WO2020256530A1 - Biomarqueur d'exosomes d'urine pour diagnostiquer un rejet à médiation par les lymphocytes t après une transplantation rénale ou pour prédire un pronostic d'un patient après une transplantation rénale - Google Patents

Biomarqueur d'exosomes d'urine pour diagnostiquer un rejet à médiation par les lymphocytes t après une transplantation rénale ou pour prédire un pronostic d'un patient après une transplantation rénale Download PDF

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WO2020256530A1
WO2020256530A1 PCT/KR2020/008094 KR2020008094W WO2020256530A1 WO 2020256530 A1 WO2020256530 A1 WO 2020256530A1 KR 2020008094 W KR2020008094 W KR 2020008094W WO 2020256530 A1 WO2020256530 A1 WO 2020256530A1
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Prior art keywords
kidney transplantation
cell mediated
rejection
kidney
mediated rejection
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PCT/KR2020/008094
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English (en)
Korean (ko)
Inventor
신성
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울산대학교 산학협력단
재단법인 아산사회복지재단
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Publication of WO2020256530A1 publication Critical patent/WO2020256530A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/136—Screening for pharmacological compounds
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2500/00—Screening for compounds of potential therapeutic value
    • G01N2500/04—Screening involving studying the effect of compounds C directly on molecule A (e.g. C are potential ligands for a receptor A, or potential substrates for an enzyme A)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/24—Immunology or allergic disorders
    • G01N2800/245—Transplantation related diseases, e.g. graft versus host disease
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis

Definitions

  • the present invention relates to a biomarker related to T cell-mediated rejection (TCMR) after kidney transplantation, a composition for diagnosing T cell-mediated rejection or predicting the prognosis for rejection after kidney transplantation, and using the same
  • TCMR T cell-mediated rejection
  • the present invention relates to a method of providing information for diagnosing T cell mediated rejection or predicting the prognosis of rejection after kidney transplantation.
  • urine biomarkers for diagnosing acute rejection after kidney transplantation are known (Suthanthiran et al., Urinary-Cell mRNA Profile and Acute Cellular Rejection in Kidney Allografts. The New England Journal of Medicine (2013) 369;1).
  • a biomarker that can differentiate between T cell mediated rejection and antibody mediated rejection and furthermore, a biomarker that can be diagnosed by distinguishing between BK virus infectious nephropathy and transplant rejection, which is a complication after kidney transplantation, was discovered.
  • kidney transplant rejection diagnostic markers As a result of the inventors' diligent efforts to discover non-invasive and accurate kidney transplant rejection diagnostic markers, the present inventors identified new biomarkers that can predict the presence or absence of kidney transplant rejection and the type of rejection through a proteomic approach. The invention was completed.
  • the present invention comprises a substance for measuring the expression level of the mRNA of any one or more proteins selected from the group consisting of MGAM, SLC6A19, ACY3 and SLC5A10 or a gene encoding the protein, T cell mediated after kidney transplantation It provides a composition for diagnosing rejection reactions or predicting the prognosis of patients after kidney transplantation.
  • the substance measuring the expression level of the mRNA may be a primer or probe that specifically binds to the gene.
  • the present invention provides a kit for diagnosing T cell mediated rejection after kidney transplantation or predicting prognosis of a patient after kidney transplantation, comprising the above-described composition.
  • the present invention comprises the step of measuring the mRNA expression level of any one or more proteins selected from the group consisting of MGAM, SLC6A19, ACY3 and SLC5A10 in a sample isolated from an individual or a gene encoding the same, Provides a method of providing information necessary for diagnosing T cell mediated rejection after transplantation or predicting a patient's prognosis after kidney transplantation.
  • the method compares the measured protein or mRNA expression level with a sample of a normal control group that did not receive a kidney transplant or a sample of a patient group that did not show rejection or BK virus infectious nephropathy after a kidney transplant. If the result corresponds to any one or more selected from the group consisting of the following a) to d), it may further include the step of determining as T cell mediated rejection:
  • the sample may be urine or urine-derived exosomes.
  • the method compares the measured protein or mRNA expression level with a sample of a normal control group that did not receive a kidney transplant or a sample of a patient group that did not show rejection or BK virus infectious nephropathy after a kidney transplant. If the result corresponds to any one or more selected from the group consisting of the following a) to d), it is determined as T cell mediated rejection, and a step of determining to apply the treatment for T cell mediated rejection is further performed.
  • the present invention provides a method comprising: a) treating a sample isolated from an individual having T cell mediated rejection after kidney transplantation with a candidate substance for a therapeutic agent for T cell mediated rejection after kidney transplantation; And b) measuring the mRNA expression level of any one or more proteins selected from the group consisting of MGAM, SLC6A19, ACY3, and SLC5A10 or a gene encoding the same; comprising, a therapeutic agent for T cell mediated rejection after kidney transplantation Provides a screening method.
  • the sample may be urine or urine-derived exosomes.
  • the screening method is c) the expression of mRNA of one or more proteins selected from the group consisting of MGAM, SLC6A19, ACY3 and SLC5A10 measured in step b) or of a gene encoding the same.
  • the step of determining the candidate substance in step a) as a treatment for T cell mediated rejection after kidney transplantation may be further included.
  • 1 is a diagram showing the selection process of biomarkers representing ABMR, TCMR and BKVN groups.
  • the present invention also provides a composition for diagnosing T cell mediated rejection after kidney transplantation or predicting the prognosis of a patient after kidney transplant, comprising a substance for measuring the expression level of the mRNA or protein thereof of the four biomarkers of the present invention. to provide.
  • the kit may be a diagnostic kit, characterized in that it contains essential elements necessary to perform a reverse transcription polymerase reaction.
  • the reverse transcription polymerase reaction kit includes each primer pair specific for the gene encoding the biomarker protein.
  • the primer is a nucleotide having a sequence specific to the nucleic acid sequence of each gene, and is about 7 bp to 50 bp in length, more preferably about 10 bp to 30 bp in length.
  • a primer specific to the nucleic acid sequence of the control gene may be included.
  • the present invention comprises the step of measuring the mRNA expression level of any one or more proteins selected from the group consisting of MGAM, SLC6A19, ACY3 and SLC5A10 or a gene encoding the same in a sample isolated from an individual.
  • the "measurement of the expression level of mRNA” is the presence of mRNA of a gene encoding a biomarker protein in a biological sample in order to diagnose T cell mediated rejection after kidney transplantation or predict the prognosis of a patient who has undergone a kidney transplant. It is a process of confirming the level of expression and can be determined by measuring the amount of mRNA. Analysis methods for this include RT-PCR, competitive RT-PCR, Real-time RTPCR (RT-PCR), RNase protection method, northern blotting, or DNA. There is a chip (DNA chip technology) and the like, but is not limited thereto.
  • the method of providing information necessary for diagnosing T cell mediated rejection after kidney transplantation or predicting the prognosis of patients after kidney transplantation of the present invention is to determine the expression level of the measured protein or mRNA as a normal control group without a kidney transplant or after a kidney transplant. If the result of comparison with the sample of the patient group that did not show rejection reaction or BK virus infectious nephropathy falls under any one or more selected from the group consisting of the following a) to d), further determining a T cell mediated rejection reaction.
  • the method of providing the information necessary for determining the treatment for rejection after kidney transplantation of the present invention does not show the measured protein or mRNA expression level as a normal control group without a kidney transplant or a rejection reaction after kidney transplantation or BK virus infectious nephropathy. If the result of comparison with the sample of the non-patient group falls under any one or more selected from the group consisting of the following a) to d), it is determined as T cell mediated rejection, and treatment for T cell mediated rejection is applied. It may further include the step of determining:
  • the method for diagnosing and treating T cell mediated rejection includes the following steps:
  • step c) As a result of the comparison of step b), the expression level in the sample isolated from the subject in step a) was in a sample of a normal control group that did not receive a kidney transplant or a patient group that did not show rejection or BK virus infectious nephropathy after a kidney transplant. If it is higher than the expression level of, determining as T cell mediated rejection after kidney transplantation; And
  • a method of providing information necessary for determining treatment for rejection after kidney transplantation according to the present invention, diagnosis and treatment of T cell mediated rejection after kidney transplantation, and/or screening of T cell mediated rejection treatment after kidney transplantation Other specific details of the method are the same as the method of providing information necessary for diagnosing T cell mediated rejection after kidney transplantation or predicting a patient's prognosis after kidney transplantation, and thus description thereof will be omitted.
  • Sample preparation for proteomic analysis was subjected to freeze drying, protein solubilization and digestion.
  • the resulting peptide mixture was desalted, dried using C18 reverse phase chromatography, and then analyzed by high resolution mass spectrometry combined with nano-flow liquid chromatography.
  • LFQ label free quantitation

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  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Immunology (AREA)
  • Analytical Chemistry (AREA)
  • Organic Chemistry (AREA)
  • Molecular Biology (AREA)
  • Zoology (AREA)
  • General Health & Medical Sciences (AREA)
  • Biotechnology (AREA)
  • Urology & Nephrology (AREA)
  • Wood Science & Technology (AREA)
  • Physics & Mathematics (AREA)
  • Biochemistry (AREA)
  • Hematology (AREA)
  • Biomedical Technology (AREA)
  • Microbiology (AREA)
  • Genetics & Genomics (AREA)
  • General Engineering & Computer Science (AREA)
  • Cell Biology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Biophysics (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • General Physics & Mathematics (AREA)
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  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La présente invention concerne un biomarqueur non invasif pour diagnostiquer un rejet de transplantation rénale et une utilisation de celui-ci et, plus spécifiquement, une composition de biomarqueur et un kit pour diagnostiquer un rejet à médiation par les lymphocytes T après une transplantation rénale ou prédire le pronostic d'un patient après une transplantation rénale, la composition comprenant une ou plusieurs protéines choisies dans le groupe constitué par MGAM, SLC6A19, ACY3, et SLC5A10 ou un gène codant pour celle-ci, un procédé pour fournir des informations nécessaires pour diagnostiquer un rejet à médiation par les lymphocytes T après une transplantation rénale ou prédire le pronostic d'un patient après une transplantation rénale à l'aide de la composition de marqueur, un procédé pour fournir des informations nécessaires pour déterminer un traitement pour un rejet après une transplantation rénale, un procédé pour diagnostiquer ou traiter le rejet à médiation par les lymphocytes T après une transplantation rénale, et un procédé pour cribler un agent thérapeutique pour le rejet à médiation par les lymphocytes T après une transplantation rénale.
PCT/KR2020/008094 2019-06-21 2020-06-22 Biomarqueur d'exosomes d'urine pour diagnostiquer un rejet à médiation par les lymphocytes t après une transplantation rénale ou pour prédire un pronostic d'un patient après une transplantation rénale WO2020256530A1 (fr)

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KR1020190074074A KR102350228B1 (ko) 2019-06-21 2019-06-21 신장이식 후 t세포 매개성 거부반응의 진단 또는 예측을 위한 소변 엑소좀 바이오마커
KR10-2019-0074074 2019-06-21

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20080067460A (ko) * 2007-01-16 2008-07-21 동아대학교 산학협력단 Ｓｌｃ６ａ１９ 유전자의 다형성 소위성과 이를 이용한ｄｎａ 타이핑 키트 및 상기 유전자 관련 질병의 진단키트
US20090176656A1 (en) * 2006-07-21 2009-07-09 Halloran Philip F Tissue rejection
WO2017136709A2 (fr) * 2016-02-03 2017-08-10 The Scripps Research Insitute Dosages moléculaires pour réguler l'immunosuppression, prévenir le rejet à médiation immune et prolonger la survie d'un greffon

Family Cites Families (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20150167085A1 (en) * 2013-09-09 2015-06-18 Daniel R. Salomon Methods and Systems for Analysis of Organ Transplantation

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20090176656A1 (en) * 2006-07-21 2009-07-09 Halloran Philip F Tissue rejection
KR20080067460A (ko) * 2007-01-16 2008-07-21 동아대학교 산학협력단 Ｓｌｃ６ａ１９ 유전자의 다형성 소위성과 이를 이용한ｄｎａ 타이핑 키트 및 상기 유전자 관련 질병의 진단키트
WO2017136709A2 (fr) * 2016-02-03 2017-08-10 The Scripps Research Insitute Dosages moléculaires pour réguler l'immunosuppression, prévenir le rejet à médiation immune et prolonger la survie d'un greffon

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
G EINECKE, KAYSER D., VANSLAMBROUCK J. M., SIS B., REEVE J., MENGEL M., FAMULSKI K. S., BAILEY C. G., RASKO J. E. J., HALLORAN P. : "Loss of Solute Carriers in T Cell-Mediated Rejection in Mouse and Human Kidneys: An Active Epithelial Injury-Repair Response", AMERICAN JOURNAL OF TRANSPLANTATION, vol. 10, no. 10, 29 July 2010 (2010-07-29), pages 2241 - 2251, XP055766975, ISSN: 1600-6135, DOI: 10.1111/j.1600-6143.2010.03263.x *
SOFIA CHRISTAKOUDI, RUNGLALL MANOHURSINGH, MOBILLO PAULA, TSUI TJIR-LI, DUFF CLAIRE, DOMINGO-VILA CLARA, KAMRA YOGESH, DELANEY FLO: "Development of a multivariable gene-expression signature targeting T-cell-mediated rejection in peripheral blood of kidney transplant recipients validated in cross-sectional and longitudinal samples", EBIOMEDICINE, vol. 41, pages 571 - 583, XP055766978, ISSN: 2352-3964, DOI: 10.1016/j.ebiom.2019.01.060 *

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KR20200145279A (ko) 2020-12-30

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