WO2006028202A1 - リンパ球増殖抑制因子の吸着材及び処理方法 - Google Patents
リンパ球増殖抑制因子の吸着材及び処理方法 Download PDFInfo
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- WO2006028202A1 WO2006028202A1 PCT/JP2005/016601 JP2005016601W WO2006028202A1 WO 2006028202 A1 WO2006028202 A1 WO 2006028202A1 JP 2005016601 W JP2005016601 W JP 2005016601W WO 2006028202 A1 WO2006028202 A1 WO 2006028202A1
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- Prior art keywords
- lymphocytes
- porous body
- lymphocyte
- body fluid
- porous
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- ZRKFYGHZFMAOKI-QMGMOQQFSA-N tgfbeta Chemical compound C([C@H](NC(=O)[C@H](C(C)C)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CC(N)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H]([C@@H](C)O)NC(=O)[C@H](CC(C)C)NC(=O)CNC(=O)[C@H](C)NC(=O)[C@H](CO)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@@H](NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@@H](NC(=O)[C@H](CC(C)C)NC(=O)[C@@H](N)CCSC)C(C)C)[C@@H](C)CC)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](C)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](C)C(=O)N[C@@H](CC(C)C)C(=O)N1[C@@H](CCC1)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CO)C(=O)N[C@@H](CCCNC(N)=N)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC(C)C)C(O)=O)C1=CC=C(O)C=C1 ZRKFYGHZFMAOKI-QMGMOQQFSA-N 0.000 description 1
- 238000010257 thawing Methods 0.000 description 1
- 150000003573 thiols Chemical class 0.000 description 1
- 229910052719 titanium Inorganic materials 0.000 description 1
- 239000010936 titanium Substances 0.000 description 1
- XSQUKJJJFZCRTK-UHFFFAOYSA-N urea group Chemical group NC(=O)N XSQUKJJJFZCRTK-UHFFFAOYSA-N 0.000 description 1
- 235000013343 vitamin Nutrition 0.000 description 1
- 239000011782 vitamin Substances 0.000 description 1
- 229940088594 vitamin Drugs 0.000 description 1
- 229930003231 vitamin Natural products 0.000 description 1
Classifications
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
- A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
- A61K35/14—Blood; Artificial blood
- A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/461—Cellular immunotherapy characterised by the cell type used
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K39/46—Cellular immunotherapy
- A61K39/464—Cellular immunotherapy characterised by the antigen targeted or presented
- A61K39/4643—Vertebrate antigens
- A61K39/4644—Cancer antigens
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61M—DEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
- A61M1/00—Suction or pumping devices for medical purposes; Devices for carrying-off, for treatment of, or for carrying-over, body-liquids; Drainage systems
- A61M1/36—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits
- A61M1/3679—Other treatment of blood in a by-pass of the natural circulatory system, e.g. temperature adaptation, irradiation ; Extra-corporeal blood circuits by absorption
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0636—T lymphocytes
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2533/00—Supports or coatings for cell culture, characterised by material
-
- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N2533/00—Supports or coatings for cell culture, characterised by material
- C12N2533/30—Synthetic polymers
Definitions
- the present invention is directed to cancer, infection by removing the immunocompetent cells (especially lymphocytes) in the blood from the body, culturing them, and stimulating them to proliferate and returning them to the body again.
- immunocompetent cells especially lymphocytes
- the present invention relates to a proliferation device.
- the present invention relates to a method for preparing a body fluid with a reduced lymphocyte proliferation inhibitory factor concentration, and a method for growing lymphocytes using a medium to which the body fluid is added.
- lymphocyte fraction is collected by density gradient centrifugation, and autologous plasma is added to a dedicated culture medium for culturing.
- TGF- ⁇ 'Growth factor 1 beta
- IL4 interleukin 4
- IL6 interleukin 6
- IL10 interleukin 10
- PGE2 prostaglandin ⁇ 2
- Patent Document 1 an adsorbent that adsorbs and removes immunosuppressive acidic protein (IAP) (Patent Document 1), an adsorbent that adsorbs and removes interleukins in body fluid (Patent Document 2), and TGF in body fluid.
- Patent Document 3 an adsorbent that adsorb ⁇ (Patent Document 3) and the like are disclosed, all are limited to the adsorption and removal of cytodynamic ins, and there are no reports of adsorbents that improve the proliferation of lymphocytes.
- an adsorbent in which a material that adsorbs an immunosuppressive protein such as cytodynamic ins is bound to a water-insoluble carrier (Patent Documents 4, 5, and 6).
- the adsorbent is based on the affinity of immunosuppressive proteins such as amine residues and cytodynamic ins. Therefore, the adsorbent requires the presence of an amine residue.
- Patent Document 1 Japanese Patent Laid-Open No. 56-092824
- Patent Document 2 Japanese Patent Laid-Open No. 08-257398
- Patent Document 3 Japanese Patent Laid-Open No. 2001-218840
- Patent Document 4 Japanese Unexamined Patent Publication No. 2003-310751
- Patent Document 5 Japanese Patent Laid-Open No. 2003-339854
- Patent Document 6 Japanese Unexamined Patent Application Publication No. 2004-73618 Disclosure of the invention
- an object of the present invention is to provide an adsorbent useful for a treatment for promoting the proliferation of the lymphocyte, a treatment method thereof, and a lymphocyte proliferated by treatment with the porous material.
- the present inventors have conducted intensive research on a porous material that eliminates the suppression of the proliferation of lymphocytes without losing useful substances necessary for the proliferation of lymphocytes as much as possible.
- a water-insoluble porous body containing a polymer compound having a water contact angle of about 40 ° within a force range of 98 ° or a porous body containing activated carbon is used in advance.
- the present invention relates to a porous body for body fluid treatment that promotes lymphocyte proliferation in lymphocyte culture, comprising a polymer compound having a water contact angle in the range of 40 ° force and 98 ° force;
- the present invention relates to a porous body made of activated carbon for treating body fluid that promotes lymphocyte proliferation in lymphocyte culture.
- the present invention also relates to a treatment device for promoting lymphocyte proliferation in lymphocyte culture comprising the above porous body in a container.
- the present invention provides a method for proliferating lymphocytes; a method for producing lymphocytes in mammals; a method for producing a pharmaceutical composition; a body fluid for addition to a culture solution during lymphocyte culture; and a method for producing a mammal activated in vitro.
- a method for treating diseases that have a therapeutic effect by returning lymphocytes to the body; the contact angle of activated carbon or water is 40 to produce a porous material for treatment of body fluid that promotes lymphocyte proliferation in lymphocyte culture. ° It relates to the use of polymer compounds whose force is also in the range of 98 °.
- the porous body of the present invention is a polymer compound in which the contact angle of water is within the range of 40 ° force and 98 °.
- the contact angle of water in the present invention is that a smooth film made of a polymer compound as a main constituent is produced, and droplets are formed thereon using a micro-injector in a horizontal state. Can be determined by measuring at room temperature.
- the porous body can be dissolved in an organic solvent, it is possible to measure the contact angle by dissolving the porous body and preparing a cast film on the flat plate using the solution. Details of the measurement method can be referred to, for example, “New Experimental Chemistry Course 18 Interface and Colloid” (Maruzen Co., Ltd., issued October 20, 1977, first edition).
- a flat specimen with a mirror-finished smoothness is placed horizontally so as to be filled with the saturated vapor of the liquid to be measured, and liquid droplets are made on it using a microinjector.
- the droplet size should be such that the contact diameter is about 3 mm or less.
- the contact angle is a measurement of the angle formed when the droplet is advanced relative to the solid surface (when the liquid spreads on the sample and the liquid spreads and then settles to a certain size). It can be measured with a reading microscope with a square tool (magnification approximately 20 times). If the lens barrel is tilted 1-2 degrees below horizontal, the image will be very sharp.
- the drop is illuminated from the front with light through milky glass or parallel light through heat-absorbing glass.
- the contact angle was measured by the method described in Examples described later.
- Typical polymer compounds having a water contact angle within a range of 40 ° force and 98 ° include, for example, nylon 6, nylon 6, 6, nylon 11, polyethylene, poly (vinylidene chloride) , Poly (Butyl chloride), Poly (Butylacetate acetate), Polystyrene, Styrene-dibulene benzene copolymer, Poly (trifluoroethylene), Poly (Black-end trifluoroethylene), Poly (ethylene terephthalate), Polypropylene , Polyacrylic acid esters (poly (methyl acrylate), etc.), polymethacrylic acid esters (poly (methyl methacrylate), etc.), cross-linked polyacrylates, cross-linked polyamides and other synthetic polymer compounds, cellulose and other water-insoluble materials Powers that include things are not limited to these.
- aromatic monomers for example, methyl styrene, ethyl styrene, etc. may be substituted from the viewpoint of lymphocyte proliferation rate, alkyl styrene; dibutylbenzene; dibinaphthalene, dibianthracene, etc. are substituted.
- a polymer or copolymer obtained by polymerizing a monomer having a benzo-fused ring force selected is preferable.
- Restyrene and styrene divininolebenzene copolymers are preferred.
- polystyrene any known polystyrene can be used.
- Polystyrene is any styrene polymer and styrene-based polymer.
- the styrene-dibulene benzene copolymer can be obtained by crosslinking the above styrene compound with m-, o or p dibutylbenzene, if desired.
- the above polymer compounds are halogen, alkyl, alkyl, alkynyl, aralkyl, aryl, heteroaryl, arylylcarbonyl, heteroarylcarbonyl, alkylenoreboninore, anorecoxicanoleponore, It may be optionally substituted with linoles norehoninole, heterolinoles noleshonol, alkylsulfonyl and the like.
- the substituent can be further substituted with other than amine, and the substituent of the substituent is preferably other than an amide group, a urea group, an ester group or an ether group.
- the polymer compound is a compound having an amine residue bonded thereto.
- amine residues include those in which ammonia, primary to tertiary amines, and the like are chemically bonded to a polymer compound.
- the polymer compound is preferably one in which no other compound is immobilized.
- the other compound is not particularly limited as long as it is other than the above polymer compound.
- the contact angle of the water is preferably more than 60 ° and no more than 96 °, more preferably about 70 ° force 94 °, Preferably, it is about 75 ° to 91 °.
- the porous body is preferably water-insoluble.
- the porous body of the present invention contains about 50% by weight or more of the polymer compound, preferably about 60% by weight or more, more preferably about 70% by weight or more, and further preferably about 80% by weight or more. It is included.
- components other than the polymer compound that can be contained in the porous body and have a water contact angle of 40 ° and a force of 98 ° include, for example, polyvinyl alcohol (contact angle 36 °), poly (meta) Hydroxyethyl acrylate (13 °) and paraffin (105-106 °).
- two or more of the above polymer compounds having a water contact angle of 40 ° and a force of 98 ° are used in combination, or the above polymer compound having a water contact angle of 40 ° and a force of 98 ° is used as a main raw material.
- the water contact angle of the resulting porous body can be adjusted by, for example, blending components other than the high molecular compound as an auxiliary material.
- the water contact angle of the porous body is preferably within the range of the water contact angle of the polymer compound. That is, the water contact angle of the porous body is preferably from 40 ° force 98 °, more preferably more than 60 ° to 96 °, more preferably about 70 ° force 94 °, particularly preferably about 75 °. It is 91 °.
- the porous body of the present invention is solid at normal temperature and pressure and has pores of an appropriate size, that is, has a porous structure.
- the exclusion limit molecular weight of the water-insoluble porous material using polystyrene beads is preferably 1.5 ⁇ 10 5 or less. More preferably, 1.4 ⁇ 10 5 or less is used.
- the exclusion limit molecular weight is larger than 1.5 ⁇ 10 5 , non-specific adsorption tends to increase, loss of useful proteins in body fluids, and lymphocyte proliferation tend to decrease.
- the exclusion limit molecular weight is more preferably 1.3 ⁇ 10 5 or less. Particularly preferred is 1.2 ⁇ 10 5 or less, and most preferred is 1.0 ⁇ 10 5 or less.
- Adjustment of the exclusion limit molecular weight can be easily controlled, for example, by adjusting the content of the main polymer compound constituting the porous body at the time of producing the porous body. That is, when the content of the polymer compound is increased, the exclusion limit molecular weight is decreased, and when the content of the polymer compound is decreased, the exclusion limit molecular weight is increased.
- the exclusion molecular weight is the molecular weight of the smallest molecular weight that cannot enter (exclude) the pores in chromatography.
- the exclusion limit molecular weight can be measured as follows. Polystyrene beads with different particle diameters are allowed to flow through a column packed with a porous material, and the pore size is determined from the outflow curve of the polystyrene beads that have flowed out. Next, by extrapolating the size of the pores to a globular protein (such as dextran) having a different diameter and molecular weight, the globular protein The molecular weight in terms of conversion is obtained and used as the exclusion limit molecular weight.
- a globular protein such as dextran
- any of spherical shape, granular shape, flat membrane shape, fibrous shape, hollow fiber shape and the like can be used effectively, but the adsorption performance surface force spherical shape or granular shape is more preferably used.
- the average particle size is preferably about 5 ⁇ m to 1000 ⁇ m, more preferably about 20 to 800 ⁇ m, and still more preferably about 30 to 600 ⁇ m.
- the average particle size can be measured as follows. In a wet state, the porous body is spread on a petri dish and several tens of grains are photographed with a CCD camera. Next, the average particle size of the captured image is calculated using a particle size measurement software (Image-Pro plus, Medical Cybernetics, Inc.).
- the porous body of the present invention can be produced, for example, as follows.
- One or two or more raw material monomer compounds are dispersed and suspended in a suitable viscous solvent (for example, water). While stirring the suspension, suspension polymerization is carried out by a known method to obtain the target porous material.
- a suitable viscous solvent for example, water
- porous body of the present invention may have activated carbon power.
- the activated carbon examples include fibrous activated carbon such as phenol fibrous activated carbon; granular activated carbon such as coconut shell activated carbon, petroleum pitch activated carbon, peat activated carbon, and charcoal activated carbon.
- the average particle size of the activated carbon is not particularly limited, but is preferably about 5 m to 1000 m, more preferably about 20 to 800 ⁇ m, and more preferably about 30 to 600 ⁇ m.
- polystyrene polystyrene, styrene-dibutylbenzene copolymer, and activated carbon are preferred from the viewpoint of lymphocyte proliferation rate.
- Polymers are preferred.
- a high molecular weight compound having a contact angle force of 0 ° in activated carbon or water is also in the range of 98 °. Can be used.
- the processing device of the present invention is a processing device that promotes lymphocyte proliferation in lymphocyte culture, comprising the porous body in a container.
- the shape, size, and material of the container used for the processing device are not particularly limited.
- the form may be any form such as a sphere, container, bag, tube, column, and the like. Like Specific examples include a transparent or translucent cylindrical container having a capacity of about 0.1 to 400 ml and a diameter of about 0.1 to about LOcm.
- the container can be made using any structural material.
- the structural material include non-reactive polymers, biocompatible metals, alloys, and glass.
- Non-reactive polymers include acrylonitrile butadiene styrene terpolymers and other acrylonitrile polymers; polytetrafluoroethylene, polychloroethylene, tetrafluoroethylene and hexafluoropropylene copolymers, polychlorinated butyl, etc.
- Halogenated polymers Polyamide, polysulfone, polycarbonate, polyethylene, polypropylene, polyvinyl chloride acrylic copolymer, polycarbonate acrylonitrile butadiene styrene, polystyrene, polymethylpentene and the like.
- Metal materials useful as container materials are stainless steel, titanium, platinum, tantalum, gold, and alloys thereof, as well as gold-plated alloy iron, platinum-plated alloy iron, cobalt chromium alloy, titanium nitride-coated stainless steel, etc. Is mentioned.
- Particularly preferred is a material having sterilization resistance, and specific examples include silicon-coated glass, polypropylene, polyvinyl chloride, polycarbonate, polysulfone, and polymethylpentene.
- the treatment device preferably has a liquid inlet and outlet and is filled with a water-insoluble porous body in a container provided with a means for preventing the porous body from flowing out of the container.
- the present invention is not limited to this.
- Examples of the outflow prevention tool include filters such as mesh, nonwoven fabric, and cotton plug.
- the method for proliferating lymphocytes of the present invention is a method comprising contacting the porous body with a body fluid and culturing lymphocytes using the body fluid brought into contact with the porous body.
- lymphocyte proliferation method of the present invention that is, the treatment method for promoting lymphocyte proliferation include the following methods.
- the above-described treatment device a container having a body fluid inlet and outlet and a body filter that passes through the body fluid but does not pass through the porous body
- the above-described treatment device is filled with the porous body.
- the porous body is filled with the porous body.
- the porous body is filled with the porous body.
- cultivate lymphocytes How to nourish is obtained in which a body fluid is collected in a bag containing a porous body in advance, and contacted for a certain period of time, and then the porous body is separated by filtration and lymphocytes are cultured.
- a method in which a porous material is allowed to coexist in a lymphocyte culture system, and the lymphocytes and the porous material are separated by filtration during or at the end of the culture.
- contact methods include a method in which body fluid is brought into contact for a certain period of time in a reflux state with a liquid feed pump or the like, a method in which the body fluid is brought into contact for a certain time without being refluxed, and the like.
- the contact time is preferably 1 minute or longer, but it is more preferable that the surface force of the adsorption performance and the force of about 15 minutes are 6 hours. From the standpoint of sufficient adsorption performance and cell treatment efficiency, it is more preferable that the contact be performed for about 20 minutes to 4.5 hours, and more preferably for about 30 minutes to 3 hours.
- the body fluid is directly collected in a bag containing a porous body in advance and contacted for a certain period of time; after blood is prepared into plasma or serum by centrifugation or the like, it is injected into the bag.
- the contact time is preferably 10 minutes to 10 hours, more preferably about 15 minutes to 6 hours, from the viewpoint of the adsorption performance that is preferably contacted for about 1 minute or longer. In view of sufficient adsorption performance and cell treatment efficiency, contact for about 30 minutes to 3 hours is particularly preferable.
- the porous body is directly added to and coexisted with a system in which lymphocytes are cultured in a culture solution to which patient plasma is added, and a filter that does not pass through the porous body after a predetermined time has passed.
- the porous material and lymphocytes can also be separated by filtration.
- the temperature at which the porous body described in the above (1) and (2) is brought into contact with the body fluid can be selected, but is preferably about 4 ° C to 50 ° C, more preferably about 10 ° C. ⁇ 45 ° C.
- a porous material is allowed to coexist with lymphocytes in a lymphocyte culture container, and the porous material and lymphocytes are filtered at the time of medium replacement or at the end of the culture.
- the contact time is the longest, and until the lymphocyte culture is completed, the amount of porous material added is preferably such that a sufficient amount of space can be secured without the lymphocyte proliferation being physically suppressed! /, .
- the present invention is not limited to these, but the method (1) is easy to operate, and is most preferred as a method for releasing suppression of lymphocyte proliferation in lymphocyte culture. .
- the porous body of the present invention can function as an adsorbent for the lymphocyte proliferation inhibitory factor.
- an anticoagulant when the treatment device is used, an anticoagulant can be used.
- Anticoagulants include heparin, low molecular weight heparin, nafamostat mesylate, gabexate mesilate, argatroban, acid citrate dextrose solution (ACD solution), citrate phosphate dextrose solution (CPD solution), etc.
- V-displacement may be used, such as citrate-containing anticoagulant.
- henolin can be mentioned as an anticoagulant which is generally most preferably used.
- the said anticoagulant does not need to be included.
- the body fluid includes blood, plasma, and serum.
- the body fluid contains other body fluids such as ascites, lymph fluid, intra-articular fluid and fraction components obtained therefrom, as well as other biological fluid components.
- blood is conveniently collected from a subject, optionally separated from blood cell fractions by means such as centrifugation, and used after preparing plasma. Furthermore, it may be used after serum preparation.
- the body fluid in addition to blood, plasma, and serum, a diluted solution thereof, or phenol, percoll, Batatina tube, lymphoprep, or the like is used, and pretreatment is performed by specific gravity centrifugation.
- the applied supernatant can be used.
- the body fluid can be used immediately after blood collection, but can also be used for blood fluids after refrigerated storage or cryopreservation.
- after treatment of the body fluid with an adsorbent it can be refrigerated and frozen and used after thawing as necessary, but is not limited thereto.
- lymphocytes refer to mammalian peripheral blood, lymphatic vessels, T cells, B cells, etc. in bone marrow.
- the lymphocytes also include neither natural T cells nor B cells, such as natural killer cells.
- T cells include, but are not limited to, helper T cells, cytotoxic T cells, and killer T cells.
- lymphocyte culture can be performed, for example, as follows.
- a mammalian body fluid is used to contact the porous body and then seeded in a lymphocyte culture solution.
- the lymphocyte culture can be used at any temperature (preferably about 20 ° C. or 45 ° C., more preferably about 30 ° C. force or 40 ° C., more preferably about 37 ° C.) for any time (eg, about Culturing for 3 to 30 days, preferably about 7 days, and also for 21 days, more preferably about 10 to 18 days, most preferably about 14 days).
- lymphocytes proliferate.
- lymphocyte culture solution a known culture solution can be used.
- lymphocyte culture medium PB-MAX medium, AIM V medium, CHANG medium, LGM-3 medium, KBM400, GIT, Ham F-12, Dulbecco MEM, a-MEM, MEM, IMEM, RPMI-1640, McCoy 'S5A Power including medium etc. It is not limited to these.
- An antibody or the like can also be used to activate lymphocytes during lymphocyte culture.
- Examples of the antibody include anti-CD3 antibody (OKT3).
- the method for growing lymphocytes is more effective.
- Lymphocyte proliferative failure refers to a case where the lymphocyte proliferation rate when a patient body fluid is added to a lymphocyte culture system is equal to or less than the lymphocyte proliferation rate obtained using a healthy human body fluid.
- the lymphocyte proliferation rate is defined as 0.1% (V / V) to 20% of the body fluid of a patient treated with a porous body or the body fluid of a healthy human body that has not been treated with a porous body.
- V / V) Refers to the proliferation rate (number of cells after 7 days Z number of seeded cells) when lymphocytes are cultured at 37 ° C for 1 week using the added culture medium.
- the porous body used in the present invention is more preferably hard.
- Hard here for example, in the case of a granular gel, the gel is uniformly packed in a cylindrical column, and the relationship between the pressure loss ⁇ and the flow rate when flowing an aqueous fluid has a linear relationship up to about 0.3 kgZcm 2. . But when using this porous body in a bag, it may be soft.
- a mammalian body fluid is brought into contact with the porous body, and the lymphocytes are cultured using the body fluid brought into contact with the porous body. And recovering the produced lymphocytes.
- Lymphocytes can be collected by any method such as centrifugation, membrane filtration, or chromatography.
- the lymphocyte is produced according to the lymphocyte production method, and the lymphocyte is mixed with a pharmaceutically acceptable additive. It is a method comprising that.
- Examples of the pharmaceutically acceptable additive include anticoagulants, nutrient sources such as vitamins, and antibiotics.
- the manufacture of the pharmaceutical composition can be brought into a composition in a suitable galenic form (eg for transfusion, infusion, injection, etc.) according to accepted pharmaceutical practice.
- a suitable galenic form eg for transfusion, infusion, injection, etc.
- the addition body fluid to be added to the culture solution during lymphocyte culture according to the present invention is obtained by bringing a mammalian body fluid into contact with the porous body.
- the body fluid for addition is brought into contact with the above-mentioned porous body with a body fluid of a mammal affected or unaffected by a disease having a therapeutic effect by, for example, activating lymphocytes outside the body and then returning them to the body.
- a body fluid of a mammal affected or unaffected by a disease having a therapeutic effect by, for example, activating lymphocytes outside the body and then returning them to the body.
- the method for treating a disease having a therapeutic effect by returning the lymphocytes of a mammal activated in vitro to the body according to the present invention is necessary or not necessary for treatment of the mammal.
- a method comprising contacting a body fluid with the porous body, culturing lymphocytes using the body fluid contacted with the porous body, and administering the obtained lymphocytes to the mammal. It is.
- Diseases that have a therapeutic effect by returning lymphocytes activated outside the body to the body include, but are not limited to, cancer, infectious diseases, immune diseases, and the like.
- the activity is a change in lymphocyte population as the number of lymphocytes increases and proliferates. , Including improving the original function of lymphocytes.
- lymphocyte proliferation inhibitory factors it is necessary for the proliferation of lymphocytes from a body fluid of a subject suffering from a disease that has a therapeutic effect by activating lymphocytes outside the body and then returning them to the body, for example, a subject with poor lymphocyte proliferation. Without adsorbing various factors, it is possible to adsorb lymphocyte proliferation inhibitory factors, release the suppression of lymphocyte proliferation in lymphocyte culture, and greatly increase the proliferation rate of lymphocytes. It was.
- the present invention treats a disease or recovers a disease by taking out and culturing immunocompetent cells (especially lymphocytes) in the blood outside the body and cultivating them, and returning them to the body after stimulating and activating them.
- a porous body for releasing the suppression of lymphocyte proliferation in the lymphocyte culture for the target body fluid and a lymph body using this porous body It is useful as a sphere growth method.
- the contact angle of water, the exclusion limit molecular weight, and the average particle diameter were measured as follows.
- a sample of the polymer compound was compressed under high pressure to produce a smooth film.
- the obtained flat plate specimen was placed horizontally, and water droplets were formed thereon using a microinjector.
- the size of the water droplet was set so that the contact diameter was about 1 to 2 mm.
- the angle formed when the water droplet was advanced with respect to the solid surface was measured at room temperature (20 ° C) using a reading microscope (approximately 20 times magnification) with a goniometer.
- the polystyrene beads having different particle diameters were passed through a column packed with a porous material, and the pore size was determined from the outflow curve of the outflowing polystyrene beads.
- the molecular weight in terms of dextran was obtained by extrapolating the size of the pores to dextran, which is a globular protein having both a diameter and a molecular weight, and was used as the exclusion limit molecular weight.
- the porous body was spread on a petri dish, and several tens of grains were photographed with a CCD camera.
- the average particle size of the captured image was calculated using a particle size measurement software (Image-Pro plus, Medical Cybernetics, Inc.).
- the adapter was connected to an intravenous needle with wings, and a holder was connected to the other end of the adapter.
- a lymphocyte separation tube (Pactiner tube (Betaton Dickinson)
- the Pactina tube was immediately centrifuged at 3000 rpm for 20 min at room temperature.
- the lymphocyte layer was collected, 40 ml of physiological saline was added, and centrifuged at 1500 rpm, 5 min, 4 ° C.
- lymphocytes were washed and resuspended in KBM400 medium (manufactured by Kojin Bio) to prepare a lymphocyte suspension with a predetermined concentration.
- ⁇ 3 (Dainippon Pharmaceutical Co., Ltd.) was prepared to a concentration of 5 ⁇ g / ml with physiological saline, and 500 ⁇ l was injected into a 24-well polystyrene microplate (Sumitomo Bakelite). After standing at room temperature for about 2 hours, the ⁇ 3 solution was removed and washed twice with an equal amount of physiological saline to prepare a ⁇ 3 solid-phase plate.
- a monomer mixture consisting of 100 parts by weight of industrial dibutene benzene (dibulene content 57%), 100 parts by weight of toluene, 60 parts by weight of isoamyl alcohol, and 1 part by weight of benzoyl peroxide (content 75%) Add 572 parts by weight, sodium chloride 23 parts by weight, polyvinyl alcohol 1 part by weight, sodium nitrite 0.03 part by weight, and stir so that the droplets of the monomer mixture are dispersed and suspended.
- polymerization was carried out at 80 ° C for 5 hours in a nitrogen atmosphere. The polymer particles produced are filtered and washed with water, and then the residue of solvent, monomer, initiator, etc.
- porous styrene-dibulene benzene copolymer beads were thoroughly washed with physiological saline, and then 0.17 ml was weighed into a cryotube. Saline was sufficiently removed from the porous beads, and 1 ml of cancer patient plasma was added thereto and incubated at 37 ° C for 2 hours on a MIX rotor with stirring (40 rpm).
- lymphocyte culture solution KBM400 manufactured by Kojin Bio
- VZV lymphocyte count
- Lymphocytes were collected on the seventh day of culture, the number of cells was counted with a hemocytometer, and the lymphocyte proliferation fold was determined by the following formula 1).
- Multiplication rate lymphocyte count after 7 days of culture Z lymphocyte count at seeding 1)
- the number of lymphocytes when cancer patient plasma was treated with the adsorbent increased to 16.7 times the proliferation number.
- the lymphocyte proliferation fold was determined in the same manner as in Example 1 except that the adsorbent was changed from porous styrene-dibulene benzene copolymer beads to petroleum pitch-based activated carbon having a particle size of about 500 ⁇ m. As a result, the number of lymphocytes increased to 10.6 times the proliferation number.
- Exclusion limit molecular weight of 1 X 10 4 or less except for using a particle size of about 400 m of the polystyrene (contact angle about 85 ° in water) porous beads, in the same manner as in Example 1, determined lymphoproliferative multiples I tried. As a result, the number of lymphocytes increased to 11.5 times the proliferation number.
- Preparation of porous body While directly applying vibration of about 20000 Hz to a cellulose solution having a viscosity of about 10OOcP, it was ejected into the gas phase as uniform droplets. After flying over a flight distance that makes the droplets spherical, they are captured in a coagulation bath, desolvated, and washed to give a particle size of about 40 Cellulose porous particles of 0 ⁇ m were obtained (exclusion limit molecular weight of 3 ⁇ 10 4 or less, water contact angle of about 50).
- lymphocyte proliferation fold was determined in the same manner as in Example 1 except that the porous particles were used. As a result, the number of lymphocytes increased to 6.9 times the number of cells at the time of seeding (multiplication rate).
- Exclusion limit molecular weight of 6 X 10 4 or less except for using porous beads (approximately 40 ° contact angle of water) cellulose having a particle size of about 400 mu m in a similar manner as in Example 1, the lymphocyte proliferation multiples Asked. As a result, the number of lymphocytes increased to 5.7 times the proliferation number.
- the lymphocyte proliferation factor was determined in the same manner as in Example 1 except that patient plasma not in contact with the adsorbent was used. As a result, the number of lymphocytes was 3.9 times the proliferation number.
- Example 4 Except that dextran sulfate was bound to the porous particles used in Example 4 with epichlorohydrin (exclusion limit molecular weight 3 ⁇ 10 4 or less, water contact angle about 35 °). This method was used to determine the lymphocyte proliferation fold. As a result, the number of lymphocytes was 3.6 times the proliferation number.
- Example 5 Except that dextran sulfate was bound to the porous particles used in Example 5 by epichlorohydrin (exclusion limit molecular weight 3 X 10 4 or less, water contact angle about 30 °). This method was used to determine the lymphocyte proliferation fold. As a result, the number of lymphocytes was 3.2 times the proliferation number.
- Table 1 shows the results of evaluating the lymphocyte proliferation folds of Examples 1 to 5 and Comparative Examples 1 to 3. From this result, when lymphocytes were cultured using a specific porous body of the present invention in contact with body fluid, the porous body (adsorbent) was not used, or dextran sulfate was immobilized. Thus, it can be seen that the proliferation rate of lymphocytes was significantly increased compared to the case where the polymer compound was hydrophilized.
- a factor necessary for lymphocyte proliferation from a body fluid of a subject suffering from a disease that has a therapeutic effect by activating lymphocytes outside the body and then returning them to the body, such as a subject with poor lymphocyte proliferation is obtained. Without adsorbing, it was possible to adsorb lymphocyte proliferation-inhibiting factor, release the suppression of lymphocyte proliferation in lymphocyte culture, and greatly increase the proliferation rate of lymphocytes.
- the present invention treats a disease or recovers a disease by taking out and culturing immunocompetent cells (especially lymphocytes) in the blood outside the body and cultivating them, and returning them to the body after stimulating and activating them.
- a porous body for releasing the suppression of lymphocyte proliferation in the lymphocyte culture for the target body fluid, and a lymph body using this porous body It is useful as a sphere growth method.
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Priority Applications (4)
Application Number | Priority Date | Filing Date | Title |
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EP05782324.7A EP1808191B1 (en) | 2004-09-10 | 2005-09-09 | In vitro lymphocyte proliferation method |
US11/575,024 US20080159990A1 (en) | 2004-09-10 | 2005-09-09 | Adsorbent For Lymphocyte Proliferation Inhibitor and Treating Method |
JP2006535836A JP4958554B2 (ja) | 2004-09-10 | 2005-09-09 | リンパ球増殖抑制因子の吸着材及び処理方法 |
US12/771,373 US8932854B2 (en) | 2004-09-10 | 2010-04-30 | Adsorbent for lymphocyte proliferation inhibitor and treating method |
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JP2004-264044 | 2004-09-10 | ||
JP2004264044 | 2004-09-10 |
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US11/575,024 A-371-Of-International US20080159990A1 (en) | 2004-09-10 | 2005-09-09 | Adsorbent For Lymphocyte Proliferation Inhibitor and Treating Method |
US12/771,373 Division US8932854B2 (en) | 2004-09-10 | 2010-04-30 | Adsorbent for lymphocyte proliferation inhibitor and treating method |
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WO2006028202A1 true WO2006028202A1 (ja) | 2006-03-16 |
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US (2) | US20080159990A1 (ja) |
EP (1) | EP1808191B1 (ja) |
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JP2015195762A (ja) * | 2014-04-01 | 2015-11-09 | 大日本印刷株式会社 | 細胞培養容器 |
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JPWO2006106763A1 (ja) * | 2005-03-30 | 2008-09-11 | 株式会社カネカ | リンパ球増殖抑制因子の除去方法 |
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- 2005-09-09 US US11/575,024 patent/US20080159990A1/en not_active Abandoned
- 2005-09-09 JP JP2006535836A patent/JP4958554B2/ja not_active Expired - Fee Related
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Also Published As
Publication number | Publication date |
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JP4958554B2 (ja) | 2012-06-20 |
US20100221832A1 (en) | 2010-09-02 |
US20080159990A1 (en) | 2008-07-03 |
EP1808191A1 (en) | 2007-07-18 |
JPWO2006028202A1 (ja) | 2008-05-08 |
EP1808191A4 (en) | 2010-12-29 |
EP1808191B1 (en) | 2014-01-01 |
US8932854B2 (en) | 2015-01-13 |
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