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US20130260394A1 - Method for the diagnosis and/or prognosis of inflammatory states - Google Patents

Method for the diagnosis and/or prognosis of inflammatory states Download PDF

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Publication number
US20130260394A1
US20130260394A1 US13/824,902 US201013824902A US2013260394A1 US 20130260394 A1 US20130260394 A1 US 20130260394A1 US 201013824902 A US201013824902 A US 201013824902A US 2013260394 A1 US2013260394 A1 US 2013260394A1
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receptor
rbd
neutrophils
membrane
expression
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Rabindra Tirouvanziam
Julie Laval
Jean-Luc Battini
Marc Sitbon
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Centre National de la Recherche Scientifique CNRS
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Centre National de la Recherche Scientifique CNRS
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Publication of US20130260394A1 publication Critical patent/US20130260394A1/en
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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
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/566—Immunoassay; Biospecific binding assay; Materials therefor using specific carrier or receptor proteins as ligand binding reagents where possible specific carrier or receptor proteins are classified with their target compounds
    • 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
    • G01N33/564—Immunoassay; Biospecific binding assay; Materials therefor for pre-existing immune complex or autoimmune disease, i.e. systemic lupus erythematosus, rheumatoid arthritis, multiple sclerosis, rheumatoid factors or complement components C1-C9
    • 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
    • G01N33/56966—Animal cells
    • G01N33/56972—White blood cells
    • 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
    • G01N33/6872—Intracellular protein regulatory factors and their receptors, e.g. including ion channels
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/12—Pulmonary diseases
    • G01N2800/122—Chronic or obstructive airway disorders, e.g. asthma COPD
    • 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
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/38—Pediatrics
    • G01N2800/382—Cystic fibrosis

Definitions

  • the invention relates to a method for the diagnosis and/or prognosis of inflammatory states.
  • Virus receptor-binding domain are found in particular in the envelope glycoprotein (Env) of viruses and are able to bind to membrane receptors of different target cells.
  • Gamma and deltaretroviruses have been shown to interact with cell surface through active receptors that belong to the multimembrane protein family. Those receptors for which a function has been identified (or most certainly those with no identified function) are directly involved in cellular metabolism.
  • Retroviral envelope-derived probes which can be used for specific, high-affinity tagging of metabolic transporters on human cells, have been disclosed in WO 2010/079208. These transporters carry a wide variety of metabolites, including, but not limited to: neutral amino acids (AA), cationic AA, glucose, heme and vitamins.
  • Retroviral envelope-derived probes of WO 2010/079208 have been used for the detection of membrane receptors present in a target cell such as haematopoietic stem cells, such as CD34 cells, or differentiated cells such as B-cell or T-cell
  • Myelocyte and monocyte lines play a major role in body's response to stress.
  • regulated signals by epithelial and inflammatory cells get position to coordinate innate and acquired immunity.
  • a rapid intervention is necessary and involves a complete reprogramming of quiescent circulating myelocyte and monocyte lines to be activated and migrate to injury sites. This turn over, requiring gene transcription and protein production, is energy-dependent. It needs nutrients and metabolites absorption that can be reflected with an increase of metabolic transporters at the surface of inflammatory cells.
  • Asthma is a chronic disease characterized by bronchoconstriction, wheezing, cough and breath difficulties during exacerbations. This pathology affects about 300 million worldwide. The airway inflammation is generated by an influx of myelocyte and monocyte lines in the lungs; mostly eosinophils seem to be implied as well as neutrophils.
  • Allergy is also a disorder of the immune system caused by the suractivation of mast cells and basophils when they identify allergen-specific immunoglobulin IgE. Activated cells release histamine and cytokines maintaining and aggravating the reaction of inflammation. Allergic crisis could manifest minor symptoms but also serious reactions as respiratory difficulties and coma.
  • Cystic fibrosis (also known as CF) is a common disease which affects the entire body, causing progressive disability and often early death.
  • Difficulty breathing is the most serious symptom and results from frequent lung infections that are treated, though not cured, by antibiotics and other medications.
  • a multitude of other symptoms, including sinus infections, poor growth, diarrhea, and infertility result from the effects of CF on other parts of the body.
  • One of the aims of the present invention is to provide RBD for the detection of membrane receptors present in granulocytes indicating an inflammatory state.
  • Another aim of the invention is to provide a diagnosis and/or prognosis process of an inflammation state.
  • Still another aim of the invention is to provide a method for measuring the therapeutic efficacy of a potential anti-inflammatory drug in a mammal
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD), for the identification and quantification of the expression of membrane receptors present on the surface of target granulocytes, said identification and quantification taking place at a given time or during a given time interval, and allowing the diagnosis and/or prognosis of inflammatory states in a mammal
  • RBD soluble receptor-binding domain
  • receptor-binding domain is meant is a functional fragment (or a part) of a glycoprotein contained in the envelope of a virus so long it retains some or all of the binding properties of the RBD to a membrane receptor present on the surface of target granulocytes, and can be obtained for example by cloning.
  • One or more amino acids can be added to, deleted, or substituted from the RBD sequence of this fragment or part of glycoprotein so long it retains the ability to bind to a membrane receptor present on the surface of target granulocytes.
  • glycoprototein an envelope glycoprotein, a coat glycoprotein or a fusion glycoprotein.
  • Said part or fragment or totality of the RBD of the glycoprotein of the virus is liable to bind to or interact with one or more membrane receptor(s) of a target granulocyte.
  • the expression “liable to bind or to interact with at least one or more membrane receptor(s)” means that said part or fragment or totality of the RBD forms a complex with a receptor of the target granulocyte or to several receptors of the target granulocyte.
  • the complex may thus be formed in vitro in the case where the target granulocytes have been previously isolated from an animal
  • the complex can also be formed ex vivo.
  • the complex can also be formed in vivo in the case where the RBD is injected to an animal and interact with the target granulocytes in the animal organism.
  • membrane receptor any protein or polypeptide anchored in the plasma membrane of cells. Said membrane receptor allows the interaction with glycoprotein of viruses.
  • the membrane receptors according to the invention are members of the multimembrane-spanning protein family which functions as transporters, such as nutriment and metabolite transporters, i.e. multimembrane-spanning proteins that allow the transport of nutriments and metabolites across the plasma membrane.
  • transporters such as nutriment and metabolite transporters, i.e. multimembrane-spanning proteins that allow the transport of nutriments and metabolites across the plasma membrane.
  • target granulocyte is meant a cell belonging to myelocyte or monocyte lines and presenting a distinctive array of receptors anchored within the membrane of the cell.
  • target granulocyte can be isolated from an animal, and is for example a mammalian granulocyte, in particular neutrophils, eosinophils, basophils and mast cells, preferably during an inflammation state.
  • the expression “identification and the quantification of the expression of membrane receptors present on the surface of target granulocyte” means that when a target granulocyte expresses a membrane receptor, i.e. said receptor is present on the surface of the target granulocyte, therefore a complex is formed between the membrane receptor of a biological interest target granulocyte and RBD.
  • That complex can be detected if the RBD has been for instance, but without being limited to, covalently coupled with a detectable molecule such as an antibody constant fragment (Fc) or a fluorescent compound (cyanins, alexa, quantum dots . . . . )
  • a detectable molecule such as an antibody constant fragment (Fc) or a fluorescent compound (cyanins, alexa, quantum dots . . . . )
  • That complex can also be detected if the RBD has been tagged with different means well known by a person skilled in the art.
  • the tag used in the invention can be Hemaglutinin Tag, Poly Arginine Tag, Poly Histidine Tag, Myc Tag, Strep Tag, Flag Tag, S-Tag, HAT Tag, 3 ⁇ Flag Tag, Calmodulin-binding peptide Tag, SBP Tag, Chitin-binding domain Tag, GST Tag, Maltose-Binding protein Tag, GFP and EGFP Tag, RFPs Tag, YFP Tag, CFP Tag, T7 tag, V5 tag, Xpress tag and all fluorescent molecules having an emission maximum comprised from 445 nm to 655 nm available from Olympus America Inc.
  • RBD retinal deficiency virus
  • the use of a RBD allows therefore on the one hand the identification of the receptor expressed on the target granulocyte depending on the RBD used and on the other hand the quantification of the complex formed, and thus the presence or not of a membrane receptor on the target granulocyte and its quantification.
  • the expression “at a given time or during a given time interval” means that the detection and/or the quantification of the complex formed can be made just after the contacting of the RBD and the membrane receptor of the target granulocyte or after several minutes, in particular from 1 to 59 minutes, or several hours, in particular from 1 to 47 h, preferably 24 h, or days, in particular from 2 to 7 days, preferably 3 days, or several weeks, preferably 3 to 6 weeks when evaluating decay of said membrane receptors on the target granulocyte, after said contacting, depending on the cells and the contacting conditions, in order to evaluate the modification of the expression of membrane receptors.
  • Contacting conditions include also the temperature that can vary from 0° C. to 37° C., in particular 0, 1, 2, 3 or 4° C., preferably near room temperature, in particular from 18° C. to 25° C., in particular 18, 19, 20, 21, 22, 23, 24 or 25° C., more preferably from 26 to 37° C., in particular 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, or 37° C., preferably 30 or 37° C. depending on the target granulocytes.
  • inflammation state is meant acute or chronic inflammation occurring during allergy, asthma, acne vulgaris, autoimmune diseases, chronic prostatitis, glomerulonephritis, hypersensitivities, inflammatory bowel diseases, pelvic inflammatory disease, reperfusion injury, rheumatoid arthritis, sarcoidosis, transplant rejection, vasculitis, interstitial cystitis.
  • said inflammatory state is an inflammation of the respiratory tract.
  • the invention thus allows, by using the receptor binding domains defined above, the identification and quantification of particular expressed receptors at the surface of granulocytes cells, indicating an inflammatory state of said granulocytes, said expressed receptors being not expressed or expressed in a lesser extent in normal conditions, and therefore allowing the diagnosis and/or the prognosis of pathologies in which an inflammatory state is implicated such as pathologies defined above.
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, for the identification and quantification of the expression of membrane receptors present on the surface of target granulocytes, said identification and quantification taking place at a given time or during a given time interval, and allowing the diagnosis and/or prognosis of inflammatory states, provided that when only one RBD is used, said membrane receptor is not GLUT1.
  • RBD soluble receptor-binding domain
  • said membrane receptor identified and quantified is not GLUT1.
  • said membrane receptor is a membrane receptor other than GLUT1.
  • Said inflammatory states can be as defined above or in particular, inflammation of the respiratory tract.
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said at least one soluble receptor-binding domain is a set of three to twenty soluble receptor-binding domains, preferably a set of three to twelve soluble receptor-binding domain in particular three, four, five, six seven, eight, nine, ten, eleven, or twelve receptor-binding domain.
  • RBD soluble receptor-binding domain
  • three to up to twenty RBD are used, depending of the number of receptors being present at the surface of the cell.
  • Each RBD recognizes at least one membrane receptor and each membrane receptor is recognized by at least one RBD.
  • each RBD of said set can interact either with only one receptor, or with two or more distinct receptors, and that two or more RBDs can interact with the same membrane receptor or with two or more distinct receptors.
  • each RBD can recognize the same receptor named R 1 for example, or two or more distinct receptors R 1 and R 2 for example, or more than two distinct receptors R 1 to R n (n>3) for example, the receptors recognized by each RBD being the same or different.
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said at least one soluble receptor-binding domain is a set of three to twenty soluble receptor-binding domain, preferably a set of three to twelve soluble receptor-binding domain in particular three, four, five, six seven, eight, nine, ten, eleven, or twelve receptor-binding domain, provided that at least one soluble receptor-binding domain of said set does not interact with GLUT1 membrane receptor.
  • RBD soluble receptor-binding domain
  • each RBD recognizes at least one membrane receptor and each membrane receptor is recognized by at least one RBD.
  • each RBD of said set can interact either with the same receptor, but in this case at least one soluble receptor-binding domain of said set does not interact with GLUT1 membrane receptor, that is at least one soluble receptor-binding domain of said set interacts with a membrane receptor other than GLUT1, or with two or more distinct receptors.
  • all the combinations between the three to twenty RBD and the membrane receptors are included provide that at least one soluble receptor-binding domain of said set interacts with a membrane receptor other than GLUT 1.
  • the upper limit of the number of RBD is only due to the method used to detect the formed complex, i.e. by Fluorescence Activated Cell Sorting (FACS) the number of channels of which is at present time limited to twenty but it could be higher than twenty with other methods.
  • FACS Fluorescence Activated Cell Sorting
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said target granulocytes are selected from the list consisting of neutrophils, eosinophils, basophils and mast cells.
  • RBD soluble receptor-binding domain
  • Neutrophil granulocytes are generally referred to as either neutrophils or polymorphonuclear neutrophils (or PMNs) and form an essential part of the innate immune system.
  • Neutrophils are normally found in the blood stream. However, during the beginning (acute) phase of inflammation, neutrophils are one of the first-responders of inflammatory cells to migrate toward the site of inflammation, firstly through the blood vessels, then through interstitial tissue.
  • Basophil granulocytes also referred to as basophils, are the least common of the granulocytes. Basophils appear in many specific kinds of inflammatory reactions, particularly those that cause allergic symptoms.
  • Eosinophil granulocytes usually called eosinophils, are one of the immune system components responsible for combating multicellular parasites and certain infections in vertebrates. Along with mast cells, they also control mechanisms associated with allergy and asthma.
  • Mast cells play a key role in the inflammatory process. When activated, a mast cell rapidly releases its characteristic granules and various hormonal mediators into the interstitium. Mast cells can be stimulated to degranulate by direct injury (e.g. physical or chemical [such as opioids, alcohols, and certain antibiotics such as polymyxins]).
  • direct injury e.g. physical or chemical [such as opioids, alcohols, and certain antibiotics such as polymyxins]).
  • said membrane receptors can be chosen among, but without being limited to, CAT1, PiT2, XPR1, SMIT1, Plasmolipin, PiT1, ASCT1, ASCT2, FLVCR, feTHTR1, PAR, GLUT1.
  • PAR has been identified as PAR 1 (or hRFT3) (GenBank accession no. NM — 024531) and PAR 2 (or hRFT1).
  • Said membrane receptor can also be an unidentified receptor the complex of which with a RBD can be identified and quantify in order to identify and quantify the expression of said receptor at the surface of target granulocyte.
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said target granulocytes are neutrophils and said inflammatory state is cystic fibrosis.
  • RBD soluble receptor-binding domain
  • Cystic fibrosis (also known as CF) is a common disease which affects the entire body, causing progressive disability and often early death.
  • Difficulty breathing is the most serious symptom and results from frequent lung infections that are treated, though not cured, by antibiotics and other medications.
  • a multitude of other symptoms, including sinus infections, poor growth, diarrhea, and infertility result from the effects of CF on other parts of the body.
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said neutrophils are blood neutrophils or lung neutrophils.
  • RBD soluble receptor-binding domain
  • Airway disease in cystic fibrosis is due to the massive recruitment of blood polymorphonuclear neutrophils (PMN) into lungs.
  • PMN blood polymorphonuclear neutrophils
  • PMN in this context have been shown to go through an anabolic reprogramming suspected to be due to a complete change of metabolic physiology.
  • One of the advantages of the invention is to characterize these changes of metabolic physiology, with receptor-binding domain (RBD) of retrovirus envelope glycoproteins (Env) liable to bind transporters directly linked to cell metabolism.
  • RBD receptor-binding domain
  • Env retrovirus envelope glycoproteins
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said target granulocytes are eosinophils and said inflammatory state is allergy and/or asthma.
  • RBD soluble receptor-binding domain
  • the airway inflammation is generated by an influx of myelocyte and monocyte lines in the lungs; mostly eosinophils seem to be implied as well as neutrophils.
  • the identification and quantification of membrane receptors expressed on eosinophils and/or neutrophils is thus of interest in the diagnosis and/or prognosis of allergy and/or asthma.
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said target granulocytes are basophils and said inflammatory state is allergy.
  • RBD soluble receptor-binding domain
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said target granulocytes are masts and said inflammatory state is allergy.
  • RBD soluble receptor-binding domain
  • Allergy is also a disorder of the immune system caused by the suractivation of mast cells and/or basophils when they identify allergen-specific immunoglobulin IgE.
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said RBD is selected from the list consisting of SEQ ID NO: 1 to 31.
  • RBD soluble receptor-binding domain
  • the SEQ IDs 1 to 31 are constituted of the signal peptide when known, the receptor binding domain, the proline rich region (PRR) when known and the CXXC motif located downstream of the PRR.
  • SEQ IDs 1 to 31 defined above is not limitative and can be extended to all the RBD that can be found in a mammal
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said RBD is selected from the list consisting of: Amphotropic Murine Leukemia Retrovirus (AMLV, SEQ ID NO:1), Feline endogenous retrovirus (RD114, SEQ ID NO:3), Koala endogeneous Retrovirus (KoRV, SEQ ID NO: 20), Human T Leukaemia Virus-2 (HTLV2, SEQ ID NO:28), Bovine Leukaemia Virus (BLV, SEQ ID NO: 30), or Porcine Endogeneous Retrovirus-A (Pery A, SEQ ID NO:21).
  • ALV Amphotropic Murine Leukemia Retrovirus
  • RD114 Feline endogenous retrovirus
  • KoRV Koala endogeneous Retrovirus
  • HTLV2 Human T Leukaemia Virus-2
  • BLV Bovine Leukaemia Virus
  • Pery A SEQ ID NO:21
  • one RBD can be enough to identify and quantify the membrane receptors expressed on said granulocyte, but in some cases, two or more RBD are necessary to carry out said identification and quantification.
  • single RBD or combinations of RBD of examples 1 to 3 are used as examples only and it is obvious that other single RBD or combinations of RBD can be used for identification and quantification of the expression of membrane receptors present on the surface of target granulocytes.
  • the invention discloses the use as defined above, wherein said RBD is Amphotropic Murine Leukemia Retrovirus (AMLV, SEQ ID NO:1).
  • AMLV Amphotropic Murine Leukemia Retrovirus
  • the invention discloses the use as defined above, wherein said RBD is Feline endogenous retrovirus (RD 114, SEQ ID NO:3).
  • the invention discloses the use as defined above, wherein said RBD is Koala endogeneous Retrovirus (KoRV, SEQ ID NO: 20).
  • the invention discloses the use as defined above, wherein said RBD is Human T Leukaemia Virus-2 (HTLV2, SEQ ID NO:28).
  • RBD Human T Leukaemia Virus-2 (HTLV2, SEQ ID NO:28).
  • the invention discloses the use as defined above, wherein said RBD is Bovine Leukaemia Virus (BLV, SEQ ID NO: 30).
  • BLV Bovine Leukaemia Virus
  • the invention discloses the use as defined above, wherein said RBD is Porcine Endogeneous Retrovirus-A (Pery A, SEQ ID NO:21).
  • the invention discloses the use as defined above, wherein said RBD is a combination of two soluble RBD selected from the list consisting of: Amphotropic Murine Leukemia Retrovirus (AMLV, SEQ ID NO:1), Feline endogenous retrovirus (RD114, SEQ ID NO:3), Koala endogeneous Retrovirus (KoRV, SEQ ID NO: 20), Human T Leukaemia Virus-2 (HTLV2, SEQ ID NO:28), Bovine Leukaemia Virus (BLV, SEQ ID NO: 30), or Porcine Endogeneous Retrovirus-A (Pery A, SEQ ID NO:21).
  • AMLV Amphotropic Murine Leukemia Retrovirus
  • RD114 Feline endogenous retrovirus
  • KoRV Koala endogeneous Retrovirus
  • HTLV2 Human T Leukaemia Virus-2
  • BLV Bovine Leukaemia Virus
  • Pery A SEQ ID NO:21
  • the invention discloses the use as defined above, wherein said RBD is a combination of three soluble RBD selected from the list consisting of: Amphotropic Murine Leukemia Retrovirus (AMLV, SEQ ID NO:1), Feline endogenous retrovirus (RD114, SEQ ID NO:3), Koala endogeneous Retrovirus (KoRV, SEQ ID NO: 20), Human T Leukaemia Virus-2 (HTLV2, SEQ ID NO:28), Bovine Leukaemia Virus (BLV, SEQ ID NO: 30), or Porcine Endogeneous Retrovirus-A (Pery A, SEQ ID NO:21).
  • AMLV Amphotropic Murine Leukemia Retrovirus
  • RD114 Feline endogenous retrovirus
  • KoRV Koala endogeneous Retrovirus
  • HTLV2 Human T Leukaemia Virus-2
  • BLV Bovine Leukaemia Virus
  • Pery A SEQ ID NO:21
  • the invention discloses the use as defined above, wherein said RBD is a combination of four soluble RBD selected from the list consisting of: Amphotropic Murine Leukemia Retrovirus (AMLV, SEQ ID NO:1), Feline endogenous retrovirus (RD114, SEQ ID NO:3), Koala endogeneous Retrovirus (KoRV, SEQ ID NO: 20), Human T Leukaemia Virus-2 (HTLV2, SEQ ID NO:28), Bovine Leukaemia Virus (BLV, SEQ ID NO: 30), or Porcine Endogeneous Retrovirus-A (Pery A, SEQ ID NO:21).
  • AMLV Amphotropic Murine Leukemia Retrovirus
  • RD114 Feline endogenous retrovirus
  • KoRV Koala endogeneous Retrovirus
  • HTLV2 Human T Leukaemia Virus-2
  • BLV Bovine Leukaemia Virus
  • Pery A SEQ ID NO:21
  • the invention discloses the use as defined above, wherein said RBD is a combination of five soluble RBD selected from the list consisting of: Amphotropic Murine Leukemia Retrovirus (AMLV, SEQ ID NO:1), Feline endogenous retrovirus (RD114, SEQ ID NO:3), Koala endogeneous Retrovirus (KoRV, SEQ ID NO: 20), Human T Leukaemia Virus-2 (HTLV2, SEQ ID NO:28), Bovine Leukaemia Virus (BLV, SEQ ID NO: 30), or Porcine Endogeneous Retrovirus-A (Pery A, SEQ ID NO:21).
  • AMLV Amphotropic Murine Leukemia Retrovirus
  • RD114 Feline endogenous retrovirus
  • KoRV Koala endogeneous Retrovirus
  • HTLV2 Human T Leukaemia Virus-2
  • BLV Bovine Leukaemia Virus
  • Pery A SEQ ID NO:21
  • the invention discloses the use as defined above, wherein said RBD is a combination of six soluble RBD selected from the list consisting of: Amphotropic Murine Leukemia Retrovirus (AMLV, SEQ ID NO:1), Feline endogenous retrovirus (RD114, SEQ ID NO:3), Koala endogeneous Retrovirus (KoRV, SEQ ID NO: 20), Human T Leukaemia Virus-2 (HTLV2, SEQ ID NO:28), Bovine Leukaemia Virus (BLV, SEQ ID NO: 30), or Porcine Endogeneous Retrovirus-A (Pery A, SEQ ID NO:21).
  • AMLV Amphotropic Murine Leukemia Retrovirus
  • RD114 Feline endogenous retrovirus
  • KoRV Koala endogeneous Retrovirus
  • HTLV2 Human T Leukaemia Virus-2
  • BLV Bovine Leukaemia Virus
  • Pery A SEQ ID NO:21
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said at least one soluble receptor-binding domain is a combination of two soluble receptor-binding domain (RBD).
  • RBD soluble receptor-binding domain
  • At least one of said soluble receptor-binding domain of said combination does not interact with GLUT1 membrane receptor, that is at least one soluble receptor-binding domain of said combination interacts with a membrane receptor other than GLUT1.
  • AMLV Amphotropic Murine Leukemia Retrovirus
  • RD114 Feline endogenous retrovirus
  • AMLV Amphotropic Murine Leukemia Retrovirus
  • KiRV Koala endogeneous Retrovirus
  • AMLV Amphotropic Murine Leukemia Retrovirus
  • HTLV2 Human T Leukaemia Virus-2
  • AMLV Amphotropic Murine Leukemia Retrovirus
  • BLV Bovine Leukaemia Virus
  • AMLV Amphotropic Murine Leukemia Retrovirus
  • Pery A Porcine Endogeneous Retrovirus-A
  • RD 114 Feline endogenous retrovirus (RD 114, SEQ ID NO:3) and Human T Leukaemia Virus-2 (HTLV2, SEQ ID NO:28),
  • RD114 Feline endogenous retrovirus
  • BLV Bovine Leukaemia Virus
  • HTLV2 Human T Leukaemia Virus-2 (HTLV2, SEQ ID NO:28) and Bovine Leukaemia Virus (BLV, SEQ ID NO: 30).
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said combination is the combination of HTLV-2 RBD (SEQ ID NO: 28) and KoRV RBD (SEQ ID NO: 20) and said membrane receptors are GLUT1 and PiT1 respectively, said membrane receptors being expressed in particular in lung neutrophils and blood neutrophils.
  • RBD soluble receptor-binding domain
  • the present invention relates to the use of said combination of HTLV-2 RBD (SEQ ID NO: 28) and KoRV RBD (SEQ ID NO: 20) as defined above, wherein the expression of said membrane receptors in lung neutrophils is increased compared with the expression of said membrane receptor in blood neutrophils.
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said soluble receptor binding domains are a combination of RD114 RBD (SEQ ID NO:3) and AMLV RBD (SEQ ID NO:1) and said membrane receptors are ASCT2 and PiT2 respectively.
  • RBD soluble receptor-binding domain
  • the present invention relates to the use of said combination of RD114 RBD (SEQ ID NO:3) and AMLV RBD (SEQ ID NO:1) as defined above, wherein the expression of one or both said membrane receptors in lung neutrophils is increased or decreased compared with the expression of said membrane receptors in blood neutrophils.
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein said combination is the combination of PERVA RBD (SEQ ID NO: 21) and BLV RBD (SEQ ID NO: 30) and said membrane receptors are PAR and a membrane receptor interacting with BLV respectively, said membrane receptors being potentially expressed in particular in lung neutrophils and blood neutrophils.
  • RBD soluble receptor-binding domain
  • PERVA RBD can interact with PAR1 (hRFT3) and PAR2 (hRFT1).
  • the present invention relates to the use of at least one soluble receptor-binding domain (RBD) as defined above, wherein the expression of said PAR membrane receptor in lung neutrophils is decreased compared with the expression of said membrane receptor in blood neutrophils and said receptor interacting with BLV in lung neutrophils is increased compared with the expression of said membrane receptor in blood neutrophils.
  • RBD soluble receptor-binding domain
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, comprising the identification and quantification of the expression of at least one membrane receptors, said identification and quantification being as defined as defined above, present on the surface of target granulocytes.
  • the present invention relates to a process of in vitro diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, wherein the target granulocytes have been previously isolated from a mammal
  • the present invention relates to a process of ex vivo diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above.
  • the present invention relates to a process of in vivo diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above.
  • the RBD is injected to a mammal and interact with the target granulocytes in the mammal organism, the identification and quantification of the expression of at least one membrane receptors being carried out on the surface of target granulocytes of said mammal
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, comprising the identification and quantification of the expression of at least one membrane receptors, said identification and quantification being as defined above, present on the surface of target granulocytes, provided that when only one RBD is used, said membrane receptor is not GLUT1, and when two or more RBD are used, at least one of said soluble receptor-binding domain does not interact with GLUT1 membrane receptor.
  • the present invention relates to a process of in vitro diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, wherein when only one RBD is used, said membrane receptor is not GLUT1, i.e. said membrane receptor is a membrane receptor other than GLUT1, and when two or more RBD are used, at least one of said soluble receptor-binding domain does not interact with GLUT1 membrane receptor, i.e. at least one soluble receptor-binding domain interacts with a membrane receptor other than GLUT 1.
  • the present invention relates to a process of ex vivo diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, wherein when only one RBD is used, said membrane receptor is not GLUT1, i.e. said membrane receptor is a membrane receptor other than GLUT1, and when two or more RBD are used, at least one of said soluble receptor-binding domain does not interact with GLUT1 membrane receptor, i.e. at least one soluble receptor-binding domain interacts with a membrane receptor other than GLUT 1.
  • the present invention relates to a process of in vivo diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, wherein when only one RBD is used, said membrane receptor is not GLUT1, i.e. said membrane receptor is a membrane receptor other than GLUT1, and when two or more RBD are used, at least one of said soluble receptor-binding domain does not interact with GLUT1 membrane receptor, i.e. at least one soluble receptor-binding domain interacts with a membrane receptor other than GLUT 1.
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, comprising the following steps:
  • granulocytes of a healthy mammal that has no inflammatory state is the control of the process.
  • the contact of at least one soluble receptor-binding domain, as defined above, optionally marked with a tag, with target granulocytes of a diseased mammal or of a control mammal is comprised from about 15 min to about 45 min and in particular 30 min at a temperature as defined above.
  • the overexpression or the underexpression of one membrane receptor of a diseased mammal compared with the expression of said membrane receptor in a control mammal is a specific biomarker of inflammation.
  • the process of diagnosis and/or prognosis of an inflammatory state in a mammal comprises a step a. wherein two RBD are used as specific biomarker of inflammation.
  • the process of diagnosis and/or prognosis of an inflammatory state in a mammal comprises a step a. wherein three RBD are used as specific biomarker of inflammation as specific biomarker of inflammation.
  • the process of diagnosis and/or prognosis of an inflammatory state in a mammal comprises a step a. wherein four RBD are used as specific biomarker of inflammation.
  • the process of diagnosis and/or prognosis of an inflammatory state in a mammal comprises a step a. wherein five RBD are used as specific biomarker of inflammation.
  • the process of diagnosis and/or prognosis of an inflammatory state in a mammal comprises a step a. wherein six RBD are used as specific biomarker of inflammation.
  • the process of diagnosis and/or prognosis of an inflammatory state in a mammal comprises a step a. wherein seven to twenty RBD are used as specific biomarker of inflammation.
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, wherein said control mammal is the same mammal species as the diseased mammal
  • granulocytes of said diseased mammal that has an inflammatory state is also the control of the process.
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, wherein said granulocytes are neutrophils, in particular blood neutrophils and lung neutrophils.
  • blood PMNs (quiescents) that have been sampled from each patients, at the same time, are the control of lung PMN (activated).
  • patient group having a level of inflammation significantly different from patient groups with higher level of inflammation can also be considered as controls group (see Example 2).
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, wherein the inflammatory state is cystic fibrosis.
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, comprising the following steps:
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, comprising the following steps:
  • the level of expression of both receptors is a biomarker of a severe pulmonary inflammatory state during cystic fibrosis.
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, comprising the following steps:
  • the process of diagnosis and/or prognosis of an inflammatory state in a mammal defined above comprised a step a. wherein three RBD, are used as specific biomarkers of CF.
  • Table I specifies all the combinations of three RBD that can be used:
  • the process of diagnosis and/or prognosis of an inflammatory state in a mammal defined above comprised a step a. wherein four RBD are used as specific biomarker of CF.
  • Table II specifies all the combinations of four RBD that can be used:
  • the process of diagnosis and/or prognosis of an inflammatory state in a mammal defined above comprised a step a. wherein five RBD are used as specific biomarker of CF.
  • Table III specifies all the combinations of five receptor RBD that can be used:
  • the process of diagnosis and/or prognosis of an inflammatory state in a mammal defined above comprised a step a. wherein six RBD such as HTLV-2/KoRV/RD114/AMLV/BLV/PERVA are used as specific biomarker of CF.
  • six RBD such as HTLV-2/KoRV/RD114/AMLV/BLV/PERVA are used as specific biomarker of CF.
  • the processes according to the invention defined above show that overexpression and/or underexpression membrane receptors of target granulocytes expressed in lung neutrophils compared with blood neutrophils, and identified and quantified by of one, two, three four, five or six RBD or more(up to twenty) are specific biomarkers of an inflammatory state during cystic fibrosis.
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, wherein said granulocytes are eosinophils.
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, wherein said granulocytes are basophils.
  • the present invention relates to a process of diagnosis and/or prognosis of an inflammatory state in a mammal, as defined above, wherein said granulocytes are mast cells.
  • the present invention relates to a method for measuring the therapeutic efficacy of a potential anti-inflammatory drug in a mammal, comprising the following steps:
  • the present invention relates to a method for in vitro measuring the therapeutic efficacy of a potential anti-inflammatory drug in a mammal, comprising the step a. to d. defined above, wherein the target granulocytes have been previously isolated from a mammal
  • the present invention relates to a method for ex vivo measuring the therapeutic efficacy of a potential anti-inflammatory drug in a mammal, comprising the step a. to d. defined above.
  • the present invention relates to a method for in vivo measuring the therapeutic efficacy of a potential anti-inflammatory drug in a mammal, comprising the step a. to d. defined above, wherein the RBD is injected to a mammal and interact with the target granulocytes in the mammal organism, and the drug liable to treat said inflammatory state is injected to a mammal, the identification and quantification of the expression of at least one membrane receptors being carried out on the surface of target granulocytes of said mammal
  • the present invention relates to methods for measuring the therapeutic efficacy of a potential anti-inflammatory drug in a mammal, as defined above, wherein step a. is carried out provided that when only one RBD is used, said membrane receptor is not GLUT1, i.e. said membrane receptor is a membrane receptor other than GLUT1, and when two or more RBD are used, at least one of said soluble receptor-binding domain does not interact with GLUT1 membrane receptor, i.e. at least one soluble receptor-binding domain interacts with a membrane receptor other than GLUT 1.
  • anti-inflammatory drug identified above can be used for the preparation of a drug intended for the treatment of inflammatory states, such as cystic fibrosis, allergy or asthma.
  • FIG. 1 presents the construction strategy of receptor-binding domain (RBD or RBD-derived probes) from y and 8 viral Receptor-Binding Domain (RBD) of envelope glycoprotein (Env).
  • RBD receptor-binding domain
  • Env envelope glycoprotein
  • FIG. 2 presents the sample processing in CF. Both blood and sputum are collected from children and adults, centrifuged at 400 g to pellet cells, which are fixed and then frozen at ⁇ 80° C. until analyze.
  • FIGS. 3A to 3D present the gating strategy for population discrimination.
  • single live neutrophils are gated via two analytical gates, as depicted on the upper left panel ( FIGS. 3A and 3B ).
  • FSC-A Forward light scatter-area
  • SSC-A Side light scatter-area
  • FSC-H Forward light scatter-Height
  • DRAQ5TM marker of cell viability.
  • FIGS. 4A and 4B presents the RBD binding and transporter expression.
  • FIG. 4A present the expression of GLUT1 in Blood neutrophils (upper half, upper unfilled curve corresponding to the mock and black filled curve correspond to the binding of GLUT1) and in Sputum neutrophils (lower half, upper unfilled curve corresponding to the mock and black filled curve corresponding to the binding of GLUT1).
  • FIG. 4B present the expression of PiT1 in Blood neutrophils (upper half, upper unfilled curve corresponding to the mock and black filled curve correspond to the binding of PiT1) and in Sputum neutrophils (lower half, upper unfilled curve corresponding to the mock and black filled curve corresponding to the binding of PiT1).
  • HTLV-2 and KoRV RBDs as Markers of CF in Blood and Lung Neutrophils
  • HTLV-2 RBD/KoRV RBD were mixed together to obtained a combination of probes.
  • Cells ⁇ 250.10 3 , blood and sputum neutrophils, see FIG. 2 ) are incubated with this combination holding tagged-RBD either with EGFP, mouse-IgG Fc or rabbit-IgG Fc.
  • the latters required a secondary stain with a specific antibody to the particular Fc to be detected (Anti-mouse Fc Alexa Fluor® 405 conjugate and/or Anti-rabbit Fc Alexa Fluor® 488 conjugate; both from MOLECULAR PROBES® by InvitrogenTM).
  • CTB Cholera Toxin B
  • Table IV is representative of 16 patients for Glutl and PiT1 expression.
  • HTLV-2 RBD or KoRV RBD used in example 1 could have been used alone as specific biomarkers of PMN activation in CF, and
  • HTLV-2/AMLV or HTLV-2/RD114 or KoRV/AMLV or KoRV/RD 114 would have lead to similar diagnosis prognosis, and
  • RD114 and AMLV RBDs as Markers of CF in Blood and Lung Neutrophils
  • RD114 RBD/AMLV RBD were mixed together to obtained a combination of probes.
  • Cells ⁇ 250.10 3 , blood and sputum neutrophils, see FIG. 2 ) are incubated with this combination holding tagged-RBD either with EGFP, mouse-IgG Fc or rabbit-IgG Fc.
  • the latters required a secondary stain with a specific antibody to the particular Fc to be detected.
  • CTB Cholera Toxin B
  • Results are presented on table V: Characterization of CF inflammation by airway PMN count, ASCT2 and PiT2 expression.
  • RBD of examples 1 and 2 can be combined.
  • a combination of three RBD described in example 1 and 2 HTLV-2/KoRV/RD114 or HTLV-2/KoRV/AMLV or HTLV-2/RD 114/AMLV or KoRV/RD114/AMLV, or
  • PERVA and BLV RBDs as markers of CF in blood and lung neutrophils
  • PERVA RBD/BLV RBD were mixed together to obtained a combination of probes, or used separately.
  • Cells ⁇ 250.10 3 , blood and sputum neutrophils, see FIG. 2 ) are incubated with this combination holding tagged-RBD either with EGFP, mouse-IgG Fc or rabbit-IgG Fc.
  • the latters required a secondary stain with a specific antibody to the particular Fc to be detected.
  • CTB Cholera Toxin B
  • Results are presented on table VI: PervA and BLV RBDs binding. DeltaGeomean of fluorescence measures on one patient samples.
  • PERVA RBD derived from the porcine endogenous retrovirus A, binds PAR (for PeRV A Receptor) receptors, including the human Riboflavin Transporter 1 (hRFT1 or PAR2) and hRFT3 (or PAR1), was tested in a single patient and allowed to see a down regulation of its cognate receptors on airway neutrophils.
  • PAR for PeRV A Receptor
  • hRFT1 or PAR2 human Riboflavin Transporter 1
  • hRFT3 or PAR1
  • RBDs Some of the RBDs are probes for not yet identified transporters.
  • BLV RBD derived from Bovine Leukemia Virus has been used to see if it was differentially expressed between blood and airway PMN.
  • Results obtained from one patient showed a higher binding on CF pulmonary activated neutrophils, evidencing the relevance of BLV RBD as a specific biomarker of PMN activation in CF.
  • Example 3 shows that PAR1 (hRFT3) and PAR2 (hRFT1) on airway PMN in patients is downregulated in the sputum compared to the blood and that the receptor interacting with BLV is overexpressed in blood compared with the blood.
  • the receptor interacting with BLV has not been detected in blood but it cannot be said that this receptor in not present at all in blood neutrophils.
  • RBDs as Markers of Asthma and/or Allergy in Blood and Lung Eosinophils
  • Example 4 show that overexpression and/or underexpression membrane receptors of target granulocytes expressed in lung eosinophils compared with blood eosinophils and identified and quantified by of one, two, three four, five or six RBD are specific biomarkers of allergy and/or asthma.
  • Example 5 show that overexpression and/or underexpression membrane receptors of target granulocytes expressed in lung basophils compared with blood basophils and identified and quantified by of one, two, three four, five or six RBD are specific biomarkers of allergy.
  • Example 6 show that overexpression and/or underexpression membrane receptors of target granulocytes expressed in lung mast cells compared with blood mast cells and identified and quantified by of one, two, three four, five or six RBD are specific biomarkers of allergy.

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