JPS58173552A - Blood purifying method and apparatus - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to a method and apparatus for purifying blood by removing malignant substances dissolved in the blood.

More specifically, the present invention relates to a method and apparatus for efficiently adsorbing and removing immunoglobulins and/or immune complexes dissolved in blood, particularly autoantibodies and immune complexes, in a blood purification method using an adsorbent.

In recent years, research has been closely related to the causes and progression of diseases related to the body's immune system, such as cancer, immunoproliferative syndrome, rheumatoid arthritis, autoimmune diseases such as systemic lupus erythematosus, allergies, and rejection reactions during organ transfer. Plasma exchange therapy has been used to remove certain immunoglobulins and immune complexes that may be present.

However, in plasmapheresis therapy, there is a problem of securing healthy plasma to be transfused to the patient, and there are concerns that transfusion of healthy human plasma may cause side effects such as infection with new pathogens and serum sickness. It is considered desirable to infuse it after purifying it, and there has been a desire to develop purification methods and devices for this purpose.

Conventionally, adsorbents that can be used for such purposes include (1
) Adsorbent material in which protein molecules are immobilized on an insoluble carrier, (2
) Acrylic acid ester-based porous resin (for example, XAD-
(3) 114-one exchangers such as carboxymethyl cellulose have been proposed. ★In addition, as a material that has greatly improved the drawbacks of these adsorbents (1) to (3), there is a nine-immunoadsorbent material proposed by the present applicant in which various low-molecular-weight ligands are bound to an insoluble carrier (patent application). 1982-7152, patent application 185@-18'9
23, Patent Application 1986-76776, Patent Application @ 56-159
444) oThe method for purifying blood using these adsorbents is usually the method described below.

That is, this is a method in which plasma is separated from blood, the plasma is passed through an adsorption tube filled with an adsorbent, and malignant substances such as immunoglobulin and/or immune complexes are adsorbed onto the adsorbent.

When plasma is purified by the method described above using the immunoadsorbent proposed by the present applicant, malignant immunoglobulins and immune complexes can be removed from plasma with a fairly high efficiency. In order to perform circulatory blood purification therapy, it is desirable to be able to remove malignant substances with even higher efficiency and to have very little adverse effect on the blood.

The present inventors conducted extensive research to solve the above problems. As a result, by keeping the temperature between 0°C and 25°C during contact between the adsorbent and the blood to be purified, the adsorption efficiency of immunoglobulins and/or immune complexes is improved, and in particular, the adsorption efficiency of immunoglobulins and/or immune complexes is improved. We found that the adsorption efficiency of autoantibodies and immune complexes, which are thought to be closely related to the cause or progression of diseases and phenomena, was significantly improved, and we also confirmed that the blood coagulation and fibrinolytic system was not activated. , we have completed the present invention.

Specifically, the present invention provides a method for removing immunoglobulin and/or immune complexes using an adsorbent, which comprises cooling blood or plasma and bringing it into contact with an adsorbent; Or, between the plasma inlet and the purified blood or blood outlet, there is an adsorption chamber filled with an adsorbent, and a cooler is provided between the blood inlet and the adsorption column outlet. The gist of the invention is an immunoglobulin and/or immune complex removal device for extracorporeal circulation, which is characterized by:

Here, the temperature of the blood 't'#- when the plasma and the adsorbent come into contact is preferably 0"C or more and 25"C or less, but it is desirably controlled within the range of 5 to 15C. That's true.

It is better to warm the cooled blood to around body temperature immediately after contacting the adsorbent.

The preferred temperature range is 25 to 38°C, and s1! I is 33-38°C.

Adsorbents that can be used in the present invention include immunoglobulins and/or immunoglobulins that can be used for extracorporeal circulation, such as those in which protein A is immobilized on an insoluble carrier, acrylic acid ester-based porous resins, and cation exchangers such as calxymethylcellulose. It also includes adsorbents for immune complexes, and more preferably includes immunoadsorbents proposed by the present applicant in which various low-molecular-weight ligands are bonded to insoluble carriers.

In addition, although the adsorbed and removed substances targeted by the present invention are immunoglobulins and /l or immune complexes, to explain in more detail, ordinary immunoglobulins (G, M, A, D,
E), autoantibodies of rhifmatoid factor, anti-nuclear antibodies, anti-DNA antibodies, anti-lymphocyte antibodies, anti-erythrocyte antibodies, anti-platelet antibodies, anti-acetylcholine receptor antibodies, anti-colon antibodies, immunoglobulin reduction products, chemical modification products etc., immunoglobulin enzymes, complexes between immunoglobulins or immunoglobulins and other substances, especially antigens and antigen-like substances (hereinafter collectively referred to as malignant substances). Even these cattle are susceptible to autoimmune diseases. Autoantibodies and immune complexes, which are closely related to the cause and progression, are the main substances to be adsorbed and removed in the present invention.

The present invention will be explained in more detail below.

To explain the blood purification method of the present invention according to the flow of blood, first, plasma separated from blood by a blood or plasma separator is heated to 0°C before or during contact with an adsorbent.
It is cooled to a temperature range of -25° C., and brought into contact with an adsorbent in a cooled state, whereby malignant substances such as autoantibodies and immune complexes are adsorbed and removed. The blood and plasma, from which most of the malignant substances have been removed, are then heated to near body temperature and returned to the body at Kyuryo, where they are disposed of.

What is essential in the present invention is that when the blood or plasma is brought into contact with the adsorbent, the temperature of the blood or plasma is between 0°C and 25°C.
It is maintained at a low temperature. The preferred temperature range for blood or plasma is above 5''C and below 15℃.It goes without saying that lower temperatures are preferable, but above 25℃, immunoglobulins and/or In particular, autoantibodies and immunoglobulins are easily adsorbed at temperatures below 15°C, which is preferable. Adsorption efficiency for malignant substances is the highest, and the desirable temperature range is 5°C and below. The temperature is high and below 15°C.

The blood or plasma purified by contact with the adsorbent is optionally warmed by a warmer. The temperature of blood or plasma after heating is preferably 25°C or higher and 38°C or lower, most preferably 33°C or higher and 37°C or lower.

As adsorbents that can be used in the present invention, from the viewpoint of adsorption specificity, stability, safety, and ease of sterilization, the present applicant has proposed adsorbents in which various low-molecular-weight ligands are bonded to insoluble carriers. ) is preferably used.

The insoluble carrier used for the adsorbent can be either a hydrophilic carrier or a hydrophobic carrier, but when a hydrophobic carrier is used, non-specific adsorption of albumin to the carrier may occur, so it is preferable to use a hydrophilic carrier. gives a more favorable result. Particulate carriers are particularly preferably used as the shape of the insoluble carrier from the viewpoints of permeability to blood and plasma, ease of handling during preparation of the adsorbent, and the like.

As a particulate carrier, the average particle size is 25 μm to 2500 μm.
fin, more preferably 4011m to 1000μm
1. More preferably, a diameter in the range of 50 μm to 500 μm is used.

Particulate carriers that can be used include agarose-based, dextran-based, cellulose-based, polyacrylamide-based, glass-based, and activated carbon-based carriers, but hydrophilic porous polymer particles having a gel structure are preferred. Give results.

For the polymer composition, known polymers that can have a porous structure, such as polyamide, polyester, polyurethane, and vinyl compound polymers, can be used, but in particular, vinyl alcohol made hydrophilic with a hydrophilic monomer can be used. Crosslinked synthetic polymers whose main constituents are units have excellent round performance.

The exclusion limit molecular weight (protein) of the wrinkled porous structure is 150,000 (IgG) for the target adsorbent of the present invention.
100 for immune complexes, especially IgM immune complexes.
Since it reaches 00,000, 15 to 10 million is preferable. The most general exclusion limit molecular weight for the purpose of the present invention is 100 to 5o.
It's 10,000.

The ligand can be bound to the insoluble carrier by any known method such as covalent bonding, ionic bonding, substance adsorption, embedding, or precipitation insolubilization on the polymer surface.
In view of the elution property of the bound substance, it is preferable to use it after it is immobilized and insolubilized by covalent bonding. Therefore, usually immobilized enzyme,
Known carrier activation methods and ligand binding methods used in affinity chromatography can be used.

Examples of activation methods include halogenated cyanide method, epichlorohydrin method, bisepoxide method, halogenated triazine method, bromoacetyl bromide method, ethyl chloroformate method, 1.1'-carbonyldiimidazole method, etc. I can do it. The activation method of the present invention is not limited to the above examples as long as it can perform a substitution and/or addition reaction with a nucleophilic reactive group having an active hydrogen such as an amino group, a hydroxyl group, a carboxyl group, or a thiol group of a ligand. However, in consideration of chemical stability and thermal stability, a method using an epoxide is preferable, and an epichlorohydrin method is particularly recommended. Furthermore, if necessary, a molecule (spacer) of any length may be introduced between the carrier and the ligand. In the adsorbent of the present invention, the ligand retained on the insoluble carrier will be exemplified.

The target substance to be adsorbed is autoantibodies such as rheumatoid factor and/or
Alternatively, when using an immune complex as the main target, it is recommended to use an organic low-molecular compound containing a hydrophobic compound as a ligand.

Hydrophobic compound and company, solubility in physiological saline is 100 mmol/d1 or less (25°C), more preferably 30 mmol/d1 or less
Compounds below 1.

The ligand substance used in the present invention is preferably a low-molecular substance. Here, the low molecular weight substance refers to a substance with a molecular weight of 10,000 or less, more preferably a substance with a molecular weight of 1000 or less.

A compound line whose solubility in physiological saline is greater than 100 mmol/dt has excessively high hydrophilicity, resulting in a decrease in affinity for malignant substances and, as a result, an extremely low adsorption capacity. In addition, an affinity for albumin, which is highly hydrophilic, develops,
It is also undesirable to non-specifically adsorb albumin. Among hydrophobic compounds, compounds having at least one aromatic ring give particularly favorable results.0 Aromatic ring refers to a cyclic compound with aromaticity, and any of them can be usefully used. Benzene aromatic rings such as benzene, naphthalene, and phenanthrene; nitrogen-containing 6-membered rings such as pyridine, quinoline, acridine, isoquinoline, and 7-enanthrizine; indole, carbazole, isoindole, indolizine, and porphyrin; 2.3.2' ,3
'-Nitrogen-containing 5-membered ring such as hirolopyrrole, pyridazine,
pyrimidine, iym-) riazine, 8m-butozine,
Polyvalent nitrogen-containing 6-membered rings such as quinazoline, 1,5-naphthyridine, pteridine, phenazine, pyrazole, imidazole, 1°2.4-) riazole, 1,2.3-) riazole, tetrazole, penziminazole, imidazole , polyvalent nitrogen-containing 5-membered rings such as purines, norharman rings,
Perimidine ring, oxygen-containing aromatic rings such as benzofuran, impensifuran, dipendo-7ran, sulfur-containing aromatic rings such as pendothio-7xn, chenothiophene, chepine, oxazole, isoxazole, 1.2.5-oxadia Oxygen-containing heteroaromatic rings such as sol, benzoxazole, etc.
Thiazole, inthiazole, 1,3,4-? Organic compounds containing a hydrophobic compound having at least one aromatic ring and its derivative, such as ataiazole, pentthiazole, etc., give preferable results. Among them, compounds containing an indole ring such as tributan ζ give favorable results to 41. This can be interpreted as a result of the hydrophobicity, steric structure, and molecular rigidity of the iron compound effectively acting on the bond between the globulin compound and the compound.

First, hydrophobic amino acids and their derivatives are recommended as inexpensive hydrophobic compounds that can be safely used for KII.

Hydrophobic amino acids and their derivatives are defined by Tanford
.

Nozaki (J, Am-Chem-Soe, e
LJL44240 (1962), J. Biol, Che.
m, , 246 2211 (1971)) [Tanford, Nobuki (Journal Opu American Chemical Society.

4, 4240 (1962), Journal φop Biological Chemistry 246°2211 (19
71)) According to the defined hydrophobicity scale, 1500
Amino acids and derivatives thereof with a cal of 17'mol or more, and a compound with a solubility in physiological saline [100 mm@ly/dt or less]. For example, lysine, valine, leucine,
Tyrosine, phenylalanine, isoleucine, Sirip F
These include fans and their derivatives. Among these hydrophobic amino acids and their derivatives, tryptophan and its derivatives give particularly good results. In addition, the adenosic acid can be used without any particular limitation on the t and d configurations.

When the target substance to be adsorbed is mainly autoantibodies and/or immune complexes such as anti-DNA antibodies, anti-ENM antibodies, and anti-nuclear antibodies, low molecular weight substances containing purine bases or pyrimidine bases as constituents as ligands or The low-molecular substances constituting purine bases and pyrimidine bases whose derivatives can be recommended include bases such as □7 pdenine, cytosine, guanine, uracil, chimi/, hypoxanthin, and xunthin, adenosine, Cytidine, guanosine, uridine, inocune, xanthothane,
Nucleosides such as deoxyadenosine, deoxycytidine, deoxyguanosine, deoxyuridine, thyminedine, adenosine 5'-phosphate, cytidine 5'-phosphate, guanosine 5'-phosphate, inosine 5'-phosphate, clidine 5'-phosphate acids, and nine of these ligoses to deoxyribose, and diphosphoric acid, triphosphoric acid,
In addition, nucleotides with phosphoric acid at the 2' and 3' positions such as 9-0, oligonucleotides with 9 or less nucleotides bound to sugars such as glucose or mannose, and oligonucleotides with 10 or less nucleotides, nicotinamide adenine dinucleotide (
NAD), 7F Bin Adenine Dinucleotide)” (FAD
), nucleotide coenzymes such as Buenteim A, Coen A, Bit, etc., and all of these conductors. Of these, bases, nucleosides, and nucleotides are particularly preferred, and among them, the purine base adenine, Guanine is more preferable 0 Instead of simply immobilizing one of these for a second, multiple O11 types may be immobilized on the carrier O The substance to be adsorbed is anti-native DNA antibody, anti-double strikehund DNA antibody, anti-nuclear antibody, etc. When the autoantibodies and/or immune complexes are mainly used, a low molecular weight substance containing phosphoric acid as a constituent or a derivative thereof is recommended as a ligand.

The low molecular weight substances containing sugar phosphate as a constituent here include tetroses such as erythrose and F-leose,
Aldobendoses such as arabinose, xy4-se, lyxo-, , ketohexoses such as sorbase, tagatose, psicose, fructose, N-acetyl-glue
Hexins such as thymine, aldoheptose, ketoheptose, ketoheptose, ketononose polysaccharides,
2-deoxypentose, 6-deoxyhexose, 2
-Deoxy sugars such as deoxyhexose, 2,6-dideo-cyhexose, and 3,6-sibuoxyhexose, sugar alcohol anhydrides, acidic sugars such as uronic acid, ketoaldonic acid, ascorbic acid, etc. Monose sugars, amino sugars, sialic acids, monomers, diorthophosphates, mono- or divirophosphates, tri7
Examples include osphate. These bran aD, L-form, threo-form, and erythro-form can be used without any difference. In addition, a homopolymer with a degree of polymerization of 10 or less can also be used as a hetero-oligosaccharide with an orthophosphoric acid, biphosphoric acid, or triphosphate group bonded thereto. Furthermore, homo- or heteropolymers of O sugar phosphoric acid with a degree of polymerization of 10 or less can also be used.

Derivatives of all these can also be used. Among ζO, phosphate esters of rubose and deoxyribose are particularly preferred, and 3,5 diorthophosphoric acid of deoxyribose and its O oligomer are more preferred.

Rather than simply fixing only one of these, a plurality of types of carrier KwA may be determined.

When the substance to be adsorbed is mainly an autoantibody such as an anti-lymphocyte antibody, an anti-acetylcholine receptor antibody, or an anti-kidney basement membrane antibody, and/or an immune complex, sugars or oligosaccharides are recommended as the ligand.

The bran referred to here refers to monosaccharides and their hazy conductors that constitute glycolipids, glycoproteins, groteoglycans, etc. on the surface of body tissues and cells. As a monosaccharide, 9N-acetyl-D-gluco9 has a biranose or furanose structure.
Hexonamine such as ``min, N-acetyl-D-gafuctosamine, hexose such as D-galactose, D-mannose, D-glucose, L-7 course, L-rhamnose, etc. Pentoses such as cip-ose and D-acbinose, and sialic acids such as N-acetylneuraminic acid and N-glycolylneuraminic acid are used. Can be used.

As the oligosaccharide, the above-mentioned monosaccharides may be used alone or two or more oligomers may be used, regardless of whether they are linear or branched. Dimers to dodecamers of 4I give excellent results.

In addition, the present invention uses the above-mentioned 9a/ and oligobran as agents against autoantibodies; There is no problem in binding it to a hydrophilic carrier and allowing it to act. Depending on the cost, two or more types of S or/and oligosaccharides may be bound to the same hydrophilic carrier.

The cooler used in the present invention is a round type that maintains the temperature at 0° C. or higher and 25° C. or lower, more preferably 5° C. or higher and 15° C. or lower when blood or plasma is brought into contact with the adsorption column.

For example, as shown in Fig. 6, a cooler is an adsorption column.In order to increase the heat exchange efficiency at the inlet side of the blood flow path, the blood flow path is wrapped in a coil shape, and the outside is covered with a refrigerant such as cooling water. blood t
Alternatively, a Liebig condenser type cooling device for cooling plasma can be used. Any material can be used for the coiled blood flow path of this cooler as long as it does not damage blood or plasma, is safe for the living body, and has low thermal conductivity. Silicone tubes, vinyl chloride tubes, etc. used as

What is essential is that the blood or plasma can be cooled so that the temperature when it contacts the adsorption column is maintained between 0 and 25C, more preferably between 5 and 15C.

The cooler may have a structure integrated with the adsorption column as shown in FIG. 7, for example. The ojlT diagram has a jacket through which a refrigerant can pass around the adsorption column. When the blood and plasma pass through the first column, they are cooled by a coolant such as cooling water flowing through the jacket section.

At this time, the blood or plasma is cooled to 0-25°C, more preferably 5-15°C. The material of the adsorption column and the partition wall of the jacket part may be any material as long as it has good thermal conductivity and does not cause any damage to the plasma passing through the adsorption column or to the blood cells.

The above is a typical example of a cooler that can maintain the temperature of blood or plasma when it comes into contact with an adsorbent at 0 to 25°C, preferably 5 to 15°C. f
Any adsorption column with a cU heat exchange section can be used.

As the Komin separator used in the present invention, a plasma separator using a porous p-filtration membrane or a plasma separator using centrifugation can be used. In a plasma separation device using a porous filtration membrane, a porous filtration membrane, more preferably a membrane having the shape of a hollow fiber membrane, is installed parallel to a flow path connecting an inlet and an outlet, and the hollow portion is It is best to use a structure that is used for roads.

The hollow fiber porous membrane for plasma separation used in this device is
A membrane is used that allows virtually all of the globulin compounds in the plasma to pass through, without allowing blood cell components to pass through.
A four-pore structure having an average pore diameter of , OSμ to 2.0μ, more preferably α08jI to 0.8μ is preferably used.

The material of the hollow fiber porous membrane is polyvinyl aluminum: 1
-4, methyl methacrylate, cellulose acetate, and the like are used.

A plasma separation device using centrifugation can be used regardless of its structure as long as it can continuously introduce blood from one side and separate concentrated blood cells and plasma from the other side. Although it can be used, a continuous centrifugal separator without sliding parts is particularly preferably used.

Next, the blood purification device of the present invention will be explained using the drawings.

FIG. 11 and FIG. 2 are schematic diagrams showing examples of the basic configuration of the blood purification apparatus of the present invention.

To explain Figure 181 according to the flow of blood, plasma is separated by a plasma separation device such as a porous filtration membrane or a centrifugal separator, and is sent to a cooler 4 after death, where it is cooled and has good adsorption power. The blood is then sent to the plasma membrane 5, where malignant substances present in the plasma are removed.

Blood or plasma purified by contact with the adsorbent is
After being sent to the warmer 6 and heated if necessary, the outlet port 9
It is derived from

What is essential in the device of the invention is to maintain a low temperature when the blood or plasma is brought into contact with the adsorbent, i.e. between 0 and 25°C, more preferably between 5 and 15°C. Therefore, the cooler must have the ability to maintain the temperature at 0 to 25°C, more preferably 5 to 15°C, when plasma is brought into contact with the adsorption container. Furthermore, the cooler 4 may be configured to cool the entire adsorption column as shown in FIG.

FIG. 3 is a schematic diagram showing an example of the configuration of the blood purification apparatus of the present invention, and FIG. 4 is a schematic diagram showing another example.

To explain the TSS diagram device based on the flow of blood,
Blood A is introduced from a blood introduction section 1 and is transported to a plasma separation device 3 by a pump 2 such as a low 2 pump as necessary. The plasma B separated by is sent to the cooler 4 by a pump 8 such as a roller pump as needed, and after death, it is sent to the adsorption column 5 in a cooled state, where the globulin compounds present in the plasma are removed. removed. The purified plasma is sent to a warmer 6 and heated, and then sent to a blood muse W device 7 such as a drip chamber, where it is mixed with concentrated blood drawn out from a plasma separation device. The blood is drawn out from the blood drawing section 9.

Referring to FIG. 4, the apparatus of the present invention will be explained according to the flow of blood. Blood A is introduced from a blood introduction part 1, and is transported to a cooler 4 by a pump 2, such as a roller pump, as necessary. .

The blood cooled by the cooler is sent to a plasma separator 3, where it is separated into plasma B and blood cell components.

The separated plasma Ba is sent to a plasma purification device 5 by a pump 8 such as a roller pump, if necessary, where globulin compounds, which are malignant substances, present in the plasma are removed. The purified plasma is sent to the blood-plasma mixing device 7, where it is mixed with blood cell components drawn out from the plasma separation device, sent to the warmer 6, heated, and then transferred to the blood drawing section 9.
It is clearly derived.

Examples in which the basic configurations shown in FIG. aI3 and FIG. 4 are combined are also included in the present invention.

As described above, according to the blood purification method of the present invention, when purifying blood, it is possible to remove malignant substances such as autoantibodies and immune complexes with high efficiency.
In addition, Natsutomo is a blood purification method that causes very little negative effects on the blood.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples.

Example 1 The test was carried out using the apparatus shown in FIG. 5. MuCD-added blood 70- of a rheumatism patient was used as blood 11.

For plasma separation $3, a pore size Q, 2 pongee hollow fibers were used, and a membrane area αIII was used.9. The pump used was Belistarte and Tsuku Pump, and the circuit was made of silicone tube. The cooler 2 adjusts the temperature of the water to 10°C, and the 0 adsorption column, which is used by inserting a heat exchanger made of coiled Crycon tube, contains a 15-vinyl alcohol-based synthetic polymer. Activated by the shrimp chlorohydrin method, mixed with a carbonated carbonate solution (pH') containing 360 Cape tryptophan to bind tryptophan, and excess active groups were blocked with ethanolamine to produce 141m!
The 90 warmer 6 was made by filling the adsorbent with 37" of water.
The temperature of the blood was adjusted to C and a heat exchanger made of coiled silicone tubing was inserted into the heat exchanger.The blood used was placed in a siliconized Erlenmeyer flask 10, and transported to a plasma separator 3 by a pump 2 where it was further removed. It is separated into blood cell components and plasma components. The separated blood clots are sent to a cooler 4 by a pump 8 to be cooled, and then sent to an adsorption column 5 for purification. The purified plasma is sent to a blood-blood mixer 7, where it is mixed with blood cell components derived from the plasma separator, heated by a warmer 6, and then sent from a blood drawer 9. derived. Blood purification is performed by blood flow rate 4.211 plasma flow rate 1
It was carried out for 1 hour under sNG conditions.

A T test was performed on the blood used in the experiment and the blood 1 hour after perfusion, and it was found that rheumatoid factor (Waaler-Rose method RAH)
ASTiter) was treated with 1280 reduced to 160, and immunoglobulin complex (C1g solid phase method) was reduced to 20μ9.
/wt may drop to 8597-.

Comparative Example 1 An experiment was conducted under the same conditions as in Example 1 except that the temperature of the cooler was set to 37°C. As a result, the rheumatoid factor decreased from 1280 to 320 due to treatment, and the immune complex decreased from 20 to 12μ.

Example 2 In Example I, the experiment was carried out under the same conditions as in Example 1, except that the temperature of the cooler was changed to 20°C. As a result, the rheumatoid factor decreased from 1280 to 160, and the immune complex level decreased from 20 μ9/wt to 10 μ.

[Brief explanation of the drawing]

FIG. 1 is a schematic diagram showing an example of the basic configuration of the blood purification device of the present invention, FIGS. 2 to 4 are schematic diagrams showing other examples of the basic configuration of the blood purification device of the present invention, and FIG. 6 and 7 are schematic diagrams showing an example of a cooler used in the examples.01...Blood introduction part,2.8...Pump,3...・Plasma separation device, 4...Cooler, 5~・Adsorption column, 6・
...Warmer, 7...Blood-blood clot mixing device, 9...
Blood outlet part, lO... Erlenmeyer flask, 11... Blood, 12... Coil, 13... Cooling water inlet, 14...
・Cooling water outlet, 15... - Liebig cooler, 16...
·Jacket.

Claims (1)

[Claims] 1. A method for removing immunoglobulins and/or immune complexes using an adsorbent, which method comprises cooling the blood or blood plasma and bringing it into contact with the adsorbent. . 2. The temperature when blood or plasma is brought into contact with the adsorbent is 0.
The method for removing immunoglobulins and/or immune complexes according to claim 1, wherein the temperature is higher than 25°C and lower than 25°C. 3. After cooling the blood or plasma and bringing it into contact with an adsorbent,
A method for removing immunoglobulins and/or immune complexes according to claim 1 or 2, which involves heating. 4. Blood ti after heating indicates that the plasma temperature is 25℃ or higher.3
The method for removing immunoglobulins and/or immune complexes according to claim #13, wherein the temperature is 8° C. or lower. 5. An adsorption column filled with an adsorbent is provided between the blood introduction part and the purified blood or plasma delivery part, and a cooler is installed between the blood introduction part and the adsorption column outlet. An immunoglobulin and/or immune complex removal device comprising: 6. At the connection between the blood introduction part and the purified blood outlet part,
a blood circulation system path including a plasma separator and a blood-plasma mixing device; and a plasma reflux system path connected to the scissor system path and causing plasma separated by the plasma separation device to flow into the mixing device via an adsorption column. The apparatus for removing immunoglobulin and/or immune complexes according to claim 5, further comprising a cooler between the plasma separator and the outlet of the adsorption column, is capable of removing blood from plasma. Claims include a heater for warming the blood plasma downstream of the adsorption column in the flow path! Item s5 and 9 are the immunoglobulins and/or immunoglobulins described in item 6.
or an immune complex removal device.