EP1377835A2 - Procede de recherche de toxines microbielles dans des substances aptes a l'ecoulement - Google Patents

Procede de recherche de toxines microbielles dans des substances aptes a l'ecoulement

Info

Publication number
EP1377835A2
EP1377835A2 EP02729818A EP02729818A EP1377835A2 EP 1377835 A2 EP1377835 A2 EP 1377835A2 EP 02729818 A EP02729818 A EP 02729818A EP 02729818 A EP02729818 A EP 02729818A EP 1377835 A2 EP1377835 A2 EP 1377835A2
Authority
EP
European Patent Office
Prior art keywords
flow
incubation
toxins
separating elements
liquids
Prior art date
Legal status (The legal status 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 status listed.)
Withdrawn
Application number
EP02729818A
Other languages
German (de)
English (en)
Inventor
Thomas Dr.Rer.Nat. Dr.Med. Hartung
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Individual
Original Assignee
Individual
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 Individual filed Critical Individual
Publication of EP1377835A2 publication Critical patent/EP1377835A2/fr
Withdrawn legal-status Critical Current

Links

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
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
    • G01N33/6863—Cytokines, i.e. immune system proteins modifying a biological response such as cell growth proliferation or differentiation, e.g. TNF, CNF, GM-CSF, lymphotoxin, MIF or their receptors
    • G01N33/6869—Interleukin

Definitions

  • the health of living beings depends, among other things, on the air quality of the immediate living environment.
  • the quality of the indoor climate such as in living rooms and work rooms, workshops, public buildings and means of transport, both in non-air-conditioned, but especially in air-conditioned rooms, is mainly determined by the components temperature, humidity and content of dust and immune-activating pollutants in the air.
  • Liquids such as water, aqueous liquids, biological as well as technical liquids, especially liquids and their vapors, which come into contact or are in contact with the human body, can also be renden components such.
  • B. pyrogens can be burdened with considerable consequences for products made from them. These include e.g. B. drinks, infusion and injection solutions, serums, dialysis fluids, disinfectant solutions, e.g. B. for the cleaning of medical materials, rinsing solutions, for commercial and for use in medicine, for. B.
  • This object is achieved according to the invention by a method for testing and, if necessary, quantitative analysis of gases and liquids for contents of microbiological toxins using a separation process, wherein separating elements are used to separate microbiological toxins from the gas or the liquid, which are used in a Flow-through containers are contained, the flow-through container containing separating elements after flow through the gas to be tested or the liquid to be tested is used as an incubation vessel for incubation with immunoreactive cells, such as the whole blood detection method, and then after incubation in a manner known per se Investigation is carried out on such mediators that were formed in the incubation phase in the presence of toxins.
  • Gases in the sense of the invention are gaseous, flowable media of all kinds. Games for this are in particular air, e.g. B. from the living and working area, for which reference is made to the above statements, but also aerosols such as dusts and fog.
  • gases and gas mixtures which can be tested by the method according to the invention are anesthetic gases, protective gases or reaction-inert gases, and protective gas mixtures e.g. B. for commercial, biotechnical, pharmaceutical and food technology processes such as fermentations, cell cultures and the like, carbon dioxide, nitrogen and mixtures thereof with other gases.
  • liquids in the sense of the invention generally include flowable media, in particular low and medium viscosity, Newtonian liquids and brine. Water, e.g. B.
  • Testable liquids include e.g. B. biological liquids such as urine, blood, liquid blood components such as serum or plasma and blood substitutes. To avoid repetition, reference is also made to the liquid examples mentioned above, especially from the food, medical and technical fields.
  • microbiological toxins within the meaning of the invention include, for. B. endotoxins, pyrogens, any microbial contamination, immune-activating or cell-activating substances and components, including biological, especially synthetic warfare agents, as well as substances, components and particles, which substances of the aforementioned type are capable of forming or dispensing.
  • the data gas and liquid do not necessarily relate to the physical state at room temperature, although preferably to the physical state during the separation.
  • the separation can be quantitative, e.g. B. to free the gases and liquids from toxins, in particular but for the quantitative determination of toxin contamination in the respective test medium.
  • the invention also includes the separation of toxins in an amount necessary for their qualitative detection.
  • Very preferred separating elements are filters, also in the usual sense, such as filter papers, filter mats or filter fleeces made of the most varied materials, such as filters with contents of fibers made of cellulose or cellulose esters, PVC, polyesters, polycarbonates, polytetrafluoroethylene.
  • inorganic filter materials can be used, e.g. B. with glass fibers as filter material, and glass or porcelain frits.
  • Polar, non-polar, organic, inorganic, porous or microporous granules such as exchange resins, and diatomaceous earth, perlite, activated carbon, melamine resin, proteins and / or polyamide are also suitable as separating elements, even if arranged on supports.
  • the separating elements preferably have porous granules, such as exchange resins, toxin-reactive groups or loads. This allows a special adaptation to the test medium and the expected type and amount of toxin. When using gases, such as air, as the test medium, for fluidic reasons (filtrate speed) z. B.
  • filter papers or filter mats particularly proven while for the separation of toxins from liquid test medium, such as blood or blood components, as separating elements having toxin-reactive groups, exchange resin-like granules of suitable pore size and layer thickness or toxin-reactive groups, other separating elements of the aforementioned type, in particular have proven.
  • molecular sieves can also be used.
  • Microfiltration is also suitable, as is used for the separation of proteins, pyrogens, enzymes and viruses and for the production of germ-free products with the known filters, or also ultrafiltration with membrane filters, e.g. B. with pore sizes from 0.2 ⁇ a to 20 ⁇ a.
  • Pressure filtration can be used to set the desired ratios of filtrate speed and separability.
  • Typical filters can have, for example, pore sizes of 1 to 10 ⁇ m, in particular 3 to 8 ⁇ m, depending on the viscosity of the medium to be tested and the type and amount of the expected toxin. In the case of liquids, filters with larger pores have also proven successful in some cases, whereby the particle size of the toxins to be expected must also be taken into account.
  • the separating elements are detachable or non-detachable in flow-through containers.
  • the separating elements which are detachably connected to the flow-through containers are, it has proven itself if the separating elements as inserts in a frame, for. B. made of polystyrene. Thanks to the interchangeability of the insert, the use of such inserts has the advantage that a flow container can be used several times. So z. B. Air collection devices according to EN, DIN or ISO standards can be used.
  • the detachable arrangement of granules according to the invention having toxin-reactive groups according to the type of the exchange resin has proven to be advantageous, since z. B.
  • the flow-through container itself is usually tubular, funnel-shaped or box-like made of inert material, such as plastic or metal with oval, rectangular, circular, polygonal or any other cross-section, as required, the size of the cross-sectional area in the area of the separating elements mainly from Viscosity of the test medium, the intended throughput, the predetermined throughput rate (filtration rate), the expected type and possible concentration of the toxins, whether in the main or secondary flow, and the like is determined.
  • the filtration speed and amount of the gas and liquid flow can be based on the principle of pressure filtration by pumping or suction and z. B. in the case of liquids, by using gravity through the flow-through container as a function of the cross-sectional area and the layer or filter cake thickness of the separating element. In this way, even if the toxin concentration in the flowable medium is below the detection limit or extremely low, an enrichment can still be used to detect toxins or provide reliable detection.
  • the concentration of microbiological toxins in the test medium for. B. in the blood or serum.
  • the method accordingly also relates to a flow-through Containers with at least two openings, a supply opening for supplying the flowable medium to be tested and an outlet opening as well as with separable or non-releasably connected separating elements for separating microbiological toxins, the separating element being arranged in the flow area between the supply and the outlet opening.
  • the separating element is also arranged as a filter cake essentially perpendicular to the main flow direction and / or in such a way that a forced flow through the separating element is achieved, e.g. B. by extending the separating element substantially over the entire cross-sectional area of the flow container in the region of the seat of the separating element.
  • the flow-through container has sealing elements in the respective opening area (feed opening, outlet opening) which seal a toxin-impermeable closure, e.g. B. with caps or similar cover closures.
  • covers are provided which are adapted to the openings and, if appropriate, have sealing elements.
  • a particular advantage is if the incubation with immunoreactive cells or after the whole blood detection method can be carried out in the flow-through container which contains the separating element as a carrier of any microbiological toxins of the flowable medium, without using it, for example, when using a blood serum or -plasma as test liquid and a toxin-reactive granulate as separating elements to exclude the whole blood incubation of the separating element after it has been removed from the flow device in a separate incubation vessel.
  • the procedure mentioned at the outset is particularly simple and excludes any falsification or artifacts caused by handling, such as removal, transfer and transport of the separating element for further investigation.
  • this procedure has the advantage that such a flow-through container can be closed easily, e.g. B. can be sent to specialist laboratories for testing for microbiological toxins using the immunoreactive whole blood incubation method.
  • the procedure according to the invention leads simply and reliably to clear, reproducible results.
  • Whole blood detection methods or incubation methods in the present context are understood to be methods as described in EP 0 741 294 A2 and / or EP 0 851 231 A2 and which are the content of the present statements by this express reference.
  • the separating elements of the flow-through containers after flowing through with the flowable medium, are brought into contact with preparations containing whole blood under incubation and then after incubation, the preparation in a manner known per se, e.g. B. in ELISA or EIA, on the formation of mediators, for. B. cytokines, such as IL-1, IL-6, TNF, prostaglandin E 2 , examined.
  • Animal or human whole blood such as B. freshly obtained, possibly diluted blood from healthy human donors can be used as a reagent without separation of individual components.
  • the leukocytes are thus in their natural composition and environment.
  • all serum components are present that could influence the effect of a toxin.
  • the whole blood contains anticoagulant or anticoagulant components such as citrate, such as. B. in a final concentration of 0.38%, or heparin, such as Na-heparin or heparin fractions, it being essential to recognize that the anticoagulant or anticoagulant constituents do not impair or even falsify the incubation reaction.
  • a dilution of the whole blood preparation e.g. B.
  • the process is highly sensitive and largely independent of the donor (a few pg / ml toxins lead to the release of mediators such as cytokines).
  • preparations of Gram-negative and Gram-positive bacterial walls such as endotoxin and lipoteichoic acid, can be used for negative control, e.g. B. pyrogen-free physiological saline can be used.
  • the process has a number of advantages.
  • the body's primary reaction of the formation of mediators to the administration of microbiological toxins is used for the investigation. All blood components are present those that may be necessary for the toxins to interact with the leukocytes, e.g. B. LPS-binding protein LBP, bactericidal permeability-increasing protein BPI, soluble CD 14, defensins, etc.
  • whole blood detection or incubation can also be carried out with the whole blood of those affected using a flowable test medium , Gas or liquid that comes from their individual environment. In this way, individual responsiveness can be determined and a hypersensitive patient identified.
  • whole blood preparations are made from 8 ml of physiological saline of clinical quality and 2 ml heparinized whole blood (blood collection with 7.5 ml heparinized monovettes, Sarstedt) from healthy donors.
  • the flow-through containers equipped with whole blood preparation are z. B. at 37 ° C, 5% C0 2 overnight (18 - 24 hours).
  • the incubated solution can then be mixed well with a pipette, transferred to sterile flacon tubes and z. B. centrifuged for 2 minutes at 4000 g and room temperature.
  • the supernatants can be stored in the cold, then measured in an ELISA for interleukin-1 ⁇ and optically quantified (OD) and then converted into the amount of interleukin-1 (IL-1) using a standard that is included.
  • Flow containers containing unloaded filters serve as a control (FIG. 1).
  • a physiological saline mixed with 10 pg / l endotoxin from E. coli was used to test liquids.
  • the sample was diluted 1:10 to a contamination concentration below the detection limit.
  • a polycarbonate flow container with a polyethylene styrene filter with a pore diameter of 0.2 ⁇ m was used for the separation.
  • the solution to be tested was sucked through the filter by applying a vacuum (filtration volume 100 ml, 250 ml or 500 ml).
  • the flow-through containers containing filters were incubated after addition of 400 ⁇ l of physiological (clinical) saline and 50 ⁇ l of heparinized blood at 37 ° C., 5% CO 2 , for 24 h and determined in the supernatant IL-lß- in the ELISA. It can be seen in FIG. 2 that the slightly endotoxin-contaminated sample gives a signal corresponding to the saline control.
  • the flow container containing the untreated filter itself gives a low signal (0 ml), which is increased depending on the amount of sample flushed. A quantifiable amount of endotoxin was therefore retained and enriched.
  • FIG. 3 shows an example of a flow or collecting container containing a separating element according to the invention.
  • the illustrated through-flow container 1 which is approximately 5-10 times larger than the preferred containers, has an essentially cylindrical jacket 2, a separating element 3 between the feed opening located at the bottom and the outlet opening recognizable at the top, and covers 4 and 5 for the toxin-impermeable closure.
  • the flow direction for the flowable test medium is essentially axially parallel to the cylinder axis.

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  • Life Sciences & Earth Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Immunology (AREA)
  • Molecular Biology (AREA)
  • Engineering & Computer Science (AREA)
  • Cell Biology (AREA)
  • Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Urology & Nephrology (AREA)
  • Hematology (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Food Science & Technology (AREA)
  • Medicinal Chemistry (AREA)
  • Physics & Mathematics (AREA)
  • Analytical Chemistry (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • General Physics & Mathematics (AREA)
  • Pathology (AREA)
  • Investigating Or Analysing Biological Materials (AREA)
  • Measuring Or Testing Involving Enzymes Or Micro-Organisms (AREA)

Abstract

La présente invention concerne la recherche de toxines microbiennes dans des substances aptes à l'écoulement, grâce à l'incubation de sang entier dans un récipient d'écoulement contenant un élément de séparation, et la recherche de médiateurs.
EP02729818A 2001-04-12 2002-03-25 Procede de recherche de toxines microbielles dans des substances aptes a l'ecoulement Withdrawn EP1377835A2 (fr)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
DE10118446 2001-04-12
DE10118446A DE10118446A1 (de) 2001-04-12 2001-04-12 Prüfverfahren zur Untersuchung fließfähiger Medien auf Gehalte an mikrobiellen Toxinen
PCT/DE2002/001086 WO2002084295A2 (fr) 2001-04-12 2002-03-25 Procede de recherche de toxines microbiennes dans des substances aptes a l'ecoulement

Publications (1)

Publication Number Publication Date
EP1377835A2 true EP1377835A2 (fr) 2004-01-07

Family

ID=7681476

Family Applications (1)

Application Number Title Priority Date Filing Date
EP02729818A Withdrawn EP1377835A2 (fr) 2001-04-12 2002-03-25 Procede de recherche de toxines microbielles dans des substances aptes a l'ecoulement

Country Status (5)

Country Link
US (1) US7745107B2 (fr)
EP (1) EP1377835A2 (fr)
JP (1) JP4291580B2 (fr)
DE (2) DE10118446A1 (fr)
WO (1) WO2002084295A2 (fr)

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CA3007408A1 (fr) * 2015-12-11 2017-06-15 The United States Of America, As Represented By The Secretary, Department Of Health And Human Services Souches du virus respiratoire syncytial recombinant comprenant des mutations dans l'orf de m2-2 offrant une gamme de phenotypes attenues

Citations (1)

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Also Published As

Publication number Publication date
US7745107B2 (en) 2010-06-29
WO2002084295A2 (fr) 2002-10-24
JP2004534214A (ja) 2004-11-11
DE10291657D2 (de) 2004-04-15
WO2002084295A3 (fr) 2003-04-17
JP4291580B2 (ja) 2009-07-08
DE10118446A1 (de) 2002-10-17
US20040161766A1 (en) 2004-08-19

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