JP2543606B2 - How to determine multiple sclerosis - Google Patents
How to determine multiple sclerosisInfo
- Publication number
- JP2543606B2 JP2543606B2 JP2008047A JP804790A JP2543606B2 JP 2543606 B2 JP2543606 B2 JP 2543606B2 JP 2008047 A JP2008047 A JP 2008047A JP 804790 A JP804790 A JP 804790A JP 2543606 B2 JP2543606 B2 JP 2543606B2
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- Japan
- Prior art keywords
- tnf
- multiple sclerosis
- cerebrospinal fluid
- disease
- measuring
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Links
- 201000006417 multiple sclerosis Diseases 0.000 title claims description 17
- 210000001175 cerebrospinal fluid Anatomy 0.000 claims description 17
- 238000000034 method Methods 0.000 claims description 16
- 101000611183 Homo sapiens Tumor necrosis factor Proteins 0.000 claims description 7
- 102000057041 human TNF Human genes 0.000 claims description 5
- 108060008682 Tumor Necrosis Factor Proteins 0.000 description 34
- 102000000852 Tumor Necrosis Factor-alpha Human genes 0.000 description 34
- MZOFCQQQCNRIBI-VMXHOPILSA-N (3s)-4-[[(2s)-1-[[(2s)-1-[[(1s)-1-carboxy-2-hydroxyethyl]amino]-4-methyl-1-oxopentan-2-yl]amino]-5-(diaminomethylideneamino)-1-oxopentan-2-yl]amino]-3-[[2-[[(2s)-2,6-diaminohexanoyl]amino]acetyl]amino]-4-oxobutanoic acid Chemical compound OC[C@@H](C(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CCCN=C(N)N)NC(=O)[C@H](CC(O)=O)NC(=O)CNC(=O)[C@@H](N)CCCCN MZOFCQQQCNRIBI-VMXHOPILSA-N 0.000 description 33
- 201000010099 disease Diseases 0.000 description 15
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 description 15
- 238000005259 measurement Methods 0.000 description 10
- 230000001575 pathological effect Effects 0.000 description 8
- 208000012902 Nervous system disease Diseases 0.000 description 6
- 208000025966 Neurological disease Diseases 0.000 description 6
- 230000000694 effects Effects 0.000 description 5
- 230000005713 exacerbation Effects 0.000 description 4
- 210000002540 macrophage Anatomy 0.000 description 4
- 210000000987 immune system Anatomy 0.000 description 3
- 230000003902 lesion Effects 0.000 description 3
- 230000035945 sensitivity Effects 0.000 description 3
- 102000004127 Cytokines Human genes 0.000 description 2
- 108090000695 Cytokines Proteins 0.000 description 2
- 208000016192 Demyelinating disease Diseases 0.000 description 2
- 102100040247 Tumor necrosis factor Human genes 0.000 description 2
- 230000004913 activation Effects 0.000 description 2
- 230000004071 biological effect Effects 0.000 description 2
- 210000004369 blood Anatomy 0.000 description 2
- 239000008280 blood Substances 0.000 description 2
- 210000001124 body fluid Anatomy 0.000 description 2
- 239000010839 body fluid Substances 0.000 description 2
- 201000011510 cancer Diseases 0.000 description 2
- 210000004027 cell Anatomy 0.000 description 2
- 238000002405 diagnostic procedure Methods 0.000 description 2
- 230000008595 infiltration Effects 0.000 description 2
- 238000001764 infiltration Methods 0.000 description 2
- 238000004519 manufacturing process Methods 0.000 description 2
- 206010012305 Demyelination Diseases 0.000 description 1
- 102000004190 Enzymes Human genes 0.000 description 1
- 108090000790 Enzymes Proteins 0.000 description 1
- 108010076282 Factor IX Proteins 0.000 description 1
- 102000008949 Histocompatibility Antigens Class I Human genes 0.000 description 1
- 108010088652 Histocompatibility Antigens Class I Proteins 0.000 description 1
- 102000008070 Interferon-gamma Human genes 0.000 description 1
- 108010074328 Interferon-gamma Proteins 0.000 description 1
- 102000000589 Interleukin-1 Human genes 0.000 description 1
- 108010002352 Interleukin-1 Proteins 0.000 description 1
- 208000011200 Kawasaki disease Diseases 0.000 description 1
- 108010013563 Lipoprotein Lipase Proteins 0.000 description 1
- 102100022119 Lipoprotein lipase Human genes 0.000 description 1
- 102000007651 Macrophage Colony-Stimulating Factor Human genes 0.000 description 1
- 108010046938 Macrophage Colony-Stimulating Factor Proteins 0.000 description 1
- 201000009906 Meningitis Diseases 0.000 description 1
- 102000006386 Myelin Proteins Human genes 0.000 description 1
- 108010083674 Myelin Proteins Proteins 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- 206010036105 Polyneuropathy Diseases 0.000 description 1
- 206010037075 Protozoal infections Diseases 0.000 description 1
- 206010040070 Septic Shock Diseases 0.000 description 1
- 206010054094 Tumour necrosis Diseases 0.000 description 1
- 206010047571 Visual impairment Diseases 0.000 description 1
- 230000009471 action Effects 0.000 description 1
- 229940121363 anti-inflammatory agent Drugs 0.000 description 1
- 239000002260 anti-inflammatory agent Substances 0.000 description 1
- 230000001580 bacterial effect Effects 0.000 description 1
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- 230000036765 blood level Effects 0.000 description 1
- 210000003169 central nervous system Anatomy 0.000 description 1
- 208000026106 cerebrovascular disease Diseases 0.000 description 1
- 230000001684 chronic effect Effects 0.000 description 1
- 230000006378 damage Effects 0.000 description 1
- 230000007423 decrease Effects 0.000 description 1
- 230000008260 defense mechanism Effects 0.000 description 1
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- 239000003814 drug Substances 0.000 description 1
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- 239000002158 endotoxin Substances 0.000 description 1
- 238000002474 experimental method Methods 0.000 description 1
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- 229940044627 gamma-interferon Drugs 0.000 description 1
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- 208000034783 hypoesthesia Diseases 0.000 description 1
- 238000003384 imaging method Methods 0.000 description 1
- 238000003018 immunoassay Methods 0.000 description 1
- 239000003018 immunosuppressive agent Substances 0.000 description 1
- 229940125721 immunosuppressive agent Drugs 0.000 description 1
- 208000015181 infectious disease Diseases 0.000 description 1
- 230000002757 inflammatory effect Effects 0.000 description 1
- 235000019626 lipase activity Nutrition 0.000 description 1
- 238000009593 lumbar puncture Methods 0.000 description 1
- 238000000691 measurement method Methods 0.000 description 1
- 238000012544 monitoring process Methods 0.000 description 1
- 208000022084 motor paralysis Diseases 0.000 description 1
- 208000001725 mucocutaneous lymph node syndrome Diseases 0.000 description 1
- 210000005012 myelin Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 230000007824 polyneuropathy Effects 0.000 description 1
- 238000002360 preparation method Methods 0.000 description 1
- 230000000750 progressive effect Effects 0.000 description 1
- 102000004169 proteins and genes Human genes 0.000 description 1
- 108090000623 proteins and genes Proteins 0.000 description 1
- 230000001698 pyrogenic effect Effects 0.000 description 1
- 230000001105 regulatory effect Effects 0.000 description 1
- 210000002966 serum Anatomy 0.000 description 1
- 239000000126 substance Substances 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 208000024891 symptom Diseases 0.000 description 1
- 238000010998 test method Methods 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 229940126585 therapeutic drug Drugs 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 230000007704 transition Effects 0.000 description 1
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Landscapes
- Investigating Or Analysing Biological Materials (AREA)
Description
【発明の詳細な説明】 a.産業上の利用分野 本発明は、ヒト腫瘍壊死因子（Tumor Necrosis Facto
r−alpha以下これを“TNF−α”と略称することがあ
る）の定量的測定方法を用いてヒト髄液中のTNF−αの
量を特異的に測定することによって、多発性硬化症診断
及び病態の判定の一助とするための方法に関するもので
ある。DETAILED DESCRIPTION OF THE INVENTION a. Field of Industrial Application The present invention relates to human tumor necrosis factor (Tumor Necrosis Facto).
r-alpha and below (sometimes abbreviated as "TNF-α"), by specifically measuring the amount of TNF-α in human cerebrospinal fluid using a quantitative measurement method, multiple sclerosis diagnosis And a method for helping to determine a pathological condition.
b.発明の背景 多発性硬化症（multiple sclerosis）は15〜50才まで
の年令層に好発する脱髄性疾患の代表的なものである。
臨床症状は中枢神経系の多発性病巣に起因するもであ
り、多彩である。多く手足のしびれなどの運動麻痺及び
視力障害をともなうが、これらに限定されるものではな
い。日本での罹患率は人口10万につき３〜４で少ない
が、欧米ではこの数10倍に達し、遺伝的要因が本症の発
症にからむと考えられている。しかしながら本症の原因
は不明である。本症の病巣では脱髄が生じ、マクロファ
ージなどの細胞の浸潤，ミエリンの破壊などが認められ
る。このため、MRI（magenetic recovance imaging）を
用いて本症の診断を行なうことは可能である。ところが
本症には根本的な治療薬がないためにひとたび発症する
と、寛解期と増悪期を繰り返しながら、本症が進行し続
けることが多い。本症の発症及び病態の推移をモニタリ
ングしうる特異的かつ簡便な検査法は今だに存在せず、
その開発が強く求められていた。b. Background of the invention Multiple sclerosis is a typical demyelinating disease that occurs frequently in the age group of 15 to 50 years old.
The clinical symptoms are caused by multiple lesions of the central nervous system and are diverse. It is often accompanied by, but not limited to, motor paralysis such as numbness of limbs and visual impairment. The morbidity rate in Japan is as low as 3 to 4 per 100,000 population, but in Europe and the United States, it is several tens of times higher, and it is considered that genetic factors are involved in the onset of this disease. However, the cause of this disease is unknown. Demyelination occurs in the lesion of this disease, and infiltration of cells such as macrophages and destruction of myelin are observed. Therefore, it is possible to diagnose this disease by using MRI (magenetic recovance imaging). However, since there is no fundamental therapeutic drug for this disease, once it develops, the disease often continues to progress with remission and exacerbation repeated. There is still no specific and simple test method that can monitor the onset and transition of this condition,
Its development was strongly demanded.
一方、TNF−αはマクロファージが産生するサイトカ
インの一種で、カケクチンとも呼ばれ、極めて多様の生
物学的活性を有する蛋白質である。その活性は、広く体
内の免疫系の活性化に作用する。On the other hand, TNF-α is a kind of cytokine produced by macrophages and is also called cachectin, which is a protein having extremely diverse biological activities. Its activity widely affects the activation of the immune system in the body.
TNF−αの産生は、マクロファージにエンドトキシン
や細菌菌体などが作用し１）、誘導されるが、インター
リウキン１やガンマ・インタフェロンなどサイトカイン
により調節されている２）。TNF−αはクラスＩ主要組
織適合性抗原の特異的発現を促し３）、グラニュロサイ
トマクロファージコロニー刺激因子４）,IL−15）の産
生を誘導し、リポ蛋白リパーゼ活性を減少させ６）、腫
瘍細胞７）及び血管内皮細胞８）を障害し、内因性の発
熱因子９）として働くなど多くの活性を有している。The production of TNF-α is induced by the action of endotoxin and bacterial cells on macrophages 1) and is induced, but is regulated by cytokines such as interleukin 1 and gamma interferon 2). TNF-α promotes specific expression of class I major histocompatibility antigens 3), induces the production of granulocytic macrophage colony-stimulating factor 4), IL-15), and decreases lipoprotein lipase activity 6), It has many activities such as impairing tumor cells 7) and vascular endothelial cells 8) and acting as an endogenous pyrogenic factor 9).
１）［E.A.Carswellら,Proc.Natl.Acad.Sci.,USA,72,36
66（1975）］ ２）［R.Philipら,Nature,323,86（1986）］ ３）［T.Collinら,Proc.Natl.Acad.Sci.,USA,83,446（1
986）］ ４）［L.Luら,J.Immunol.,141,201（1988）］ ５）［Nawrothら,J.Exp,Med.163,1383（1986）］ ６）［B.Beutlerら,Nature 320,584（1987）］ ７）［L.Helsonら,Nature 258,731（1975）］ ８）［N.Satoら,J.Natl.Cancer Inst.76,1113（198
6）］ ９）［Dinarelloら,J.Exp.Med.163,1433（1986）］ このように多様な活性を有するTNF−αは、感染に対
する生体防御機構そして各種疾患における免疫系の作動
において中心的役割を果たしている可能性が考えられ、
その血液等体液中の量の測定に大きな関心が寄せられて
いた。1) [EA Carswell et al., Proc. Natl. Acad. Sci., USA, 72 , 36
66 (1975)] 2) [R. Philip et al., Nature, 323 , 86 (1986)] 3) [T. Collin et al., Proc. Natl. Acad. Sci., USA, 83 , 446 (1)
986)] 4) [L.Lu et al., J. Immunol., 141 , 201 (1988)] 5) [Nawroth et al., J. Exp, Med. 163 , 1383 (1986)] 6) [B. Beutler et al. Nature 320 , 584 (1987)] 7) [L. Helson et al., Nature 258 , 731 (1975)] 8) [N. Sato et al., J. Natl. Cancer Inst. 76 , 1113 (198).
6)] 9) [Dinarello et al., J. Exp. Med. 163 , 1433 (1986)] TNF-α, which has various activities as described above, plays a central role in the biological defense mechanism against infection and the activation of the immune system in various diseases. It is possible that the
There has been great interest in measuring the amount of such substances in body fluids such as blood.
ある種の病態において血液等体液中のTNF−α量が増
加しているということは既に報告されはじめている。古
川らは、川崎病において血清中TNF−α量が増加してい
るのを認め10）、BeutlerらはTNF−αがエンドトキシン
ショックのメディエーターであると報告した11）。また
Scuderiらは原虫感染12）、Mauryらは腎移植における拒
絶反応13）、Waageらは髄膜炎14）、Balkwillらは悪性
腫瘍15）で、TNF−αの血中レベルが上昇していること
を報告した。It has already been reported that the amount of TNF-α in body fluids such as blood is increased in certain pathological conditions. Furukawa et al. Observed an increase in serum TNF-α levels in Kawasaki disease 10), and Beutler et al. Reported that TNF-α was a mediator of endotoxin shock 11). Also
Increased blood levels of TNF-α in Scuderi et al. 12) Protozoal infections, Maury et al. Rejection in renal transplants 13), Waage et al. Meningitis 14), and Balkwill et al. Malignant tumors 15). Was reported.
10）［S.Furukawaら,Clin.Immun.Immnopathol.48,247
（1988）］ 11）［B.Beutlerら,Nature,320,584（1986）］ 12）P.Scuderiら,The Lancet,December 13，（1986）p.
1364］ 13）［P.J.Mauryら,J.Exp.Med.,166,1137（1987）］ 14）［A.Waageら,The Lancet,February 14,（1987）p.3
55］ 15）［F.R.Balkwillら,The Lancet,（1987）ii,1229］ このようなTNF−αの生物活性にかんがみ、本発明者
らは多発性硬化症におけるTNF−αの関与の可能性につ
いて検討した。本症病変部では、マクロファージの浸潤
が認められること、また炎症像を呈すること、本症発症
に免疫系の関与が示唆される事実が多くあることなどの
理由から、本症病変局所を含んで貯留される髄液中にTN
F−αが存在する可能性が高いと考えるに至った。10) [S. Furukawa et al., Clin.Immun.Immnopathol. 48 , 247
(1988)] 11) [B. Beutler et al., Nature, 320 , 584 (1986)] 12) P. Scuderi et al., The Lancet, December 13 , (1986) p.
1364] 13) [PJ Maury et al., J. Exp. Med., 166 , 1137 (1987)] 14) [A. Waage et al., The Lancet, February 14, (1987) p. 3
55] 15) [FR Balkwill et al., The Lancet, (1987) ii, 1229] Considering such biological activity of TNF-α, the present inventors examined the possibility of involvement of TNF-α in multiple sclerosis. did. In the lesion area of this disease, the infiltration of macrophages, the presence of an inflammatory image, and the fact that there are many facts suggesting that the immune system is involved in the onset of this disease include the local area of this disease. TN in the stored spinal fluid
We came to think that there is a high possibility that F-α exists.
c.発明の目的 以上のように、本発明は多発性硬化症の判定方法及び
その重篤度の判定方法を提供することにある。c. Object of the Invention As described above, the present invention provides a method for determining multiple sclerosis and a method for determining the severity thereof.
d.発明の構成 そこで本発明者らは多発性硬化症の種々の病態にある
患者より髄液を採取し、他の神経疾患患者より採取した
髄液と併せてTNF−αの高感度定量的測定を行なったと
ころ、多発性硬化症患者髄液中に他の神経疾患に比し高
値にTNF−αが存在すること、さらに寛解期に比べ増悪
期でTNFが増加することを認め本症の病態の変化をモニ
タリングしうることを見出し、本発明に至った。d. Structure of the Invention Therefore, the present inventors collected cerebrospinal fluid from patients with various pathological conditions of multiple sclerosis, and combined with the cerebrospinal fluid collected from patients with other neurological diseases, highly sensitive quantitative determination of TNF-α. Upon measurement, it was confirmed that TNF-α was present in the cerebrospinal fluid of patients with multiple sclerosis at a higher level than other neurological diseases, and that TNF increased during the exacerbation period compared with the remission period. The inventors have found that changes in pathological conditions can be monitored, and have completed the present invention.
すなわち本発明は下記の発明を包含する。 That is, the present invention includes the following inventions.
（１）ヒト髄液中のヒト腫瘍壊死因子を測定することに
よる多発性硬化症の判定方法。(1) A method for determining multiple sclerosis by measuring human tumor necrosis factor in human cerebrospinal fluid.
（２）ヒト髄液中のヒト腫瘍壊死因子を測定することに
よる多発性硬化症の重篤度の判定方法。(2) A method for determining the severity of multiple sclerosis by measuring human tumor necrosis factor in human cerebrospinal fluid.
以下、本発明について更に詳細に説明する。 Hereinafter, the present invention will be described in more detail.
＜髄液検体の調製＞ 通常行なわれる腰椎穿刺により採取された髄液をその
まま測定に用いればよい。もし測定までに時間を要する
場合には、採取後できるだけ速やかに凍結し、−20℃以
下、保存が長期に及ぶ場合、望ましくは−70℃以下に保
存し、融解後測定に用いればよい。検体の凍結融解は繰
り返さない方が望ましい。<Preparation of Cerebrospinal Fluid Specimen> Cerebrospinal fluid collected by the usual lumbar puncture may be directly used for measurement. If it takes a long time before measurement, it should be frozen as soon as possible after collection, and stored at -20 ° C or lower, and if stored for a long period of time, preferably stored at -70 ° C or lower, and used for measurement after thawing. It is recommended not to freeze and thaw the sample repeatedly.
＜TNF−αの測定＞ TNF−αを特異的かつ高感度に定量できるものであれ
ば、TNF−αの測定は特に方法を選ばない。ただし１〜1
00pg/ml程度の濃度のTNFが定量的に測定できる方法であ
ることが、本症の病態を判定するためにTNF−αを測定
する上において望ましい。またバイオアッセイを用いる
場合においては、活性がTNF−αによるものであること
を抗TNF抗体による中和実験等で確認しておくことが望
ましい。<Measurement of TNF-α> As long as TNF-α can be quantified specifically and with high sensitivity, TNF-α can be measured by any method. However, 1 to 1
A method capable of quantitatively measuring TNF at a concentration of about 00 pg / ml is desirable for measuring TNF-α in order to determine the pathological condition of this disease. When using a bioassay, it is desirable to confirm that the activity is due to TNF-α by a neutralization experiment with an anti-TNF antibody.
望ましくは、先に出願された特許出願（特開平３−13
864号：平成１年６月12日出願：発明の名称“TNF−αの
測定方法、キット及び診断方法”）に記載の方法によっ
て測定するのがよいが、この方法と同等もしくはそれ以
上の感度及び特異性を有する方法であればよい。Desirably, the patent application previously filed (Japanese Patent Laid-Open No. 3-13
No. 864: Application on June 12, 1991: It is better to measure by the method described in the title of the invention “Method of measuring TNF-α, kit and diagnostic method”), but sensitivity equal to or higher than this method And a method having specificity.
＜多発性硬化症の判定＞ 本症の判定は、髄液中のTNF−αの濃度を測定するこ
とによりその一助とすることができる。すなわち本症で
は他の神経疾患と比較して高濃度にTNF−αが検出さ
れ、また、TNF−α濃度が高い程、本症の病態が増悪し
ている傾向がある。<Determination of Multiple Sclerosis> The determination of this disease can be aided by measuring the concentration of TNF-α in the cerebrospinal fluid. That is, in this disease, TNF-α is detected at a higher concentration than in other neurological diseases, and as the TNF-α concentration is higher, the pathological condition of this disease tends to be exacerbated.
e.発明の効果 本発明によれば、多発性硬化症の病態のモニタリング
が可能となり、免疫抑制剤，抗炎症剤などで本症におい
て用いられる薬剤投与の目安及び同薬剤の治療効果の判
定の一助とすることができるようになった。e. Effects of the Invention According to the present invention, it becomes possible to monitor the pathological condition of multiple sclerosis, and it is possible to determine the standard of drug administration and the therapeutic effect of the drug used in this disease such as immunosuppressive agents and anti-inflammatory agents. I can now help.
f.実施例 以下、実施例を掲げて、本発明について詳細に説明す
るのが、本発明は以下の実施例に限定されるものではな
い。f. Examples Hereinafter, the present invention will be described in detail with reference to Examples, but the present invention is not limited to the following Examples.
（多発性硬化症及び他の神経疾患患者髄液中のTNF−α
濃度の測定） 多発性硬化症患者26例、うち再発型18例（増悪期12
例、寛解期６例）、慢性進行型８例、他の神経疾患患者
12例（ポリニューロパシー７例、脳血管障害５例）につ
き、髄液を採取し、すみやかに凍結保存した。(TNF-α in cerebrospinal fluid of patients with multiple sclerosis and other neurological disorders
Concentration measurement) 26 patients with multiple sclerosis, 18 of whom were relapsing (exacerbation period 12
Example, remission period 6 cases), chronic progressive type 8 cases, patients with other neurological diseases
Cerebrospinal fluid was collected from 12 cases (7 cases of polyneuropathy and 5 cases of cerebrovascular disorder) and immediately frozen and stored.
TNF−αの定量測定直前に融解し、先に出願された特
許出願（特開平３−13864号に平成１年６月12日出願：
発明の名称“TNF−αの測定方法、キット及び診断方
法”）に記載された方法に従ってTNF−αの定量的測定
を行なった。It was melted immediately before the quantitative measurement of TNF-α, and the patent application filed previously (Japanese Patent Application Laid-Open No. 3-13864 filed on June 12, 1991:
Quantitative measurement of TNF-α was carried out according to the method described in the title of the invention “Method of measuring TNF-α, kit and diagnostic method”).
すなわち、髄液検体50μｌを用いて、蛍光基質を用い
た二抗体法によるTNF−αの酵素免疫測定方法（感度限
界3.4pg/ml）によりTNF−αの定量測定を行なった。結
果をまとめて下記表に示す。That is, 50 μl of the cerebrospinal fluid sample was used to quantitatively measure TNF-α by an enzyme immunoassay method for TNF-α (sensitivity limit of 3.4 pg / ml) by the double antibody method using a fluorescent substrate. The results are summarized in the table below.
＜患者髄液中のTNF−α量の測定＞ 上記表により、多発性硬化症患者髄液中のTNF−α濃
度は、他の神経疾患に比して危険率１％以内で、有意に
高値を示し、また本症のうち再発型では、寛解期に比べ
増悪期にTNF−αが危険率0.1％以内で有意に増加してい
たことがわかった。<Measurement of TNF-α amount in patient cerebrospinal fluid> From the above table, the TNF-α concentration in cerebrospinal fluid of patients with multiple sclerosis shows a significantly high value within a risk rate of 1% or less compared to other neurological diseases. It was found that TNF-α was significantly increased in the exacerbation period compared with the previous period within the risk rate of 0.1%.
したがって本発明による髄液中のTNF−αの測定によ
り、多発性硬化症の判定及び重篤度の判定、病態のモニ
タリングに極めて有効である。Therefore, the measurement of TNF-α in the cerebrospinal fluid according to the present invention is extremely effective in the determination of multiple sclerosis, the determination of severity, and the monitoring of pathological conditions.
───────────────────────────────────────────────────── フロントページの続き (56)参考文献 特開 平２−1552（ＪＰ，Ａ) 特表 平１−503331（ＪＰ，Ａ) Ｃｌｉｍｉｃａｌ ＆ Ｅｘｐｅｒｉ ｍｅｎｔａｌ Ｔｍｍｕｎｏｌｏｇｙ, 79（１），Ｐ15−20，（1990) ─────────────────────────────────────────────────── ─── Continuation of the front page (56) Reference JP-A-2-1552 (JP, A) Special Table 1-503331 (JP, A) Clinical & Expertial Tmmunology, 79 (1), P15-20, ( 1990)
Claims (2)
ことによる多発性硬化症の判定方法。1. A method for determining multiple sclerosis by measuring human tumor necrosis factor in human cerebrospinal fluid.
ことによる多発性硬化症の重篤度の判定方法。2. A method for determining the severity of multiple sclerosis by measuring human tumor necrosis factor in human cerebrospinal fluid.
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| JP2543606B2 true JP2543606B2 (en) | 1996-10-16 |
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