KR101234352B1 - A selective cytapheresis apparatus - Google Patents

Abstract

The present invention provides a plasma exchange unit for introducing the blood separated from the subject to remove the antibody in the blood; And a marker that specifically binds to B-lymphocytes or T-lymphocytes, which are the blood-removable substances, and includes a blood treatment unit for separating and removing the substance from the blood by a reaction between the marker and the substance to be removed. Provided is a cell separation apparatus.

Description

Selective immune cell separation device {A SELECTIVE CYTAPHERESIS APPARATUS}

The present invention relates to a separate export device that selectively removes only cells that specifically bind to specific antigens among the cells in the blood, and in particular, it is possible to selectively remove cells that are the etiology in autoimmune diseases or hypersensitivity diseases. The present invention relates to a novel export device for selective selective immune cells that can treat many patients suffering from diseases in a short time.

Diseases caused by an immune response are called hypersensitive diseases. A common cause of anaphylactic disease is the loss of self-tolerance, in which an individual does not respond to its own antigen. Diseases that result in the loss of self-tolerance resulting in an immune response to self antigens are called autoimmune diseases. Hypersensitivity diseases can also be caused by uncontrolled overreaction with foreign antigens, such as microorganisms or non-infectious antigens in the environment. These hypersensitivity diseases and autoimmune diseases may be classified according to their mechanism of action.

Antibody-mediated diseases are caused by antibodies that bind to antigens present in specific cells or extracellular tissues, or antigenic antibody complexes formed in the blood and deposited on the blood vessel walls. Diseases caused by cell and tissue specific antibodies can be caused by heterologous antigens that immunologically cross-react with autoantibodies or certain components of their tissues. Examples of diseases caused by these cell and tissue-specific antibodies include antibodies to autoimmune hemolytic anemia, platelet membrane protein (gpIIb: IIIa), which produce antibodies against erythrocyte membrane protein (RH blood type antigen, I antigen). The resulting autoimmune thrombocytopenic purpura, vulgaris spermatozoa producing antibodies against epithelial caherin, gud-passure syndrome, streptococcus cell wall antigens, which produce antibodies against the non-coliform proteins in the basement membrane of the kidney and alveolar, myocardial antigen Acute rheumatic fever produced by cross-reacting antibodies, myasthenia gravis caused by antibodies to acetylcholine receptors, hyperthyroidism, mainly due to antibodies to TSH receptors, and insulin-resistance problems with antibodies to insulin receptors Diabetes mellitus, pernicious anemia caused by intrinsic factor of gastric wall cells A variety of diseases will develop.

In the case of immune complex mediated diseases of antigen-antibodies formed in the blood, systemic lupus erythematosus, in which an antibody to DNA or nuclear protein plays an important role, nodular polyarteritis, in which an antibody to hepatitis B surface antigen plays an important role, Streptococcal acute glomerulonephritis, which is caused by the growth of streptococcal cell wall antigens in the basal membrane of the glomeruli, is present.

In addition to diseases caused by these antibodies, T lymphocyte-mediated immune diseases also exist. Insulin-dependent diabetes mellitus, rheumatoid arthritis, multiple sclerosis, peripheral neuritis and the like are known to be mediated by T cells.

This autoimmune disease results from the breakdown of the normal mechanism of maintaining autotolerance in B lymphocytes, T lymphocytes, or both lymphocytes. Some of the B lymphocytes with more than 10 ⁹ different specificities or some of the T lymphocytes, which also have various specificities, can generate an immune response to autoantigens. Normally occurring autoimmunity is prevented by a selection process that prevents the production of autoantigen specific lymphocytes (B lymphocytes, T lymphocytes) or by a mechanism that inactivates these cells. However, autoimmunity can occur due to abnormal selection or control of autoreactive lymphocytes and the loss of self-tolerance by incorrect presentation of autoantigens to the immune system.

One of the methods for treating such autoimmunity is plasma separation, one of the methods of therapeutic apheresis. Therapeutic separation is a method of removing blood cells and plasma components from blood using in vitro blood separation techniques. Depending on the component to be removed, it is called plasmaapheresis, leukapheresis and erythrocytapheresis. Plasmapheresis, also called therapeutic plasma exchange, is a technique that removes large amounts of plasma from a patient's body and substitutes fresh frozen plasma, albumin solution, or saline instead. The removal of plasma results in the removal of high molecular weight substances. The mechanism of therapeutic effect is the removal of antibodies, circulating immune complexes, homologous antibodies, etc. before the cycle.

The problem with such plasma separation ejection is that the B lymphocytes that produce the antibody are removed but remain in the blood of the autoimmune disease patients, thereby producing and secreting new antibodies. Because of this newly generated antibody, the effect of plasmapheresis can only last for a short time (Kuks J. B. M and D. Skallebaek, plasmapheresis in Myasthenia gravis. A survey, 1998. 129-136).

In particular, IgG is known as a rebound phenomenon in the antibody, and the antibody level is higher than before the treatment due to increased production of the antibody after treatment with plasma separation. Often, the use of alcohol at higher intensities and stronger immunosuppressive therapy (Kolins, J, Jones, JM (Eds). Therapeutic Apheresis. American Association of Blood Banks, Arlington, 1983, p. 2).

The present invention has been made to solve the problems of the prior art as described above, the object is to selectively remove only B cells or T cells that bind to a specific antigen from all the cells present in the blood of the patient In particular, it is possible to selectively remove the pathogenic cells from autoimmune diseases or hypersensitivity diseases, thereby providing a new means for treating many patients suffering from such diseases in a short time.

The technical problem of the present invention as described above is achieved by the following means.

(1) a plasma exchange unit into which blood separated from a subject is introduced; And a marker that specifically binds the introduced blood to remover, wherein the blood treatment unit separates and removes the remover from the blood by a reaction between the marker and the remover.

(2) The method according to claim 1,

The blood treatment section is characterized in that the affinity chromatography column consisting of an antigen or a recombinant product of the antigen specifically bound to the removal object or a marker consisting of a treatment of the antigen as a fixed phase and the removal product as a mobile phase Immune Cell Separation Device.

(3) The method according to claim 1,

The blood processing unit is a supply unit of the marker coupled to the marker and the selector; A reaction unit for combining the marker combined with the selector with the introduced blood remover to form a remover complex; And an isolation unit for separating the substance to be removed from the blood complex.

(4) The method according to claim 3,

The separation unit is a selective immune cell separation device, characterized in that for separating the markers coupled to the selector by a magnetic force.

(5) The method of paragraph 3,

The separation unit is a selective immune cell separation device, characterized in that for separating the markers bound to the selector by its own weight.

(6) the method of paragraph 3,

The separation unit is a selective immune cell separation and export device, characterized in that for separating the marker to which the selector is bound by centrifugal force.

(7) the method of paragraph 3,

Selective immune cell separation and transport apparatus, characterized in that the reaction unit consists of a spiral tube.

(8) the method of paragraph 3,

The reaction unit is made of a reaction vessel in which the reactants are mixed, selective immune cell separation and export device characterized in that the shaker provided with a shaker for shaking the reaction vessel.

(9) The method according to 1,

Selective immune cell separation and export device, characterized in that the removal target B lymphocytes or T lymphocytes.

(10) The method according to 1,

The remover is selective immune cell separation device, characterized in that the immune cells causing the autoimmune disease.

(11) The method according to 3,

The antigen-binding device for selective immune cell separation, characterized in that the antigen binding to the microbead is a multivalent antigen.

(12) The method according to 3,

The microbead complex is selective immune cell separation export device, characterized in that at least two or more antigens or antibodies are coupled to the microbeads.

According to the apparatus of the present invention, it is possible to selectively remove only cells that specifically bind to specific antigens among all the cells present in the blood of the patient. In particular, the pathogenic cells can be selectively removed from autoimmune diseases or hypersensitivity diseases, thereby providing a new means of treating many patients suffering from these diseases in a short time.

1A is a schematic diagram of a remover complex in which a marker attached to a selector used in the present invention and a remover are combined.
1B is a schematic diagram of an object to be removed complex showing a form in which a plurality of markers are attached to the selector as another embodiment of the marker to which the selector is attached.
Figure 2 is a block diagram of a device for separating blood removal products in accordance with the present invention.
3 is a configuration diagram of a first preferred embodiment of the blood processing unit according to the present invention.
4 is a configuration diagram of a second preferred embodiment of the blood processing unit according to the present invention.
5 is a configuration diagram of a third preferred embodiment of the blood processing unit according to the present invention.
6 is a configuration diagram of a fourth preferred embodiment of the blood processing unit according to the present invention.

The present invention provides a plasma exchange unit for introducing blood separated from the subject; A blood processing unit including a marker specifically binding to the blood removal product in the blood, and separating and removing the removal material from blood by a reaction between the marker and the removal object; And a blood supply unit for administering the separated blood to the subject.

In the present invention, the "subject" means an animal including a human.

In the present invention, "to remove the blood" means to be separated or removed from the blood of the subject, means B lymphocytes, T lymphocytes, and the like associated with a particular disease, and particularly relates to autoimmune diseases.

In the present invention, the "marker" is a substance that specifically binds to the substance to be removed and labels the substance to be removed, and includes an antigen, a recombinant product of the antigen, a processed product of the antigen, and the like. In the present invention, the polyvalent antigen can also be used as a marker. For example, the use of a marker that cross-links several antigens causes several B lymphocytes and T lymphocytes to bind to one marker, and thus the buoyant of these antigens and cells differs from other cells. It can be removed by centrifugation. These markers can also be used as fixed phases in columns or coupled to various selectors.

In general, a large number of antigens associated with autoimmune diseases are known. These antigens are primarily proteins or glycoproteins that bind to receptors on B and T lymphocytes. B lymphocytes or T lymphocytes recognize these antigens very specifically and can identify very small differences. For example, linear protein determinants with only one amino acid replacement are also capable of identifying. These antigens can be used to label only specific B lymphocytes or T lymphocytes.

Theoretically, there is an average of 7,000,000 B lymphocytes or T lymphocytes in 1 ml of blood, and they have 10 ⁹ different specificities. Given that the pathogenic cells to be eliminated in the present invention are B lymphocytes and T lymphocytes, which are particularly proliferating due to immune responses, their frequency is expected to be higher than 10 ^-9, which can be expected from their specificity. . As expected in previous studies, artificially using an antigen to generate an immune response results in a frequency of about 10 ^-3 leukocytes responding to that specific antigen (Ronald H. Stevens, Eric Macy, Casey Morrow and Andrew Saxon.Characterization). of a Circulating Subpopulation of Spontaneous Antitetanus Toxoid Antibody Producing B Cells Following in Vivo Booster Immunization 1.The journal of Immunology. 1972. 122. 2498-2504). Considering the results of this previous study, it can be assumed that there are about 7,000 antigen-specific B lymphocytes or T lymphocytes in 1 ml of blood. In the present invention, the antigen can be used as a marker to specifically label only about 7,000 pathogenic cells among numerous cells in the blood.

The affinity between the antigen and B lymphocyte receptors is so high that the Kd value is about 10 ^-11 M. When the immune response occurs, the specificity for the antigen is increased and the Kd value increases to about 10 ^-12 M. The specificity of T lymphocytes is also as high as Kd values of 10 ⁻⁵ to 10 ⁻⁷ M.

Antigens associated with autoimmune diseases have already been studied and found, and can be produced by commercial protein recombination methods or commercially available products. For example, the acetylcholine receptor, an antigen of Myasthenia gravis, is commercially available and can be purchased, and the antibody against the type 4 collagen a3 chain, an antigen of Goodpasture's syndrome, is also Sigma-. Commercially available from Aldrich et al.

In the present invention, the "selector" is a substance in which a marker complex is bound to the marker to separate the substance to be separated from other components of blood, which is formed by specifically binding to the substance to be removed, for example paramagnetic microbeads and dense microparticles. Beads (available from MACS Technology, etc.);

As shown in FIG. 1A, if the selector 1 is paramagnetic microbeads, the markers 2 are bound to these microbeads (hereinafter referred to as microbead complexes). 3) (hereinafter referred to as the remover complex), a magnetic field can be used to limit the movement of the remover complex, separate it from the other components, and again remove the remover from the selector. At this time, since the to-be-removed material is antigen-specific B lymphocytes or T lymphocytes, the antigen to which the to-be-removed B lymphocytes or T lymphocytes specifically bind is removed without using the antibody marker previously used in the cell separation technique for research. Cells can be labeled using a recombinant product of the antigen or a processed product of the antigen as a marker.

In the case of using the high density microbead as a selector, the antigen is labeled with the high density microbead, and then separated by precipitating the complex to be removed by self-weight or by removing only the complex to be removed by centrifugation. Lymph or T lymphocytes may be removed.

In the microbead complex, as shown in FIG. 1B, at least two or more markers 2 may be bonded to the surface of the selector 1. In this case, a plurality of markers (2) are attached to the surface of the selector (1) and can be combined with a large amount of the removal targets (3) in a small amount. The separation efficiency is further increased.

In the case where the marker constituting the microbead complex is an antigen, the antigen is preferably a polyvalent antigen having many determinants. Also in this case, as in the case shown in Figure 1b is preferable in that a single microbead can remove a large number of cells causing a variety of antibodies to autoimmune diseases.

In the present invention, "blood" is preferably used by removing a polymer fraction containing an antibody or an immune complex from the blood of a patient using a therapeutic plasma exchange method or replacing plasma with a plasma substitute. This is to prevent the marker to be administered to the blood in the present invention to bind to the antibody or immunocomplex that do not want the binding present in the blood.

For example, there are more than 10 ⁹ different types of antibodies in a patient's blood, which bind to various types of antigens, provide a defense mechanism against external etiologies, and in some cases bind to autoantigens, It can also be a cause of illness. Such pathogenic antibodies are produced in B lymphocytes, which are pathogens to be eliminated in the present invention, and have the same or almost similar specificity as the receptors of B lymphocytes or T lymphocytes, which is the pathogen to be removed. When such antibodies are present in the blood of a patient, when a specific antigen is used to label the pathogenic cells, the antibody in the blood binds to the antigen used for labeling, thereby interfering with the labeling of the pathogenic cells using the antigen. Therefore, these antibodies should be removed from the patient's blood before labeling the pathogen with the antigen specific for the pathogen.

In the present invention, the antibody is removed by replacing the patient's plasma with a replacement fluid through conventional plasma separation and removing the polymer fraction containing the antibody. Such plasma separation is already commercially available and routinely used in blood banks for the treatment of patients with component bleeding or autoimmune diseases (eg Cobe Laboratories, Lakewood co. Hematonetics, Braintree, MA). In the present invention, blood is separated from the patient by using a plasma separation ejector that is already commercialized, and the antibody and the immunocomplex are removed, which may interfere with labeling and removing the pathogenic cells from the blood. Currently commercially available plasma exchange methods include membrane plasma separation using continuous or intermittent centrifugal plasma exchangers and conventional dialysis equipment, all of which are applicable in the present invention. In addition, the antibody removal technique by immunoabsorption using a column that nonspecifically binds to an antibody such as staphylococcal protein A, dextran sulfate, polyvinyl gel, and antihuman IgG, which has recently been studied, may be used.

Hereinafter, the content of the present invention will be described in detail with reference to FIG. 2.

2 is a block diagram of a selective immune cell separation and carrying out device according to the present invention, the separation device of the blood to be removed in accordance with the present invention is composed of a plasma exchange unit 100 and a blood processing unit (200).

Plasma exchange unit 100 is a device configuration for supplying blood to the blood processing unit, simply a tube through which blood collected from a blood vessel of the subject and a pump for supplying the blood to the blood processing unit 200, and the blood of the patient It includes a set of devices for supplying blood in which a polymer fraction containing an antibody or an immunocomplex is removed or a plasma is replaced with a plasma replacement.

An example of such a plasma exchange unit 100 is disclosed in Korean Patent Publication No. 10-2005-0083627. The device configuration is shown in FIG. 1 with reference to an example of one plasma exchanger selectable in the present invention, and accordingly the contents of the present invention will be described in detail.

The apparatus of the plasma exchange unit 100 according to the present invention is a first tube 11 for transporting the blood of the patient flowing from the first catheter (not shown) for providing an inlet to the blood of the patient from the blood flow of the patient It includes.

The plasma exchange unit 100 also includes at least one plasma filtration cartridge 13 for filtering the blood of the patient, wherein the plasma filtration cartridge is surrounded by the housing and has an internal compartment and an external compartment within the protection. Inner compartments and outer compartments are separated by semipermeable membranes to remove specific plasma fractions of interest, wherein the semipermeable membranes have a plasma component having a molecular weight greater than the molecular weight of interest, for example, having a molecular weight greater than about 60 kDa to about 200 kDa. It has a retention coefficient of about 0.50 to about 1.00 for the component, which generally but not necessarily corresponds to a nominal porosity of about 60 kDa to about 200 kDa. The plasma filtration cartridge 13 is brought into a state suitable for filtration at a rate of about 1 to about 20 ml / min for about 1 to about 24 hours. The plasma filtration cartridge 13 receives the blood flowing from the first tube 11 and carries the blood filtered from the inner compartment to the second tube 24 from the inlet 12 in the housing for transporting the blood into the inner compartment. In a housing for transporting a plasma filtrate comprising a particular plasma fraction from a first outlet 15 in the housing for disposal and from an external compartment for disposal or optionally additional sorption 19 of the toxic substances in the particular plasma fraction. And a second outlet 14. The reservoir 21 for receiving a plasma replacement may optionally be contained within the device, or optionally separated therefrom, for example, the infusion bag may be completely separated from the device itself.

The plasma exchange unit 100 includes a first pump 16 for pumping blood of a patient to the plasma filtration cartridge 13 through the first tube 11. The first pump 16 is a pump, for example a roller pump, suitable for providing a predetermined stable flow rate. According to the invention, the first pump 16 may be located at any convenient location along the first tube 11 between the first catheter and the inlet 12 of the plasma filtration cartridge 13. According to the method of the present invention, the predetermined stable flow rate of the first pump 16 is preferably set at about 100 to about 200 ml / min.

The plasma exchange unit 100 also includes a second pump 17 for adjusting the transmembrane pressure across the semipermeable membrane in the plasma filtration cartridge 13 to determine the rate of plasma exchange. The second pump 17 is a pump, for example a roller pump, suitable for providing a preset stable flow rate. According to the invention, the second pump 17 is located at any convenient location along the third tube 22 between the second outlet 14 and one of the reservoir 20 and / or the plasma absorption and sorption 19. Can be located. According to the method of the present invention, the preset stable flow rate of the second pump 17 is preferably set to about 1 to about 20 ml / min.

The blood is introduced into the blood processing unit 200 of the present invention by the third pump 18.

The blood processing unit 200 includes a device configuration for separating or removing a substance to be contained in blood supplied from the plasma exchange unit 100. Such a device configuration may be implemented through various embodiments as described below.

The removal of blood from the patient's blood using such a device can be performed in 200ml to 500ml units, or each step can be performed continuously while the blood is flowing. The return process may similarly use techniques commonly used in conventional plasma exchange or hemodialysis. Preferably, the procedure for removing a specific etiology to remove the blood from the patient's blood is repeated repeatedly until the same amount to about 5 times the total blood volume of the patient.

3 shows a first preferred embodiment of the blood processing unit 200 according to the present invention. The constitution is characterized in that the blood processing unit 200 is an affinity chromatography column in which the marker specifically binding to the substance to be removed is a fixed phase and the substance is a mobile phase.

In the column, a marker 2 is specifically attached to the substance to be removed 3 as a stationary phase, and when blood passes through the substance, the substance to be removed 3 uses a high affinity for the marker 2. It can be combined to separate and remove the object to be removed (3) from the blood. Preferably, the remover 3 is B lymphocytes or T lymphocytes associated with autoimmune diseases, and the stationary marker 2 is an antigen that selectively binds to receptors of the B lymphocytes or T lymphocytes.

4 shows a second preferred embodiment of the blood processing unit 200 according to the present invention. If necessary, a pump for transferring blood may be connected between the parts, and description thereof will be omitted. The blood treatment part 200 of the second embodiment according to the present invention is to separate the substance to be removed from the reaction unit 31a consisting of a reaction vessel in which the formation reaction of the substance to be removed proceeds and the blood introduced from the reaction unit. It includes a separator 32a for. The reaction part 31a is a mixture of the microbead complex administered from the supply unit 23 of the microbead complex of FIG. To provide a place for forming the substance to be removed 10.

In this case, it is preferable to shake the reaction part 31a so that the substance to be removed 10 can be formed well in the reaction part 31a. For this purpose, the shaker 34 is placed at the bottom of the reaction part 31a. It is good to shake it at a constant speed.

The removal complex formed in the reaction part 31a is introduced into the separation part 32a together with the blood, from which the removal complex is separated from the blood. In the preferred embodiment of the present invention, the microbeads are paramagnetic, and when the electromagnet or permanent magnet 33a is attached to the lower part of the separation part, the substance to be removed is precipitated downward by magnetic force and separated from blood. .

5 shows a third preferred embodiment of the blood processing unit 200 according to the present invention. If necessary, a pump for transferring blood may be connected between the parts, and description thereof will be omitted. The blood processing part 200 of the third embodiment according to the present invention is a reaction part 31b having a spiral tube form and a separation part 32b for separating blood to be removed complex 10 by receiving blood from the reaction part. ). The reaction unit 31b is a mixture of the microbead complex and the blood flow from the plasma exchange unit 100 administered from the supply unit 23 of the microbead complex of FIG. To provide a place for forming the substance to be removed 10. As the reaction part 31b is a spiral tube as described above, the microbead complex and the object to be removed are provided with a residence time sufficient to cause a coupling reaction.

The removal complex 10 formed by the above process is introduced into the separation part 32b, where the removal complex 10 is separated from the blood. In the preferred embodiment of the present invention, the microbeads are paramagnetic, and when the electromagnet or permanent magnet 33b is attached to the lower part of the separating part, the substance to be removed 10 is precipitated and separated by magnetic force. Lose.

6 shows a fourth preferred embodiment of the blood processing unit 200 according to the present invention. FIG. 6 shows only the separating part 32c for convenience of understanding, but the remaining reaction part will be referred to since the reaction parts 31a and 31b described in the first and second embodiments of the present invention may be connected to the front end. Detailed description will be omitted. The separator constituting the blood processing unit 200 of the fourth embodiment is composed of a centrifuge 32c provided in the housing 35. The centrifuge 32c rotates the blood introduced from the reactor in the form of an open top by using a motor to discharge blood through the upper opening 36 using a weight difference according to the centrifugal force, and removes the complex to be removed. 10) uses the principle of sedimentation and separation under the centrifuge 32c by gravity and centrifugal force.

As described above, the blood processing unit 200 according to various embodiments of the present invention can separate the blood complex from the blood, and in particular, various B lymphocytes and T lymphocytes associated with autoimmune diseases can be effectively and almost completely removed from the blood of the patient. have.

As described above, the blood from which the to-be-removed object is removed from the blood processing unit 200 is discharged through the fourth tube 24 connected to the outlet of the blood processing unit 200, and the agent connected to the fourth tube. It is injected back into the patient's blood vessels through two catheters (not shown). At some point of the fourth tube 24, a pump 25 for transferring blood is connected.

1: selector
2: marker
3: removal
31a, 31b: reaction part
32a, 32b, 32c: separation part
33a, 33b: magnet
34: shaker
100: plasma exchange unit
200: blood processing unit

Claims (12)

Plasma exchange unit for removing the antibody in the blood is introduced into the blood separated from the subject; And at least one marker selected from the group of antigens that specifically bind to B-lymphocytes or T-lymphocytes, the blood-derived blood removal product, a recombinant product of the antigen, and a treatment product of the antigen, between the marker and the blood removal product. Selective immune cell separation and export device comprising a blood processing unit for separating and removing the blood to remove the object by the reaction. The method of claim 1,
The blood treatment unit selective immune cell separation and transport apparatus, characterized in that consisting of an affinity chromatography column with a specific phase that is specifically bound to the blood to be removed and the removal to the mobile phase. The method of claim 1,
The blood processing unit is a supply unit of the marker coupled to the marker and the selector; A reaction unit for combining the marker combined with the selector with the introduced blood remover to form a remover complex; And an isolation unit for separating the substance to be removed from the blood complex. The method of claim 3, wherein
The separation unit is a selective immune cell separation device, characterized in that for separating the markers coupled to the selector by a magnetic force. The method of claim 3, wherein
The separation unit is a selective immune cell separation device, characterized in that for separating the markers bound to the selector by its own weight. The method of claim 3, wherein
The separation unit is a selective immune cell separation and export device, characterized in that for separating the marker to which the selector is bound by centrifugal force. The method of claim 3, wherein
Selective immune cell separation and transport apparatus, characterized in that the reaction unit consists of a spiral tube. The method of claim 3, wherein
The reaction unit is made of a reaction vessel in which the reactants are mixed, selective immune cell separation and export device characterized in that the shaker provided with a shaker for shaking the reaction vessel. The method of claim 1,
The to remove the selective immune cell separation device, characterized in that the B lymphocytes or T lymphocytes that specifically bind to a specific antigen. The method of claim 1,
The remover is selective immune cell separation device, characterized in that the immune cells causing the autoimmune disease. The method of claim 3, wherein
Wherein said selector is a microbead and the marker is a polyvalent antigen. The method of claim 3, wherein
Wherein said selector is a microbead, and at least two or more antigens are bound to said microbead as markers.

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