from the HTLV-1 carrier;
(2) A step of determining the concentration of CD30 in the biological sample from a calibration curve representing the relationship between the CD30 concentration prepared in advance and the information amount and the measured value in (1);
(3) When the CD30 concentration in the sample determined in (2) is compared with the reference value and the CD30 concentration is higher than the reference value, the carrier is determined to have a high risk of developing ATL, and the CD30 concentration is A step of determining that the carrier has a low risk of developing ATL when the reference value is lower.
ＨＴＬＶ−１キャリアとは、前記の通り、ＨＴＬＶ−１に感染しているがＡＴＬ等の疾患を発症していない者を指すが、ＨＴＬＶ−１キャリアより採取された試料中のＣＤ３０の測定は、例えば後述のＣＤ３０測定方法により行うことができる。 As described above, the HTLV-1 carrier refers to a person who is infected with HTLV-1 but has not developed a disease such as ATL, but the measurement of CD30 in a sample collected from the HTLV-1 carrier is as follows. For example, it can be performed by a CD30 measuring method described later.
上記基準値は、測定値の平均値±２ＳＤ（ＳＤ：標準偏差）で規定することが好ましい。ここで、測定値としては、健常人に対する測定値であっても、ＨＴＬＶ−１キャリアに対する測定値であってもよいが、測定によって決定されるＣＤ３０濃度は、測定に使用する試薬の種類や測定法等の測定条件により変わり得るので、基準値は、同一の測定条件下で、あらかじめ選択した母集団に対して行った測定により規定することが好ましい。ＨＴＬＶ−１キャリアにおけるＡＴＬ発症リスクの予測に際して、母集団としては、ＡＴＬを発症していない健常人及び／又はＨＴＬＶ−１キャリアからなる集団であり、母集団の人数としては、通常１０名以上、好ましくは３０人以上、より好ましくは５０人以上である。 The reference value is preferably defined as an average value of measured values ± 2SD (SD: standard deviation). Here, the measured value may be a measured value for a healthy person or a measured value for an HTLV-1 carrier, but the CD30 concentration determined by the measurement depends on the type of reagent used for the measurement and the measurement. Since it may vary depending on measurement conditions such as the method, it is preferable that the reference value is defined by measurement performed on a preselected population under the same measurement conditions. In predicting the risk of developing ATL in an HTLV-1 carrier, the population is a group of healthy people who do not develop ATL and / or HTLV-1 carriers, and the number of population is usually 10 or more, Preferably it is 30 or more, more preferably 50 or more.
例えば、ＨＴＬＶに感染していない健常人３２名の血液中に含まれるｓＣＤ３０濃度を測定した際の平均値±ＳＤが３８．７±２８．０Ｕ／ｍＬである場合は、健常人のｓＣＤ３０濃度を規定する基準値としては、平均値＋２ＳＤである、９４．７Ｕ／ｍＬと規定することができる。 For example, when the average value ± SD when measuring the sCD30 concentration contained in the blood of 32 healthy people not infected with HTLV is 38.7 ± 28.0 U / mL, the sCD30 concentration of the healthy subject is As a standard value to prescribe | regulate, it can prescribe | regulate with 94.7U / mL which is an average value + 2SD.
また、ＨＴＬＶ−１キャリアの血液中に含まれるｓＣＤ３０濃度を測定した際１７名の平均値±ＳＤが４０．２±２３．２Ｕ／ｍＬである場合は、ＨＴＬＶ−１キャリアのｓＣＤ３０濃度を規定する基準値としては、平均値＋２ＳＤである、８６．６Ｕ／ｍＬと規定することができる。 In addition, when the sCD30 concentration contained in the blood of the HTLV-1 carrier is measured and the mean value ± SD of 17 persons is 40.2 ± 23.2 U / mL, the sCD30 concentration of the HTLV-1 carrier is specified. As a reference value, it can prescribe | regulate as 86.6U / mL which is an average value + 2SD.
同様に、急性型ＡＴＬ６症例、リンパ腫型ＡＴＬ５症例、及び慢性型ＡＴＬ２症例の血清中のｓＣＤ３０濃度がそれぞれ、１９７７〜１４９００Ｕ／ｍＬ（平均±２ＳＤ：５４０８±１０２９０）、４１５〜３７４８Ｕ／ｍＬ（平均±２ＳＤ：３６２６±８４１８）、３１４〜３６９Ｕ／ｍＬ（平均±２ＳＤ：３４１±７９）である場合は、ｓＣＤ３０の濃度が２７０Ｕ／ｍＬ以上であれば、ＡＴＬを発症していると判定でき、１００Ｕ／ｍＬ未満であればＡＴＬを発症していない、と判定できる。 Similarly, the sCD30 concentrations in the serum of acute type ATL6 cases, lymphoma type ATL5 cases, and chronic type ATL2 cases are 1977-14900 U / mL (mean ± 2SD: 5408 ± 10290), 415-3748 U / mL (average ± 2SD: 3626 ± 8418), 314 to 369 U / mL (mean ± 2SD: 341 ± 79), if the concentration of sCD30 is 270 U / mL or more, it can be determined that ATL has developed, and 100 U / If it is less than mL, it can be determined that ATL has not developed.
ＨＴＬＶ−１キャリアにおけるＡＴＬ発症リスクは、ＨＴＬＶ−１キャリアより採取された試料中のＣＤ３０濃度から判定できるが、基準値からの割合によっても判定することができる。ＨＴＬＶ−１キャリアに対してＡＴＬ発症のリスクが高いと判定できる場合の基準値に対する割合は、１．１以上であり、好ましくは３以上であり、より好ましくは４以上である。また、ＨＴＬＶ−１キャリアに対してＡＴＬ発症のリスクが高いと判定できる場合のＣＤ３０濃度としては、１００Ｕ／ｍＬ以上であり、好ましくは２７０Ｕ／ｍＬ以上であり、より好ましくは３６０Ｕ／ｍＬ以上である。 The risk of developing ATL in an HTLV-1 carrier can be determined from the CD30 concentration in a sample collected from the HTLV-1 carrier, but can also be determined from a ratio from a reference value. The ratio to the reference value when it can be determined that the risk of developing ATL is high with respect to the HTLV-1 carrier is 1.1 or more, preferably 3 or more, more preferably 4 or more. Moreover, as a CD30 density | concentration when it can be judged that the risk of ATL onset is high with respect to a HTLV-1 carrier, it is 100 U / mL or more, Preferably it is 270 U / mL or more, More preferably, it is 360 U / mL or more .
このように、ＨＴＬＶ−１キャリアより採取された試料中のＣＤ３０濃度が基準値よりも高濃度である場合に該キャリアがＡＴＬを発症するリスクが高いと判定することができる。また、基準値を適当に規定することにより、くすぶり型又は慢性型ＡＴＬと、リンパ腫型又は急性型ＡＴＬとを判別することもできる。当該判別は、例えば４００Ｕ／ｍＬを基準値として規定することにより行うことができる。 Thus, when the CD30 concentration in the sample collected from the HTLV-1 carrier is higher than the reference value, it can be determined that the carrier has a high risk of developing ATL. Further, by appropriately defining the reference value, it is possible to discriminate between smoldering type or chronic type ATL and lymphoma type or acute type ATL. The determination can be performed by defining 400 U / mL as a reference value, for example.
［ＡＴＬ患者における骨髄移植後の予後を判定する方法］
本発明において、ＡＴＬ患者における骨髄移植後の予後判定は、例えば以下の工程を含有する方法により行うことが出来る。
（１）急性型又はリンパ腫型ＡＴＬと判定された患者より採取された試料を用いて、当該試料中のＣＤ３０を測定する工程；
（２）予め作成したＣＤ３０濃度と情報量との関係を表す検量線と、（１）での測定値とから、当該生体試料中のＣＤ３０の濃度を決定する工程；
（３）（２）で決定した当該試料中のＣＤ３０濃度を基準値と照らし合わせて、ＣＤ３０濃度が当該基準値よりも高い場合、当該患者を骨髄移植後の予後が不良と判定し、ＣＤ３０濃度が当該基準値よりも低い場合、当該患者を骨髄移植後の予後が良好と判定する工程。
[Method for determining prognosis after bone marrow transplantation in ATL patients]
In the present invention, the prognosis after bone marrow transplantation in an ATL patient can be performed, for example, by a method including the following steps.
(1) a step of measuring CD30 in the sample using a sample collected from a patient determined to be acute type or lymphoma type ATL;
(2) A step of determining the concentration of CD30 in the biological sample from a calibration curve representing the relationship between the CD30 concentration prepared in advance and the information amount and the measured value in (1);
(3) When the CD30 concentration in the sample determined in (2) is compared with a reference value and the CD30 concentration is higher than the reference value, the prognosis after bone marrow transplantation is determined to be poor, and the CD30 concentration If is lower than the reference value, determining that the patient has a good prognosis after bone marrow transplantation.
通常、骨髄移植は、移植に先立ち病態を安定化させるために、化学療法、またはＣＨＯＰ療法［（i）アドリアシン（ドキソルビシン、慣用名：アドリアマイシン、抗がん剤抗生物質）、(ii)エンドキサン（シクロホスファミド、アルキル化剤）、(iii)オンコビン（ビンクリスチン、植物アルカロイド）、(iv)プレドニゾロン（プレドニン、副腎皮質ホルモン剤）の４剤を組み合わせて治療を行う方法］等の治療を行って病態を安定させ、移植の数日前に抗がん剤や放射線による前処理により骨髄中の細胞を死滅させた後に行われる。 Bone marrow transplantation usually involves chemotherapy or CHOP therapy [(i) adriacin (doxorubicin, common name: adriamycin, anticancer antibiotic), (ii) endoxan (cyclohexane) to stabilize the pathology prior to transplantation. Pathologic conditions after treatment such as (phosphamide, alkylating agent), (iii) oncobin (vincristine, plant alkaloid), (iv) prednisolone (predonin, corticosteroid)) This is performed after cells in the bone marrow are killed by pretreatment with an anticancer drug or radiation several days before transplantation.
上記（３）において、骨髄移植後の予後を判定するための基準値は、骨髄移植後の予後が良好な患者と予後が不良な患者とを母集団として、各々の母集団のＣＤ３０濃度から適宜決めることができるが、通常、１５０〜２００Ｕ／ｍＬである。例えば、骨髄移植前の急性型又はリンパ腫型ＡＴＬと判定された患者より採取された試料中のＣＤ３０濃度が４４２Ｕ／ｍＬ以上では、骨髄移植後の予後が不良と判定でき、１１１Ｕ／ｍＬ以下であれば、骨髄移植後の予後が良好と判定することができる。 In the above (3), the reference value for determining the prognosis after bone marrow transplantation is appropriately determined from the CD30 concentration of each population with patients having a good prognosis after bone marrow transplantation and patients having a poor prognosis as a population. Although it can be determined, it is usually 150 to 200 U / mL. For example, if the CD30 concentration in a sample collected from a patient determined to be acute type or lymphoma type ATL before bone marrow transplantation is 442 U / mL or more, the prognosis after bone marrow transplantation can be determined to be poor, and if it is 111 U / mL or less. For example, it can be determined that the prognosis after bone marrow transplantation is good.
［くすぶり型又は慢性型ＡＴＬ患者における急性転化を判定する方法］
慢性型ＡＴＬ、くすぶり型ＡＴＬは一般的に無治療で経過観察が行われるが、リンパ腫型や急性型に急性転化する。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。
[Method for determining acute transformation in smoldering or chronic ATL patients]
Chronic ATL and smoldering ATL are generally followed up without treatment, but are acutely transformed into lymphoma type or acute type. 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.
本発明において、くすぶり型又は慢性型ＡＴＬ患者における急性転化の判定は、例えば以下の工程を含有する方法により行うことが出来る。
（１）くすぶり型又は慢性型ＡＴＬと判定された患者より採取された試料を用いて、当該試料中のＣＤ３０を測定する工程；
（２）予め作成したＣＤ３０濃度と情報量との関係を表す検量線と、（１）での測定値とから、当該試料中のＣＤ３０濃度を決定する工程；
（３）（２）で決定した当該試料中のＣＤ３０濃度を基準値と照らし合わせて、ＣＤ３０濃度が当該基準値よりも高い場合、当該患者を急性転化が進行したと判定し、ＣＤ３０濃度が当該基準値よりも低い場合、当該患者を急性転化が進行していないと判定する工程。
In the present invention, the determination of acute conversion in a smoldering or chronic ATL patient can be performed, for example, by a method including the following steps.
(1) a step of measuring CD30 in a sample collected from a patient determined to be smoldering or chronic ATL;
(2) A step of determining the CD30 concentration in the sample from a calibration curve representing the relationship between the CD30 concentration prepared in advance and the information amount, and the measured value in (1);
(3) When the CD30 concentration in the sample determined in (2) is compared with a reference value, and the CD30 concentration is higher than the reference value, it is determined that the patient has undergone acute transformation, and the CD30 concentration is A step of determining that the patient is not undergoing acute transformation when the reference value is lower than the reference value;
くすぶり型又は慢性型ＡＴＬ患者における急性転化は基準値を基に判定することができ、該患者より採取された試料中のＣＤ３０濃度そのものからも、該ＣＤ３０濃度の基準値に対する割合からも判定することができる。くすぶり型又は慢性型ＡＴＬ患者より採取された試料中のＣＤ３０濃度の基準値に対する割合は、２．０倍以上、好ましくは３．０倍以上、より好ましくは４．０倍以上である。また、くすぶり型又は慢性型ＡＴＬ患者より採取された試料中のＣＤ３０濃度の基準値は、４００Ｕ／ｍＬ以上、好ましくは６００Ｕ／ｍＬ以上、より好ましくは８００Ｕ／ｍＬ以上である。 Acute transformation in smoldering or chronic ATL patients can be determined based on the reference value, and can be determined from the CD30 concentration itself in the sample collected from the patient or from the ratio of the CD30 concentration to the reference value. Can do. The ratio of the CD30 concentration in the sample collected from the smoldering type or chronic type ATL patient to the reference value is 2.0 times or more, preferably 3.0 times or more, more preferably 4.0 times or more. In addition, the reference value of the CD30 concentration in a sample collected from a smoldering or chronic ATL patient is 400 U / mL or more, preferably 600 U / mL or more, more preferably 800 U / mL or more.
［くすぶり型又は慢性型ＡＴＬ患者が急性転化したときの治療方針を決定する方法］
本発明において、くすぶり型又は慢性型ＡＴＬ患者における治療開始時期の決定は、例えば以下の工程を含有する方法により行うことが出来る。
（１）くすぶり型又は慢性型ＡＴＬと判定された患者より採取された試料を用いて、当該試料中のＣＤ３０と、ＩＬ−２Ｒ及び／又はＬＤＨ活性とを測定する工程；
（２）予め作成したＣＤ３０濃度と情報量との関係を表す検量線と、（１）でのＣＤ３０の測定値とから、当該試料中のＣＤ３０濃度を決定する工程；
（３）（２）で決定した当該試料中のＣＤ３０濃度を基準値と照らし合わせて、ＣＤ３０濃度が当該基準値よりも高い場合、当該患者を急性転化したと判定し、ＣＤ３０濃度が当該基準値よりも低い場合、当該患者を急性転化していないと判定する工程；
（４）（３）で急性転化したと判定された患者について、（１）でのＩＬ−２Ｒの測定値の、くすぶり型又は慢性型ＡＴＬと判定されたときのＩＬ−２Ｒの測定値に対する割合（基準値）、及び／又は、（１）でのＬＤＨ活性の測定値の、くすぶり型又は慢性型ＡＴＬと判定されたときのＬＤＨ活性の測定値に対する割合（基準値）を算出する工程；及び
（５）（４）で算出された割合に基づいて、急性転化と判定された患者の急性転化後の治療方針を決定する工程。
[Method for determining treatment policy when smoldering or chronic ATL patient is acutely transformed]
In the present invention, the determination of the treatment start time in a smoldering or chronic ATL patient can be performed, for example, by a method including the following steps.
(1) a step of measuring CD30 and IL-2R and / or LDH activity in a sample collected from a patient determined to be smoldering or chronic ATL;
(2) A step of determining the CD30 concentration in the sample from a calibration curve representing the relationship between the CD30 concentration prepared in advance and the information amount, and the measured value of CD30 in (1);
(3) When the CD30 concentration in the sample determined in (2) is compared with the reference value, and the CD30 concentration is higher than the reference value, it is determined that the patient has been acutely converted, and the CD30 concentration is the reference value. If lower than determining that the patient is not acutely transformed;
(4) The ratio of the measured value of IL-2R in (1) to the measured value of IL-2R when determined to be smoldering type or chronic type ATL for the patient determined to be acutely converted in (3) (Reference value) and / or calculating the ratio (reference value) of the measured value of LDH activity in (1) to the measured value of LDH activity when determined as smoldering type or chronic type ATL; and (5) A step of determining a treatment policy after acute change of a patient determined to be acute change based on the ratio calculated in (4).
上記（３）におけるＣＤ３０濃度に係る基準値は、前記くすぶり型又は慢性型ＡＴＬ患者における急性転化を判定する方法の基準値を用いることができる。また、（４）におけるＩＬ−２Ｒに係る基準値は、１．５以上であり、２．０以上が好ましく、３．０以上がより好ましい。また、ＬＤＨ活性に係る基準値は、１．５以上であり、２．０以上が好ましい。 As the reference value relating to the CD30 concentration in the above (3), the reference value of the method for determining the acute change in the smoldering type or chronic type ATL patient can be used. Moreover, the reference value concerning IL-2R in (4) is 1.5 or more, preferably 2.0 or more, and more preferably 3.0 or more. Moreover, the reference value regarding LDH activity is 1.5 or more, and preferably 2.0 or more.
上記（４）において、ＩＬ−２ＲまたはＬＤＨ活性に係る基準値を超えない場合は、弱めの治療を施せばよく、当該基準値を超える場合は強めの治療を施す必要がある。弱めの治療としては、３週間隔で投与するＣＯＰ療法、ＴＨＰ−ＣＨＯＰ療法［ＣＨＯＰ療法のアドリアマイシンをピラルビシンに置き換えた方法］等が挙げられ、強めの治療としては、２週間隔ＣＨＯＰ療法やＬＳＧ１５（Leukemia Study Group 15）療法等が挙げられる。 In the above (4), if the reference value for IL-2R or LDH activity is not exceeded, a weaker treatment may be applied, and if the reference value is exceeded, a stronger treatment is required. Examples of weaker treatment include COP therapy administered at intervals of 3 weeks, THP-CHOP therapy [method in which adriamycin in CHOP therapy is replaced with pirarubicin], etc., and examples of stronger treatment include 2-week interval CHOP therapy and LSG15 ( Leukemia Study Group 15) and the like.
本発明において使用される試料は、被検者より採取された試料であって、ＣＤ３０、ＩＬ−２Ｒ及びＬＤＨ活性が測定され得る試料であれば特に制限はないが、血漿、血清等が好ましい。 The sample used in the present invention is a sample collected from a subject and is not particularly limited as long as CD30, IL-2R and LDH activities can be measured, but plasma, serum and the like are preferable.
本発明において、試料中のＣＤ３０、ＩＬ−２Ｒ及びＬＤＨ活性の測定は、例えば公知の方法およびキットを用いることにより行うことができる。 In the present invention, CD30, IL-2R and LDH activities in a sample can be measured by using, for example, known methods and kits.
当該測定方法としては、生体試料中のＣＤ３０、ＩＬ−２Ｒ又はＬＤＨ活性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、酵素学的測定方法等が挙げられる。 The measurement method is not particularly limited as long as it can measure CD30, IL-2R or LDH activity in a biological sample, and examples thereof include an immunological measurement method and an enzymatic 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（Luminescent immunoassay）、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), luminescence immunoassay (Luminescent immunoassay), physicochemical assay [turbidimetric immunoassay (TIA), latex agglutination method (LAPIA), microparticle counting immunoagglutination assay (PCIA)], The Western blotting method and the like can be mentioned, but the ELISA method is preferably used [Monoclonal antibody experiment manual (Kodansha Scientific, 1987), Secondary Biochemistry Laboratory Lecture 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.
酵素学的測定法としては、任意の公知の酵素学的測定方法があげられる。 Examples of the enzymatic measurement method include any known enzymatic measurement method.
ＣＤ３０測定用試薬を含有する本発明のキットは、ＨＴＬＶ−１キャリアにおけるＡＴＬ発症リスクの判定、ＡＴＬ患者における骨髄移植後の予後判定、くすぶり型又は慢性型のＡＴＬ患者におけるＡＴＬの急性転化の予測に用いることができ、ＣＤ３０測定用試薬及びＩＬ−２Ｒ測定用試薬又はＬＤＨ活性測定用試薬を含有する本発明のキットは、くすぶり型又は慢性型のＡＴＬ患者における急性転化後の治療方針の決定に用いることができる。 The kit of the present invention containing a reagent for measuring CD30 is used to determine the risk of developing ATL in an HTLV-1 carrier, to determine the prognosis after bone marrow transplantation in an ATL patient, and to predict the acute conversion of ATL in a smoldering or chronic ATL patient. The kit of the present invention, which can be used and contains a reagent for measuring CD30 and a reagent for measuring IL-2R or a reagent for measuring LDH activity, is used for determining a therapeutic strategy after blast crisis in smoldering or chronic ATL patients be able to.
ＣＤ３０測定用試薬としては、ＣＤ３０に特異的に結合する第１の抗体が結合した固相、及びＣＤ３０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ＣＤ３０の抗原決定部位と、第２の抗体におけるＣＤ３０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。 As a reagent for measuring CD30, a reagent comprising a solid phase bound to a first antibody that specifically binds to CD30, and a labeled second antibody bound to a second antibody that specifically binds to CD30. It can be illustrated. The antigen determining site of CD30 in the first antibody and the antigen determining site of CD30 in the second antibody may be the same or different. 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、ＣＤ３０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）、ラッテクス、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などがあげられる。 The solid phase is not particularly limited as long as it immobilizes the first antibody and enables immunoassay of CD30. For example, a polystyrene plate such as a microtiter plate, glass or synthetic resin is used. Examples include particles (beads), glass or synthetic resin spheres (balls), latex, magnetic particles, various membranes such as nitrocellulose membrane, and synthetic resin test tubes.
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ＣＤ３０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ＣＤ３０測定用試薬を用いることにより、試料中のＣＤ３０を測定することができる。試料中のＣＤ３０濃度は、例えば以下の工程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ＣＤ３０とを反応させて、固相上に第１の抗体−ＣＤ３０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−ＣＤ３０−標識化第２抗体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−ＣＤ３０−標識化第２抗体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ＣＤ３０濃度と標識量との関係を表す検量線とから、該試料中のＣＤ３０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 CD30 in the sample and the antibody on the solid phase. This is preferable. By using this CD30 measurement reagent, CD30 in the sample can be measured. The concentration of CD30 in the sample can be determined, for example, by a method including the following steps.
[1] A step of reacting a first antibody bound on a solid phase with CD30 in a sample to form a first antibody-CD30 complex on the solid phase;
[2] A step of reacting the complex produced in step [1] with the labeled second antibody to form a first antibody-CD30-labeled second antibody complex 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 first antibody-CD30-labeled second antibody complex produced on the solid phase after the step [3];
[5] A step of determining the CD30 concentration in the sample from the measurement value in the step [4] and a calibration curve representing the relationship between the CD30 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ＣＤ３０濃度を決定するに際して使用する検量線は、既知濃度のＣＤ３０を用いて作成することができる。すなわち、既知濃度のＣＤ３０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ＣＤ３０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ＣＤ３０濃度を決定することができる。 A calibration curve used in determining the CD30 concentration in a sample can be prepared using a known concentration of CD30. That is, a calibration curve can be created by subjecting a sample containing a known concentration of CD30 to, for example, the measurement method described above and correlating the obtained information amount with the CD30 concentration. Here, examples of the information amount include absorbance, fluorescence intensity, emission intensity, radioactivity, and turbidity. The CD30 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ＣＤ３０の測定においては、市販のＣＤ３０測定用キットを用いることもできる。市販のＣＤ３０測定用キットとしては、例えばhuman sCD30 ELISA(Bender MedSystems社製)等を挙げることができる。 In preparing a calibration curve and measuring CD30 in a sample, a commercially available CD30 measurement kit can also be used. Examples of commercially available CD30 measurement kits include human sCD30 ELISA (manufactured by Bender MedSystems).
本発明において、試料中のＩＬ−２Ｒは、ＩＬ−２Ｒ測定用試薬を用いて測定することができる。ＩＬ−２Ｒ測定用試薬としては、例えばＩＬ−２Ｒに特異的に結合する第１の抗体が結合した固相、及びＩＬ−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ＩＬ−２Ｒの抗原決定部位と、第２の抗体におけるＩＬ−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, IL-2R in a sample can be measured using a reagent for measuring IL-2R. As a reagent for measuring IL-2R, for example, a solid phase in which a first antibody that specifically binds to IL-2R is bound, and a label in which a label is bound to a second antibody that specifically binds to IL-2R A reagent containing the second antibody can be exemplified. The antigen-determining site of IL-2R in the first antibody and the antigen-determining site of IL-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、例えば前述の標識等が挙げられる。 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、ＩＬ−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、例えば前述の固相等が挙げられる。 The solid phase is not particularly limited as long as the first antibody is immobilized and an IL-2R immunoassay is possible, 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ＩＬ−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ＩＬ−２Ｒ測定用試薬を用いることにより、試料中のＩＬ−２Ｒを測定することができる。試料中のＩＬ−２Ｒ濃度は、例えば上記のＣＤ３０濃度測定方法と同様の方法で測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 IL-2R in the sample and the antibody on the solid phase. This is preferable because it can be removed. By using this IL-2R measurement reagent, IL-2R in the sample can be measured. The IL-2R concentration in the sample can be measured, for example, by the same method as the CD30 concentration measuring method described above.
検量線作成および試料中のＩＬ−２Ｒの測定においては、市販のＩＬ−２Ｒ測定用キットを用いることもできる。市販のＩＬ−２Ｒ測定用キットとしては、例えばセルフリー(R)ＩＬ−２Ｒメデックス（協和メデックス株式会社製）等が挙げられる。 In preparing a calibration curve and measuring IL-2R in a sample, a commercially available kit for measuring IL-2R can also be used. Examples of commercially available kits for measuring IL-2R include Cell Free (R) IL-2R Medex (manufactured by Kyowa Medex Co., Ltd.).
ＬＤＨ活性測定用試薬を用いたＬＤＨ活性の測定方法としては、ピルビン酸から乳酸への反応を利用したWroblewski-LaDue法や、Ｌ−乳酸からピルビン酸への反応を利用したＩＦＣＣ（国際臨床化学連合）勧告法やＪＳＣＣ（日本臨床化学会）常用基準法がある。ピルビン酸から乳酸への反応は、検体中のＬＤＨがＮＡＤＨ［ニコチンアミドアデニンジヌクレオチド（還元型）］の存在下でピルビン酸と反応し、乳酸とＮＡＤ＋［ニコチンアミドアデニンジヌクレオチド（酸化型）］へと変化することを利用し、このときのＮＡＤＨの減少速度を測定することでＬＤ活性を測定することができる。 As a method for measuring LDH activity using a reagent for measuring LDH activity, the Wroblewski-LaDue method using a reaction from pyruvic acid to lactic acid, or IFCC (international clinical chemistry association using a reaction from L-lactic acid to pyruvic acid). ) There are recommended law and JSCC (Japanese Society of Clinical Chemistry) common reference law. In the reaction from pyruvic acid to lactic acid, LDH in the sample reacts with pyruvic acid in the presence of NADH [nicotinamide adenine dinucleotide (reduced form)], and lactic acid and NAD + [nicotinamide adenine dinucleotide (oxidized form) The LD activity can be measured by measuring the decrease rate of NADH at this time.
Ｌ−乳酸からピルビン酸への反応は、検体中のＬＤＨがＮＡＤ＋の存在下で乳酸と反応し、ピルビン酸とＮＡＤＨへと変化することを利用し、このときのＮＡＤＨの増加速度を測定することでＬＤＨ活性を測定することができる。 The reaction from L-lactic acid to pyruvic acid utilizes the fact that LDH in the sample reacts with lactic acid in the presence of NAD + and changes to pyruvic acid and NADH, and the rate of increase of NADH at this time is measured. Thus, LDH activity can be measured.
検量線作成および試料中のＬＤＨ活性の測定においては、市販のＬＤＨ活性測定キットを用いることもできる。市販のＬＤＨ活性測定キットとしては、例えばデタミナー(R)ＬＤ（協和メデックス株式会社製）等が挙げられる。 In preparing a calibration curve and measuring LDH activity in a sample, a commercially available kit for measuring LDH activity can also be used. Commercially available LDH activity measurement kit, for example Determiner (R) LD (manufactured by Kyowa Medex Co., Ltd.) and the like.
このように、試料中のＣＤ３０を測定することにより、ＨＴＬＶ−１キャリアにおけるＡＴＬ発症リスク、ＡＴＬ患者における骨髄移植後の予後、及び、くすぶり型又は慢性型のＡＴＬ患者におけるＡＴＬの急性転化の判定ができる。さらにくすぶり型又は慢性型のＡＴＬ患者より採取された試料中のＣＤ３０と共に、ｓＩＬ−２Ｒ及び／又はまたはＬＤＨ活性を測定することにより、急性転化した患者に対する治療方針を決定することができる。このことは、ＣＤ３０が、ＨＴＬＶ−１キャリアにおけるＡＴＬ発症リスク判定用マーカー、ＡＴＬ患者における骨髄移植後の予後判定用マーカー、くすぶり型又は慢性型のＡＴＬ患者における急性転化判定用マーカーとして機能し得ることを意味する。 Thus, by measuring CD30 in a sample, it is possible to determine the risk of ATL onset in HTLV-1 carriers, the prognosis after bone marrow transplantation in ATL patients, and the acute conversion of ATL in smoldering or chronic ATL patients it can. Furthermore, by measuring sIL-2R and / or LDH activity together with CD30 in samples collected from smoldering or chronic ATL patients, it is possible to determine a treatment strategy for patients who have become acutely converted. This means that CD30 can function as a marker for determining the risk of developing ATL in HTLV-1 carriers, a marker for determining the prognosis after bone marrow transplantation in ATL patients, and a marker for determining acute change in smoldering or chronic ATL patients. Means.
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。
本実施例においては、以下のメーカーの試薬類を使用した［human sCD30 ELISA(Bender MedSystems社製)］。
EXAMPLES Hereinafter, although an Example demonstrates this invention, this invention is not limited to this Example.
In this example, reagents from the following manufacturers were used [human sCD30 ELISA (manufactured by Bender MedSystems)].
ＨＴＬＶ−１キャリア１７症例のｓＣＤ３０濃度とｓＩＬ-２Ｒ濃度
インフォームドコンセントを得たＨＴＬＶ−１キャリア１７人（ＨＴＬＶ−１感染以外に疾患に罹患していない人）の血清中のｓＣＤ３０濃度を、ｓＣＤ３０測定用キット［human sCD30 ELISA(Bender MedSystems社製)］、および可溶性ＩＬ−２Ｒ測定キット[セルフリー(R)ＩＬ−２Ｒメデックス（協和メデックス社製）]を用いて測定した。また、１７名のｓＣＤ３０およびｓＩＬ−２Ｒの測定値が正規分布であることを確認した後、この群より平均値と標準偏差（ＳＤ）を算出した。その結果を表１に示す。
SCD30 concentration and sIL-2R concentration in 17 cases of HTLV-1 carrier The sCD30 concentration in the serum of 17 HTLV-1 carriers who obtained informed consent (who are not affected by a disease other than HTLV-1 infection) Measurement was performed using a measurement kit [human sCD30 ELISA (manufactured by Bender MedSystems)] and a soluble IL-2R measurement kit [Cell-Free (R) IL-2R Medex (manufactured by Kyowa Medex)]. In addition, after confirming that the measured values of sCD30 and sIL-2R of 17 subjects were normal distribution, an average value and a standard deviation (SD) were calculated from this group. The results are shown in Table 1.
ｓＣＤ３０測定キット[human sCD30 ELISA]の添付文書に記載された健常人のｓＣＤ３０基準値の上限（平均＋２ＳＤ）は、９４．７Ｕ／ｍＬ、可溶性ＩＬ−２Ｒの基準値は２２０〜５３０Ｕ／ｍＬ(株式会社エスアールエルの検査案内書を参照)であった。１７症例のｓＣＤ３０値はいずれも基準値である９４．７Ｕ／ｍＬ以下で、発症リスクが低いと判断される。一方、ＩＬ−２Ｒ値は、１７症例のうち６症例で基準値を超えていた。１７名のＨＴＬＶ−１キャリアはいずれもＡＴＬを発症していないが、ＩＬ−２Ｒ値を指標とした場合、基準値を超えている人がいる。 The upper limit (average + 2SD) of the sCD30 standard value of healthy persons described in the package insert of the sCD30 measurement kit [human sCD30 ELISA] is 94.7 U / mL, and the standard value of soluble IL-2R is 220 to 530 U / mL (stock) (See the inspection guide of SRL). The sCD30 value of 17 cases is 94.7 U / mL or less which is the reference value, and it is judged that the risk of onset is low. On the other hand, the IL-2R value exceeded the reference value in 6 out of 17 cases. None of the 17 HTLV-1 carriers have developed ATL, but when the IL-2R value is used as an index, there are people who exceed the reference value.
ＩＬ−２Ｒ濃度は、ＡＴＬを発症していないＨＴＬＶ−１キャリアであっても基準値を超えており、誤って発症のリスクが高いと判断してしまう恐れがある。一方、ｓＣＤ３０濃度は、１７症例における濃度がいずれも健常人の基準値以下でありＡＴＬ発症リスクが低いことを証明している。つまり、この結果は、ＨＴＬＶ−１キャリアより採取された試料中のｓＣＤ３０を測定することでＡＴＬ発症リスクを判定できることを示している。 The IL-2R concentration exceeds the reference value even in an HTLV-1 carrier that does not develop ATL, and there is a possibility that it is erroneously determined that the risk of developing is high. On the other hand, the sCD30 concentration proves that the concentrations in 17 cases are all below the reference value of healthy individuals and the risk of developing ATL is low. That is, this result indicates that the risk of developing ATL can be determined by measuring sCD30 in a sample collected from an HTLV-1 carrier.
ＨＴＬＶ−１キャリアのＡＴＬ発症例および未発症例のモニター
ＨＴＬＶ−１キャリアの血液中のｓＣＤ３０濃度とｓＩＬ−２Ｒ濃度をモニターした結果を表２および図１に示す。日数とは、ｓＣＤ３０濃度及びｓＩＬ−２Ｒ濃度の追跡調査を始めた日を基準（０日）とした時の相対的な日数を示す。
Monitoring of HTLV-1 Carrier ATL Onset and Non-Affected Cases Table 2 and FIG. 1 show the results of monitoring sCD30 concentration and sIL-2R concentration in the blood of HTLV-1 carrier. The number of days indicates the relative number of days when the day when the follow-up of the sCD30 concentration and the sIL-2R concentration is started is defined as the reference (day 0).
３３６日目で、ＡＴＬを発症していないＨＴＬＶ−１キャリアの血液中のｓＣＤ３０濃度は、健常人基準値上限である９４．７Ｕ／ｍＬを越えていないことが分かる。 On day 336, it can be seen that the sCD30 concentration in the blood of the HTLV-1 carrier that does not develop ATL does not exceed the upper limit of 94.7 U / mL, which is the upper limit of the normal healthy subject.
急性型ＡＴＬ患者、リンパ腫型ＡＴＬ患者、慢性型ＡＴＬ患者の血清中のｓＣＤ３０濃度
インフォームドコンセントを得た、急性型ＡＴＬ７症例、リンパ腫型ＡＴＬ４症例、慢性型ＡＴＬ２症例の血清中のｓＣＤ３０濃度を、ｓＣＤ３０測定用キットを用いて測定し、その結果を表３に示した。
SCD30 concentration in serum of acute type ATL patient, lymphoma type ATL patient, chronic type ATL patient sCD30 concentration in serum of acute type ATL7 case, lymphoma type ATL4 case, chronic type ATL2 case obtained informed consent was expressed as sCD30. The measurement was performed using a measurement kit, and the results are shown in Table 3.
急性型７症例は１１５４〜１４９００Ｕ／ｍＬ、リンパ腫型は４１５〜９５３３Ｕ／ｍＬ、慢性型は３１４〜３６９Ｕ／ｍＬであった。実施例１で示したとおり、健常人のｓＣＤ３０基準値の上限（平均＋２ＳＤ）は、９４．７Ｕ／ｍＬ、ＨＴＬＶキャリアのｓＣＤ３０の上限（平均＋２ＳＤ）は、９７．７Ｕ／ｍＬであり、急性型、リンパ腫型及び慢性型ＡＴＬ患者のｓＣＤ３０濃度は何れも健常人及びＨＴＬＶキャリアのｓＣＤ３０濃度の上限を超えていた。 Seven acute cases were 1154-14900 U / mL, lymphoma types were 415-9533 U / mL, and chronic types were 314-369 U / mL. As shown in Example 1, the upper limit (average + 2SD) of sCD30 reference values of healthy persons is 94.7 U / mL, and the upper limit of sCD30 of HTLV carriers (average + 2SD) is 97.7 U / mL. The sCD30 concentration in lymphoma type and chronic ATL patients exceeded the upper limit of the sCD30 concentration in healthy subjects and HTLV carriers.
インフォームドコンセントを得たＡＴＬ患者４症例（患者Ａ、Ｂ、Ｅ、Ｖ）について、骨髄移植前のｓＣＤ３０濃度およびｓＩＬ−２Ｒ濃度を測定し、移植後の患者の状態を観察した。その結果を第４表〜第７表、および第２図〜第５図に示す。第４表〜第７表における移植後日数とは、移植日を基準（０日）とした時の相対的な日数を示す。また、化学療法（先がダイヤ型の矢印）、ＣＨＯＰ療法（実線矢印）、前処理（点線矢印）が施された日を、図に矢印で示した。 For four ATL patients (patients A, B, E, and V) who obtained informed consent, sCD30 and sIL-2R concentrations before bone marrow transplantation were measured, and the patient's condition after transplantation was observed. The results are shown in Tables 4 to 7 and FIGS. 2 to 5. The number of days after transplantation in Tables 4 to 7 indicates the relative number of days when the date of transplantation is used as a reference (0 day). In addition, the days on which chemotherapy (pointed with diamond-shaped arrows), CHOP therapy (solid arrows), and pretreatment (dotted arrows) were performed are indicated by arrows in the figure.
患者Ａ（表４、図２）は、化学療法中のｓＣＤ３０濃度が７４１〜８０８Ｕ／ｍＬと基準値よりもはるかに高い値を示した。移植６日前に前処理が施され移植が行われた。その後、既存マーカーであるｓＩＬ−２Ｒ濃度は落ち着いていたが、移植後５２日目にｓＩＬ−２Ｒ濃度が急激に上昇し、移植後９９日目に死亡した。 Patient A (Table 4, FIG. 2) showed sCD30 concentrations during chemotherapy of 741-808 U / mL, much higher than the baseline value. Pretreatment was performed 6 days before transplantation, and transplantation was performed. Thereafter, although the existing marker sIL-2R concentration was calm, the sIL-2R concentration rapidly increased 52 days after transplantation, and died 99 days after transplantation.
患者Ｂ（表５、図３）は、化学療法中のｓＣＤ３０濃度が２７８８Ｕ／ｍＬと基準値よりもはるかに高い値を示した。移植７日前に前処置が施され、骨髄移植が行われた。移植後２０日目、ｓＩＬ−２Ｒ濃度、ｓＣＤ３０濃度はいずれも高値を示していた。移植後６４日目に死亡した。 Patient B (Table 5, FIG. 3) showed a sCD30 concentration during chemotherapy of 2788 U / mL, much higher than the baseline value. Pretreatment was performed 7 days before transplantation, and bone marrow transplantation was performed. On day 20 after transplantation, both sIL-2R concentration and sCD30 concentration showed high values. Died 64 days after transplantation.
患者Ｅ（表６、図４）は、移植１１７日前、９７日前、７６日前に化学療法を、移植５０日前にＣＨＯＰ療法を行った。前処置直前のｓＣＤ３０濃度は２３８４Ｕ／ｍＬと基準値をはるかに超える値を示した。移植８日前に前処置が施され、骨髄移植が行われた。移植後３２日目に死亡した。 Patient E (Table 6, FIG. 4) received chemotherapy 117 days, 97 days, and 76 days before transplantation, and CHOP therapy 50 days before transplantation. The sCD30 concentration just before the pretreatment was 2384 U / mL, a value far exceeding the reference value. Pretreatment was performed 8 days before transplantation, and bone marrow transplantation was performed. Died 32 days after transplantation.
患者Ｖ（表７、図５）は、化学療法中のｓＣＤ３０濃度が９３２Ｕ／ｍＬと基準値よりもはるかに高い値を示した。移植７日前に前処置が施され、骨髄移植が行われた。移植後４１日目以降、ｓＩＬ−２Ｒ濃度、ｓＣＤ３０濃度はいずれも高値を示していた。移植後５８日目に死亡した。 Patient V (Table 7, FIG. 5) showed a sCD30 concentration during chemotherapy of 932 U / mL, a value much higher than the baseline value. Pretreatment was performed 7 days before transplantation, and bone marrow transplantation was performed. From the 41st day after transplantation, both sIL-2R concentration and sCD30 concentration showed high values. Died 58 days after transplantation.
患者Ｗ（表８、図６）は、化学療法中のｓＣＤ３０濃度が４４２Ｕ／ｍＬと基準値よりもはるかに高い値を示した。移植７日前に前処置が施され、骨髄移植が行われた。移植後５６日目に死亡した。 Patient W (Table 8, FIG. 6) showed a sCD30 concentration during chemotherapy of 442 U / mL, a value much higher than the reference value. Pretreatment was performed 7 days before transplantation, and bone marrow transplantation was performed. Died 56 days after transplantation.
患者ＡＦ（表９、図７）は、化学療法中のｓＣＤ３０濃度が７２０Ｕ／ｍＬと基準値よりもはるかに高い値を示した。移植５日前に前処置が施され、骨髄移植が行われた。移植後１４日目に死亡した。 Patient AF (Table 9, FIG. 7) showed a sCD30 concentration during chemotherapy of 720 U / mL, a value much higher than the reference value. Pretreatment was performed 5 days before transplantation, and bone marrow transplantation was performed. Died 14 days after transplantation.
患者Ｇ（表１０、図８）は、化学治療中のｓＣＤ３０濃度が１１１Ｕ／ｍＬと健常人の基準値の上限付近の値となっていた。移植４日前に前処理が施され、骨髄移植が行われた。移植後１９０日目まで、ｓＣＤ３０濃度は２００Ｕ／ｍＬ以下で落ち着いており、容態も安定していた。移植後４４２日目現在も容態は安定しており、生存している。ｓＩＬ−２Ｒは移植後に免疫反応の影響を受けるため２１２５Ｕ／ｍＬと高値であった。 In patient G (Table 10, FIG. 8), the sCD30 concentration during chemotherapy was 111 U / mL, which was a value near the upper limit of the reference value for healthy individuals. Pretreatment was performed 4 days before transplantation, and bone marrow transplantation was performed. Until 190 days after transplantation, the sCD30 concentration was stable at 200 U / mL or less, and the condition was stable. The condition is stable and alive as of 442 days after transplantation. Since sIL-2R was affected by immune reaction after transplantation, it was as high as 2125 U / mL.
これらの結果をまとめると、骨髄移植前（前処置直前）にｓＣＤ３０濃度を測定し、２００Ｕ／ｍＬ以上であれば、骨髄移植後の予後は不良となり、２００Ｕ／ｍＬ以下であれば骨髄移植後の予後が良好であると判定することができる。すなわち、骨髄移植前にｓＣＤ３０濃度を測定することで、骨髄移植後の予後を判定することができる。 To summarize these results, the sCD30 concentration was measured before bone marrow transplantation (immediately before the pretreatment). If it was 200 U / mL or more, the prognosis after bone marrow transplantation was poor. It can be determined that the prognosis is good. That is, the prognosis after bone marrow transplantation can be determined by measuring the sCD30 concentration before bone marrow transplantation.
ｓＩＬ−２Ｒは、ＡＴＬにおいて病態を把握する指標として用いられている。しかしながら、ｓＩＬ−２Ｒは腫瘍細胞数を反映すると同時に、生体内における免疫反応の活性化も反映しているため、ＡＴＬやリンパ腫特異的な指標とはならない。また、慢性関節リウマチや間質性肺炎、Ｃ型肝炎患者では、ｓＩＬ−２Ｒ値が基準値を遙かに超えて数千Ｕ／ｍＬを示す事があることが報告されている。このため、骨髄移植前のｓＩＬ−２Ｒ濃度を測定することで、誤って予後が悪いと判断してしまう恐れがある。よって、ｓＩＬ-２Ｒ濃度を測定するのと同時にｓＣＤ３０濃度を測定することで、ｓＩＬ−２Ｒ濃度を単独で測定するよりも優れた予後判定ができる。 sIL-2R is used as an index for grasping a disease state in ATL. However, since sIL-2R reflects the number of tumor cells and also the activation of immune response in vivo, it is not an index specific to ATL or lymphoma. In addition, it has been reported that sIL-2R value far exceeds the reference value and shows several thousand U / mL in patients with rheumatoid arthritis, interstitial pneumonia, and hepatitis C. For this reason, there is a possibility that the prognosis is erroneously determined by measuring the sIL-2R concentration before bone marrow transplantation. Therefore, by measuring the sCD30 concentration at the same time as measuring the sIL-2R concentration, a better prognosis determination can be made than by measuring the sIL-2R concentration alone.
慢性型ＡＴＬから急性転化した患者の血液中ｓＣＤ３０濃度の経時的変化
インフォームドコンセントを得た慢性型ＡＴＬ患者２症例（患者ＡＩ、ＢＡ）について、血液中のＬＤＨ活性、ｓＣＤ３０濃度およびｓＩＬ−２Ｒ濃度を測定し、患者の状態を観察した。その結果を第１１表〜第１２表、および第９図〜第１０図に示す。第１１表〜第１２表における日数とは、ｓＣＤ３０濃度およびｓＩＬ−２Ｒ濃度の観察を開始した日を基準（０日）とした時の相対的な日数を示す。また、第１１表〜第１２表における上昇率とは、慢性型ＡＴＬ患者のｓＣＤ３０濃度を観察し始めた日（０日）のｓＣＤ３０濃度を基準として、それぞれの日数における濃度との比を示している。
Changes in blood sCD30 concentration over time in patients who have been acutely converted from chronic ATL In LD2 activity, sCD30 concentration and sIL-2R concentration in blood for two chronic ATL patients (patient AI, BA) who obtained informed consent And the patient's condition was observed. The results are shown in Tables 11 to 12 and FIGS. 9 to 10. The number of days in Tables 11 to 12 indicates the relative number of days when the day on which the observation of the sCD30 concentration and the sIL-2R concentration is started is used as the reference (day 0). In addition, the rate of increase in Tables 11 to 12 indicates the ratio of the sCD30 concentration on the day when the sCD30 concentration of the chronic ATL patient started to be observed (day 0) to the concentration on each day. Yes.
患者ＢＡ（表１１、図９）は、慢性型ＡＴＬ患者で、５７日目に急性型ＡＴＬと診断された症例であった。 Patient BA (Table 11, FIG. 9) was a chronic ATL patient who was diagnosed with acute ATL on the 57th day.
外来受診で、ｓＣＤ３０濃度を観察し始めて２１日目にＬＤＨが２８０ＩＵ／Ｌと高値を示したため２７日目より入院した。同日（２７日目）の血液検査の結果増悪傾向を示さず、頚部リンパ節腫脹も自然に縮小していたため、２８日目に退院した。５６日目（ｓＣＤ３０は未測定）にＬＤＨが４５０ＩＵ／Ｌと急上昇しため翌５７日目に入院し急性型ＡＴＬと診断された（急性転化）。 At the outpatient visit, he started to observe the sCD30 concentration. On the 21st day, LDH showed a high value of 280 IU / L. The blood test on the same day (day 27) showed no tendency to worsen, and the cervical lymphadenopathy had also shrunk naturally. On day 56 (sCD30 was not measured), LDH rapidly increased to 450 IU / L, and the patient was hospitalized on the next day 57 and diagnosed as acute type ATL (acute change).
ｓＣＤ３０の濃度観測開始後５８日目から１回目の化学療法、７１日目から２回目の化学療法、８４日目より３回目の化学療法を実施した。３回目の化学療法後にＬＤＨの上昇がみられたため１１７日目から４回目の化学療法が実施され軽快したため退院した（寛解はしていない）。その後、通院治療が施され、ＡＴＬ細胞も減少しているが完全寛解には至っていない。 From the 58th day after the start of sCD30 concentration observation, the first chemotherapy, the 71st to 2nd chemotherapy, and the 84th day of the third chemotherapy were performed. Since LDH increased after the third chemotherapy, the fourth chemotherapy was carried out from day 117, and the patient was discharged. Thereafter, treatment was performed and ATL cells decreased, but complete remission was not achieved.
ｓＣＤ３０の濃度観測開始当日（０日目）のｓＣＤ３０が３６９Ｕ／ｍＬ、ｓＩＬ−２Ｒが３７５６Ｕ／ｍＬとＨＴＬＶ−１キャリアの基準値より高い値を示したが、急性型やリンパ腫型のような高値を示していなかった（表３参照）。４２日目で８０７Ｕ／ｍＬ、４９日目で１０４８Ｕ／ｍＬまで上昇し、急性型ＡＴＬと診断された直後の５８日目では１５５４Ｕ／ｍＬとなった。また、慢性型ＡＴＬのｓＣＤ３０濃度の基準値（平均＋２ＳＤ、表３参照）を基準とした上昇率を観察すると、ｓＣＤ３０濃度の上昇率は４２日目で１．９３倍、４９日目で２．５０倍まで上昇し、急性転化が確認された直後の５８日目では３．７１倍まで上昇した。一方、既存マーカーであるｓＩＬ−２Ｒ濃度やＬＤＨ活性の上昇も見られたが、ｓＩＬ−２Ｒ濃度が４２日目で１．５０倍、４９日目で１．６６倍、ＬＤＨ活性が４２日目で１．２２倍、４９日目で１．３６倍であった。既存マーカーであるｓＩＬ−２ＲやＬＤＨ活性に比べてｓＣＤ３０濃度の上昇率は高かった。また、治療を開始した５８日目のＬＤＨ活性およびｓＩＬ−２Ｒ濃度の上昇率は、それぞれ３．１３倍、２．２７倍であった。患者ＢＡは、完全に寛解には至っていないが、ＡＴＬ細胞が減少し慢性型ＡＴＬとなった。 The sCD30 concentration was 369 U / mL and sIL-2R was 3756 U / mL on the day of sCD30 concentration start (day 0), which was higher than the standard value of the HTLV-1 carrier. (See Table 3). It increased to 807 U / mL on Day 42, increased to 1048 U / mL on Day 49, and reached 1554 U / mL on Day 58 immediately after diagnosis of acute ATL. Further, when the rate of increase of sCD30 concentration of chronic type ATL based on the standard value (average + 2SD, see Table 3) was observed, the rate of increase of sCD30 concentration was 1.93 times on the 42nd day and 2.3 on the 49th day. It increased to 50 times, and increased to 3.71 times on the 58th day immediately after the blast crisis was confirmed. On the other hand, sIL-2R concentration and LDH activity, which are existing markers, were also increased, but sIL-2R concentration was 1.50 times on day 42, 1.66 times on day 49, and LDH activity was on day 42 It was 1.22 times and 1.36 times on the 49th day. The increase rate of sCD30 concentration was high compared with existing markers sIL-2R and LDH activity. Moreover, the increase rate of LDH activity and sIL-2R density | concentration on the 58th day which started the treatment was 3.13 times and 2.27 times, respectively. Patient BA was not in complete remission, but had decreased ATL cells and became chronic ATL.
患者ＡＩ（表１２、図１０）は、慢性型ＡＴＬ患者で、１８９日目にリンパ腫型ＡＴＬと診断された症例であった。 Patient AI (Table 12, FIG. 10) was a chronic ATL patient who was diagnosed with lymphoma type ATL on day 189.
担当医による詳細な情報は以下の通りである。
ｓＣＤ３０測定の観察を始める９８日前、胸部異常陰影、末梢血中のＡＴＬ細胞を認め受診を開始した。胸腔鏡下右肺部分切除術の施行後から末梢血中にＡＴＬ細胞が増加し慢性型ＡＴＬと診断された。その後、１６８日目に胸部レントゲンの異常に気づき１６９日目に入院した（この時点で、ＬＤＨの上昇はみられず）。１８９日目に、胸部ＣＴ検査の結果、縦郭と右肺門部のリンパ節腫脹が認められリンパ腫型ＡＴＬと診断された（急性転化）。おそらく１６８〜１８９日目で急性転化したと推測された。
Detailed information by the attending physician is as follows.
98 days before starting the observation of sCD30 measurement, abnormal chest shadows and ATL cells in peripheral blood were observed, and a medical examination was started. From the time of thoracoscopic partial right pneumonectomy, ATL cells increased in peripheral blood and a diagnosis of chronic ATL was made. Later, on day 168, he noticed an abnormality in chest x-rays and was hospitalized on day 169 (at this point no increase in LDH was observed). On day 189, chest CT examination revealed lymph node swelling in the longitudinal and right hilar regions, and a lymphoma type ATL was diagnosed (acute transformation). It was presumed that it had changed acutely on days 168-189.
ＬＳＧ(Leukemia Study Group)１５のプロトコールに従い、１９８日目、２３３日目、２８６日目に、３回の化学療法を行った。同時に肺病変が消失した。３５７日目に完全寛解した。 According to the protocol of LSG (Leukemia Study Group) 15, the chemotherapy was performed 3 times on the 198th, 233th and 286th days. At the same time, the lung lesion disappeared. Complete remission on day 357.
ｓＣＤ３０測定の観察を始めた当日（０日目）のｓＣＤ３０濃度が３１４Ｕ／ｍＬ、ｓＩＬ−２Ｒ濃度が２６９１Ｕ／ｍＬとＨＴＬＶキャリアの基準値より高い値を示したが、急性型やリンパ腫型のような高値を示していなかった（表３参照）。９１日目で６１３Ｕ／ｍＬ、１２６日目で７３５Ｕ／ｍＬ、１６８日目で１９８３Ｕ／ｍＬ、１８０日目に２８３１Ｕ／ｍＬ、急性転化が確認された直前の１８７日目では３５６９Ｕ／ｍＬまで上昇した。また、０日目のｓＣＤ３０濃度を基準とした場合の上昇率を観察すると、ｓＣＤ３０濃度の上昇率は１２６日目で１．７５倍、１６８日目で４．７３倍まで上昇した。一方、既存マーカーであるｓＩＬ−２Ｒ濃度やＬＤＨ活性の上昇はほとんど見られず、ｓＩＬ−２Ｒ濃度が１２６日目で０．９７倍、１６８日目で１．１６倍、ＬＤＨ活性が１２６日目で０．８３倍、１６８日目で０．９２倍であった。ｓＣＤ３０濃度の急激な上昇を確認したことにより確定診断が行われ、リンパ腫型ＡＴＬに急性転化していることが確認された。また、治療を開始する直前の１９７日目のＬＤＨ活性およびｓＩＬ−２Ｒ濃度の上昇率は、それぞれ１．５２倍、１．５４倍であった。３回の化学療法で患者ＡＩの肺病変が完全に消失し、３５７日目に完全寛解した。 The sCD30 concentration on the day (day 0) when observation of sCD30 measurement was started was 314 U / mL, and the sIL-2R concentration was 2691 U / mL, which was higher than the reference value of the HTLV carrier. The high value was not shown (see Table 3). 913 U / mL on day 91, 735 U / mL on day 126, 1983 U / mL on day 168, 2831 U / mL on day 180, and increased to 3569 U / mL on day 187 just before the acute change was confirmed . Further, when the rate of increase when the sCD30 concentration on the 0th day was used as a reference, the rate of increase of the sCD30 concentration increased 1.75 times on the 126th day and 4.73 times on the 168th day. On the other hand, almost no increase in sIL-2R concentration or LDH activity, which is an existing marker, was observed. The sIL-2R concentration was 0.97 times on day 126, 1.16 times on day 168, and LDH activity was on day 126. 0.83 times and 0.92 times on the 168th day. A definitive diagnosis was made by confirming the rapid increase in the sCD30 concentration, and it was confirmed that the sCD30 concentration was acutely transformed into a lymphoma type ATL. Further, the increase rates of LDH activity and sIL-2R concentration on day 197 immediately before the start of treatment were 1.52 times and 1.54 times, respectively. Three times of chemotherapy, the lung lesions of patient AI disappeared completely, and a complete remission was achieved on day 357.
急性転化した２症例の治療効果を比べてみると、患者ＡＩが完全寛解に至ったのに対し、患者ＢＡは完全寛解には至らなかった。両症例の違いを比較してみると、症例ＡＩではＬＤＨ活性およびｓＩＬ−２Ｒ濃度の上昇が起こらないうちに治療を開始しているのに対し、症例ＢＡでは、ＬＤＨ活性の上昇率が２．２７倍、ｓＩＬ−２Ｒ濃度の上昇率が３．１３倍になったときに治療を開始している。ＬＤＨやｓＩＬ−２Ｒは腫瘍細胞数を反映している診断マーカーであるので、腫瘍細胞数が少ない段階で治療を開始した症例ＡＩの方が治療の効果が出たと判断される。つまり、ＬＤＨ活性やｓＩＬ−２Ｒ濃度の上昇率が低い症例の方が、上昇率が高い症例に比べて、同じ化学療法を施行した場合、高い治療効果を期待することができる。また、急性転化が予測され、ＬＤＨ活性やｓＩＬ−２Ｒ濃度の上昇率に応じて治療の強弱を選択することもできる。すなわち、ＬＤＨ活性やｓＩＬ−２Ｒ濃度の上昇率が低いときには弱めの治療でも効果が期待できるが、上昇率が高いときには強めの治療を施す必要がある。このように、ｓＣＤ３０濃度により急性転化が判定できた段階で、ＬＤＨ活性とｓＩＬ−２Ｒ濃度を観察することで、治療法や治療の開始時期などの治療方針を決定することが出来る。 Comparing the therapeutic effects of the two cases that became acute, patient AI reached complete remission, whereas patient BA did not reach complete remission. Comparing the differences between the two cases, treatment started before the increase in LDH activity and sIL-2R concentration in case AI, whereas in case BA, the rate of increase in LDH activity was 2. The treatment is started when the rate of increase in sIL-2R concentration becomes 3.13 times 27 times. Since LDH and sIL-2R are diagnostic markers that reflect the number of tumor cells, it is determined that the treatment effect is more effective in case AI in which treatment is started at a stage where the number of tumor cells is small. That is, in the case where the increase rate of LDH activity and sIL-2R concentration is low, a higher therapeutic effect can be expected when the same chemotherapy is performed compared to the case where the increase rate is high. In addition, acute transformation is predicted, and the strength of treatment can be selected according to the rate of increase in LDH activity and sIL-2R concentration. That is, when the rate of increase in LDH activity or sIL-2R concentration is low, a weaker treatment can be expected, but when the rate of increase is high, it is necessary to give a stronger treatment. In this way, at the stage where sCD30 concentration has determined the acute conversion, the LDH activity and the sIL-2R concentration can be observed to determine the treatment policy such as the treatment method and the start time of treatment.
本発明により、ＨＴＬＶ−１キャリアやＡＴＬ患者のＱＯＬ向上に有用な、ＨＴＬＶ−１キャリアにおけるＡＴＬ発症リスク、ＡＴＬ患者における骨髄移植後の予後、及び、くすぶり型又は慢性型のＡＴＬ患者におけるＡＴＬの急性転化を判定する方法、及び、くすぶり型又は慢性型のＡＴＬ患者における急性転化後の治療方針を決定する方法、並びにこれらの方法に用いるキットが提供される。 INDUSTRIAL APPLICABILITY The present invention is useful for improving QOL of HTLV-1 carriers and ATL patients, risk of developing ATL in HTLV-1 carriers, prognosis after bone marrow transplantation in ATL patients, and acute ATL in smoldering or chronic ATL patients Methods for determining conversion, methods for determining treatment strategies after acute conversion in smoldering or chronic ATL patients, and kits for use in these methods are provided.
Claims (4)
The kit according to claim 3, wherein CD30 is a soluble type.
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