WO2020120459A1 - Procédé d'analyse d'un échantillon de sang humain pour la détection de la tuberculose par l'expression de cd154 stimulée par l'antigène tb en combinaison avec cd38, ki-67 ou hla-dr - Google Patents

Procédé d'analyse d'un échantillon de sang humain pour la détection de la tuberculose par l'expression de cd154 stimulée par l'antigène tb en combinaison avec cd38, ki-67 ou hla-dr Download PDF

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Publication number
WO2020120459A1
WO2020120459A1 PCT/EP2019/084392 EP2019084392W WO2020120459A1 WO 2020120459 A1 WO2020120459 A1 WO 2020120459A1 EP 2019084392 W EP2019084392 W EP 2019084392W WO 2020120459 A1 WO2020120459 A1 WO 2020120459A1
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WO
WIPO (PCT)
Prior art keywords
cells
marker
status
tuberculosis
marking
Prior art date
Application number
PCT/EP2019/084392
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German (de)
English (en)
Inventor
Petra Bacher
Andrej MANTEI
Christian Meisel
Tim Meyer
Alexander Scheffold
Hans-Dieter Volk
Original Assignee
Labor Berlin - Charité Vivantes Services GmbH
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Labor Berlin - Charité Vivantes Services GmbH filed Critical Labor Berlin - Charité Vivantes Services GmbH
Priority to EP19821062.7A priority Critical patent/EP3894858A1/fr
Publication of WO2020120459A1 publication Critical patent/WO2020120459A1/fr
Priority to ZA2021/03675A priority patent/ZA202103675B/en

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Classifications

    • 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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
    • G01N33/56911—Bacteria
    • G01N33/5695—Mycobacteria
    • 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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/502—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects
    • G01N33/5023—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing non-proliferative effects on expression patterns
    • 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
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5044—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics involving specific cell types
    • G01N33/5047—Cells of the immune system
    • G01N33/505—Cells of the immune system involving T-cells
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70503—Immunoglobulin superfamily, e.g. VCAMs, PECAM, LFA-3
    • G01N2333/70539—MHC-molecules, e.g. HLA-molecules
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70575—NGF/TNF-superfamily, e.g. CD70, CD95L, CD153 or CD154
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
    • G01N2333/705—Assays involving receptors, cell surface antigens or cell surface determinants
    • G01N2333/70596—Molecules with a "CD"-designation not provided for elsewhere in G01N2333/705

Definitions

  • the present invention relates to a method for the analysis of a human blood sample for an active tuberculosis infection (ATBI).
  • ATBI active tuberculosis infection
  • Tuberculosis is a chronic infection caused by mycobacteria from the Mycobacterium tuberculosis complex (MTBC).
  • MTBC Mycobacterium tuberculosis complex
  • tuberculosis infections in humans are caused by M. tuberculosis sensu stricto and M. africanum.
  • Infection with tuberculosis bacteria only leads to tuberculosis or active tuberculosis infection in humans in approx. 10% of cases.
  • LTBI latent tuberculosis infection
  • tuberculosis bacteria remain in humans. A transition from a latent to an active tuberculosis infection and thus an illness is possible.
  • tuberculosis In order to select a tuberculosis therapy or to verify the success of the therapy, the clearest possible proof of a tuberculosis disease is necessary.
  • the detection of tuberculosis is carried out in a wide variety of ways. In principle, the detection of a tuberculosis infection is possible on the basis of blood samples. Here the reaction of the immune system to tuberculosis antigens is examined. If there is a reaction, it can be concluded that the patient in question is infected with tuberculosis bacteria. However, blood tests currently used cannot be used to determine whether the person in question is only latently infected with tuberculosis or whether there is an active tuberculosis disease.
  • a method of analyzing a human blood sample for a tuberculosis disease is based on examining an immune response against tuberculosis bacteria. Such a process has the following steps:
  • a tuberculosis infection in the blood sample of a human is to be detected and classified here too.
  • cells from a blood sample for example in the form of isolated mononuclear cells or whole blood
  • the starting material can thus be obtained minimally invasively in the form of a peripheral venipuncture. Biopsies and time-consuming cultivation of tuberculosis bacteria are eliminated.
  • a key concept of the present invention is based on the analysis of T cells (for example CD4 + T cells) which are part of the cells made available.
  • T cells for example CD4 + T cells
  • the cells made available are stimulated with tuberculosis antigens.
  • Structures which are part of bacteria of the Mycobacterium tuberculosis complex (MTBC), for example ESAT-6 / CFP-10 peptides or purified protein derivative (PPD) can be used as tuberculosis antigens.
  • the T cells that respond to stimulation with tuberculosis antigens are labeled and characterized.
  • the marking is made possible by the induction of the at least one presence marker on these T cells.
  • the method can be described as a two-stage process.
  • tuberculosis-antigen-specific T cells are identified using the at least one presence marker. These cells are found in both latent and actively infected patients with tuberculosis.
  • it is examined whether the cells which carry the at least one presence marker also carry one of the status markers. This at least one status marker allows a conclusion to be drawn about the activation status of the tuberculosis-antigen-specific cells, as cells with presence markers.
  • the presence marker can be used to draw conclusions about the presence of tuberculosis bacteria and the status marker, the status, that is to say the distinction between latent and active manifestation of the tuberculosis infection.
  • the frequency of the presence markers and T cell-bearing status markers or the marking strength of the status marker on the T-cell bearing presence marker is determined and compared with a combination limit value.
  • Combination limit values can be defined as a clear limit value or as a transition range, as will be explained later. In other words, in the set of cells made available, marked cells can now be recognized and evaluated, which carry a combination of at least one presence marker and at least one status marker.
  • the number of such cells with a combined marking or the marking strength of a status marker as a measure of its frequency on the cells which also carry the at least one status marker can now be normalized to a total number of cells and compared with a combination limit. If the number of combined labeled cells exceeds the Combination limit, an active tuberculosis infection can be assumed, in particular with a certain probability.
  • a presence marker and a status marker are proteins on a subgroup of the cells made available which have specific correlations with the parameters to be analyzed.
  • the frequency of the cells that carry the presence marker after stimulation with tuberculosis antigens correlates with the frequency of tuberculosis-specific T cells in the patient's blood.
  • a presence marker must meet two conditions in particular: After in vitro stimulation, it should, if possible, only be formed by cells which specifically recognize the stimulant (here: tuberculosis antigen).
  • the duration that the presence marker can be found on the cells after stimulation should be limited, so that the method does not erroneously identify cells that were activated before in vitro stimulation.
  • tuberculosis antigens allow the analysis of tuberculosis-specific T cells in the cells made available.
  • the stimulation takes place over a defined period of 1 to 72 hours, of which in particular 1 to 48 hours, of which in particular 1 to 24 hours, of which in particular 1 to 12 hours, of which in particular 1 to 7 hours, of which in particular 4 to 6 hours.
  • the stimulation and the associated induction of the at least one presence marker therefore make it possible to recognize the cells and distinguish them from other cells which are specific for tuberculosis antigens.
  • Live bacteria, dead bacteria or, in particular, fragments or synthesized structures that resemble structures of tuberculosis bacteria e.g. lysates, protein extracts, purified proteins, protein mixtures, recombinantly produced proteins or protein fragments, peptides or nucleic acid sequences
  • tuberculosis bacteria are often closed in an encapsulated area of the body and in this state only have a limited interaction with the patient's adaptive immune system (including T cells).
  • T cells including T cells
  • the activation of the T cells by this contact leads to them starting to form activation markers, which are sometimes used as status markers.
  • the analysis of the marking of the at least one status marker in a quantitative and / or qualitative manner allows a statement to be made regarding the distinction between latent and active tuberculosis. It should also be pointed out that the status markers on the T cells already arise in the body and that no separate stimulation is necessary for this. The status markers differ from the at least one presence marker.
  • the blood sample is evaluated in a method according to the invention.
  • a comparison of a defined total cell population to the cells contained therein, which have the at least one presence marker and one or more of the status markers, is carried out in the marking result.
  • a combination limit value which indicates the relative frequency of the T cells that carry the presence marker and one of the status markers or the marking strength of one of the status markers, an active tuberculosis disease can now be assumed above the limit value.
  • the at least one presence marker specifically indicates the contact of the cells with at least one tuberculosis bacterial antigen in humans.
  • the presence markers are expressed on the T cells which are specific against tuberculosis antigens.
  • tuberculosis bacteria produce corresponding biological, chemical and / or biochemical reactions in the body. This is based in particular on a corresponding reaction of the human immune system.
  • the presence marker is stimulated specifically and without a second indication only in T cells, which in turn are specific for a tuberculosis infection. This is the case with a stimulation duration of 1 to 72 hours, of which in particular 1 to 48 hours, of which in particular 1 to 24 hours, of which in particular 1 to 12 hours, of which in particular 1 to 7 hours, of which in particular 4-6 hours.
  • the at least one status marker has at least one activity parameter for the activation status of the T cells in the blood sample.
  • the activation status of the T cells in humans they have corresponding status markers on the surface.
  • Activated T cells can be distinguished from other T cells.
  • the activation and thus the presence of a status marker is not limited to a tuberculosis infection. In combination with the at least one presence maker, however, the combination limit can be used to restrict tuberculosis infection.
  • the status marker has at least one of the following configurations:
  • the at least one status marker is changed by in vivo stimulation of the specific T cells
  • the list above is a non-exhaustive list.
  • the quantitative correlation allows an activity parameter to also provide a quantitative and thus a probability statement as to whether it is active or latent tuberculosis.
  • the activity parameter is mapped in the combination limit.
  • a stability of the activity parameter for the duration of the test can be used to provide a sample that is easier to handle and, in particular, also to provide transport between the sampling location and the analysis location. Since the status marker is not generated by the patient's own stimulation in the method, but is already in the blood sample when the blood sample is taken, this temporal stability ensures greater flexibility in the use of the method according to the invention.
  • a limit value is defined for the combination limit value, when it is exceeded an active tuberculosis disease is recognized.
  • This limit value is preferably equipped with a safety margin in order to have the corresponding safety for the subsequent treatment for a positive test result.
  • the combination limit has at least two limit values with different probabilities for the detection of an active tuberculosis disease. This means that not only can a distinction be made between a negative and a positive test result, but different probabilities can be assumed in particular in the positive result. If the test result is between the two limit values, for example, the likelihood of tuberculosis is lower than if both limit values are exceeded. At least gradually, a quantitative statement is possible regarding the probability of the test procedure.
  • a further advantage can be if, in a method according to the invention, the marking of the at least one presence marker and the at least one status marker is carried out in parallel at least in sections.
  • the marking preferably takes place simultaneously or essentially simultaneously. It is irrelevant whether a common marking mixture should be used for marking both markers or separate marking agents.
  • the design of this marking step, which is parallel at least in sections, further reduces the time required for a method according to the invention and the corresponding costs.
  • the at least one presence marker and the at least one status marker are colored with the same marker mixture. This is particularly the case in combination with the embodiment according to the preceding paragraph.
  • At least some of the cells made available from the blood sample are stimulated and / or at least some of the cells made available from the blood sample remain unstimulated.
  • the stimulation of the blood sample is in particular biological, chemical and / or biochemical. In a qualitative and / or quantitative manner, it can provide reinforcement or simplification in the analysis according to the invention.
  • Such a negative control is combined in particular with a positive control.
  • a further advantage can be achieved if, in a method according to the invention, the cells are made available from a blood sample with peripheral blood. This further reduces the invasiveness of the preliminary procedure necessary for the blood sample.
  • the blood sample can be made available quickly and easily and can serve as a starting point for a method according to the invention.
  • a further advantage can be achieved if, in a method according to the invention, the marking steps are carried out free of permeabilization on the cells made available. It is therefore not necessary to loosen or open the cell walls of the cells made available, so that the preparation effort when carrying out a method according to the invention can be reduced. The time required for the analysis can also be reduced. In this way, a further simplification and reduction of the complexity can be made available for a method according to the invention.
  • Fig. 3 shows an embodiment in the evaluation of a presence marker
  • Fig. 4 shows a further embodiment in the evaluation of an inventive
  • FIG. 1 schematically shows how cells (110) made available from a peripheral blood sample 100 are stimulated with a stimulation agent ST.
  • Markers FM either in the form of a mixture of markers or different FM markers, can be used to mark presence markers AM and status markers SM on / in the cells 110 provided.
  • this marking is evaluated in an evaluation unit 200 so that the combination limit value KG can be analyzed qualitatively and / or quantitatively.
  • FIG. 3 and 4 schematically show how the corresponding limits for the presence marker AM and the status marker SM can be designed.
  • Three blood sample analysis results can be seen in FIG. 3. While the left analysis is a combination limit value KG with a single limit value, FIG. 4 shows a combination limit value KG with two individual partial limit values. The combination of the two markers AM and SM is above the combination limit value KG in the right sample of FIG. 3, so that the presence of an active tuberculosis disease can be affirmed here. The left sample accordingly designates a negative test since the combination of the two markers AM and SM is below the combination limit value KG.
  • FIG. 2 shows a further embodiment of a method according to the invention, in which the cells 110 made available are divided. While for further processing and marking with the marking means FM there is a stimulation with the aid of a stimulation means ST, a negative sample is previously branched off from the cells 110 provided.
  • the present invention is described only by way of examples. Of course, if technically meaningful, individual features of the embodiments can be freely combined with one another without departing from the scope of the present invention.

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  • Health & Medical Sciences (AREA)
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  • Engineering & Computer Science (AREA)
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Abstract

L'invention concerne un procédé d'analyse d'un échantillon de sang (100) d'un humain pour la détection de la tuberculose, basée sur les bactéries responsables de la tuberculose, comprenant les étapes suivantes : - fourniture de cellules (110) de l'échantillon de sang (100), -stimulation des cellules fournies (110) avec des antigènes de la tuberculose pour l'induction d'au moins un marqueur de présence (AM) sur les cellules T des cellules fournies (110), - marquage d'au moins un des marqueurs de présence induits (AM) sur les cellules T dans les cellules fournies (110), qui est spécifiquement formé sur les cellules T qui ont reconnu l'antigène de la tuberculose pendant la stimulation, - marquage d'au moins un marqueur de statut (SM) sur les cellules T dans les cellules fournies (110), qui est spécifique à leur état d'activation et qui se distingue d'au moins un marqueur de présence (AM), - évaluation du résultat des étapes de marquage par l'analyse de la fréquence des cellules T des cellules (110) fournies avec le marqueur d'état (SM) et le marqueur de présence (AM) marqué ou par l'analyse de l'intensité du marquage du marqueur d'état (SM) dans les cellules (110) fournies avec le marqueur de présence (AM) marqué et la comparaison avec une valeur limite de combinaison (KG).
PCT/EP2019/084392 2018-12-11 2019-12-10 Procédé d'analyse d'un échantillon de sang humain pour la détection de la tuberculose par l'expression de cd154 stimulée par l'antigène tb en combinaison avec cd38, ki-67 ou hla-dr WO2020120459A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
EP19821062.7A EP3894858A1 (fr) 2018-12-11 2019-12-10 Procédé d'analyse d'un échantillon de sang humain pour la détection de la tuberculose par l'expression de cd154 stimulée par l'antigène tb en combinaison avec cd38, ki-67 ou hla-dr
ZA2021/03675A ZA202103675B (en) 2018-12-11 2021-05-28 Method for analyzing a blood sample from a human for a tuberculosis disease by detection of tb antigen-stimulated cd154 expression in combination with cd38, ki-67 or hla-dr

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
DE102018131696.8 2018-12-11
DE102018131696.8A DE102018131696B4 (de) 2018-12-11 2018-12-11 Verfahren für die Analyse einer Blutprobe eines Menschen auf eine Tuberkuloseerkrankung

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WO2020120459A1 true WO2020120459A1 (fr) 2020-06-18

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PCT/EP2019/084392 WO2020120459A1 (fr) 2018-12-11 2019-12-10 Procédé d'analyse d'un échantillon de sang humain pour la détection de la tuberculose par l'expression de cd154 stimulée par l'antigène tb en combinaison avec cd38, ki-67 ou hla-dr

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EP (1) EP3894858A1 (fr)
DE (1) DE102018131696B4 (fr)
WO (1) WO2020120459A1 (fr)
ZA (1) ZA202103675B (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214371A1 (fr) * 2021-04-08 2022-10-13 Labor Berlin - Charité Vivantes Services GmbH Procédé d'analyse d'un échantillon de sang pour détecter une maladie

Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180164287A1 (en) * 2016-12-14 2018-06-14 Becton, Dickinson And Company Methods and compositions for obtaining a tuberculosis assessment in a subject

Patent Citations (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20180164287A1 (en) * 2016-12-14 2018-06-14 Becton, Dickinson And Company Methods and compositions for obtaining a tuberculosis assessment in a subject

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
MARCO FRENTSCH ET AL: "Direct access to CD4+ T cells specific for defined antigens according to CD154 expression", NATURE MEDICINE, vol. 11, no. 10, 25 September 2005 (2005-09-25), pages 1118 - 1124, XP055004658, ISSN: 1078-8956, DOI: 10.1038/nm1292 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022214371A1 (fr) * 2021-04-08 2022-10-13 Labor Berlin - Charité Vivantes Services GmbH Procédé d'analyse d'un échantillon de sang pour détecter une maladie

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DE102018131696A1 (de) 2020-06-18
DE102018131696B4 (de) 2020-09-17
ZA202103675B (en) 2024-04-24
EP3894858A1 (fr) 2021-10-20

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