JPS5810054A - Artificial endocorneae 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 an artificial reticuloendothelial system, which appears in the blood of diseases involving the immune system, such as collagen disease and nephritis, and is closely related to the progression and activity of the disease. This relates to a device developed for the purpose of removing related antigen-antibody combinations.

Due to diseases such as collagen disease, nephritis, or systemic lupus erythematosus, undesirable substances such as antigen-antibody conjugates, denatured immunoglobulins, and aggregated immunoglobulins appear in the blood. It is desirable to actively remove them from the blood in order to prevent the progression of the disease, alleviate its symptoms, and even hasten its healing. However, it is extremely difficult to selectively extract and remove only unnecessary or harmful substances contained in body fluids such as blood. Even useful components are removed, which is why such a selective removal device has not yet been developed.

The present invention has been made in view of such circumstances, and
Selectively removes and cleans substances such as unnecessary or harmful antigen-antibody conjugates, denatured immunoglobulins, aggregated immunoglobulins, etc. (substances to be removed) present in blood, plasma, or other body fluids. The purpose of the present invention is to provide a device that can transform neutrophils, mononuclear cells, macrophages, lymphocytes, platelets, eosinophils, basophils, or red blood cells, or their membrane components, or their membrane components. Fc receptor and/or C3b complement receptor isolated from membrane components [hereinafter referred to as
A support body to which these components are fixed (called bonds) or a container equipped with a mechanism for accommodating any of these components is provided, and blood, plasma, other blood components, other body fluids, or these components are placed in the container. A liquid obtained from a liquid by methods such as dialysis and filtration is removed by binding the substance to be removed to the bond.

Therefore, according to the present invention, unnecessary or harmful substances such as antigen-antibody conjugates, denatured immunoglobulins, and aggregated immunoglobulins existing in body fluids such as blood are collected in a predetermined manner in the container. Due to the contact with the bond held by the means, the bond is selectively bound due to the biological affinity between the bond and the bond,
- The useful substances present in body fluids such as blood are not removed by the bond but remain as they are in the body fluids flowing out from the container, so that only the substances to be removed can be effectively removed. Elimination is achieved. Of course, in addition to the above-mentioned exemplified objects to be removed, components (compounds) having binding properties with the above-mentioned bonds, complexes thereof, cells, cell components, etc. can also be advantageously removed (removed) by applying the above-mentioned apparatus of the present invention. Needless to say.

The bond used in the present invention can be easily extracted from plasma containing the target bond using conventional gel chromatography, affinity chromatography, etc. The cells themselves, such as neutrophils and monocytes, and their membrane components themselves,
As long as they have F c +) septa and/or C3b complement receptors, they can be used in the present invention.

Furthermore, the bond according to the present invention can be immobilized on a support such as a sol-like substance, a gel-like substance, a solid, or a composite thereof, depending on the desired processing mechanism, and generally using a reagent such as cyanogen bromide. They are chemically bonded and held within a container. In particular, preferred examples of the support include hollow fibers, fibrous materials such as membranes, tubular materials, or membrane materials (these materials include
V (cellulose-based, polyacrylonitrile-based, and polyvinylpyrrolidone-based polymers are available), and the bonding hands are fixed to these and housed in a container to allow body fluids such as blood to flow or pass through. By bringing them into contact (through the fiber wall or membrane, etc.), it is possible to effectively bond the target object to be removed with the bond. In addition, depending on the shape of the support to which the bond is fixed (for example, when it is in the form of granules or powder), a filter or a semipermeable membrane may be installed at the entrance and exit of the container to ensure that the bond is purified and returned to the body. In some cases, care must be taken to prevent the support from being mixed into body fluids such as blood. Furthermore, when the bond is used in the state of a cell, membrane component, or fixed to an object having a shape such as a polymeric substance, the interior of the container may be A mechanism is preferably adopted in which body fluids are allowed to flow through the semipermeable membrane or the like by dividing the body into compartments, and housing an object having the binding hands in the compartments, thereby purifying the body fluids.

A more specific example of such a device according to the present invention is shown in FIGS. 1 and 2. 2 is a blood supply tube connected to an artery, and blood is sent to the plasma separation device 4 through the blood supply tube 3 when the blood pump 2 is operated. Although not shown in the drawings, a mechanism is provided for supplying an anticoagulant such as heparin into the blood in order to prevent blood coagulation during the blood feeding process.

The plasma separator 4 has a large number of holes in its inner wall (fiber wall) through which only plasma can pass, and has an oxidation diameter of approximately 0.5.
Approximately 8,000 micron-sized hollow capillary cellulose triacetate hollow fibers are bundled and housed in a box, and have the same structure as the removal container 6 shown in FIG. 2. Blood supplied through the blood feeding tube 3 passes through the hollow portion of the hollow fiber in the plasma separation device 4, and during this time, plasma in the blood (containing the object to be removed) passes through the hollow fiber. The blood passes through the semi-permeable wall of the blood and is separated from other blood components. The plasma separated by the plasma separator 4, in other words, the plasma containing the object to be removed, which has leaked out from the hollow part of the hollow fiber through the permeable wall of the fiber, is collected, and the plasma is fed from the outlet 4a. The removal container 6 II (liquid is sent through the tube h).

On the other hand, the remaining blood components from which plasma has been separated in the plasma separator 4 pass through the hollow portion of the hollow fibers to a return tube 8, and are taken out from the plasma separator 4 through the return tube 8.

Further, as shown schematically in FIG. 2, approximately 4,000 cellulose hollow fibers 10 in the shape of hollow capillaries with a diameter of 500 microns and a length of 30 holes are arranged in a bundle in the removal container 6. Both ends of 10 are adhered and fixed with polyurethane to form an inlet 11 and an outlet 12 for plasma. Note that a predetermined bond is fixed to the inner surface of the hollow fiber 10 by a predetermined method, and exists in plasma flowing through the hollow part of the hollow fiber 19 or passing through the wall of the hollow fiber 10. The object to be removed comes into contact with the bond and is bonded and removed. Then, the purified plasma obtained by binding and removing the object to be removed with the binding hands fixed to 10 hollow fibers reaches the outlet 12 and passes through the plasma return tube 7 connected to the bottom of the removal container 6 into the container 6. It is taken out, joins with the remaining blood components taken out through the return tube 8, and is returned to the vein through the blood return tube 9.

In fact, such a device was used to purify blood in eight cases of systemic lupus erythematosus. In addition,
Prior to storage in the removal container 6, the inner surface V (of the cellulose hollow fibers 10) is treated with cyanogen bromide (treatment with a solution), and the cellulose hollow fibers 10 are treated with f (F c receptors) separated from the membrane components of the neutrophils. and the C3b complement receptor were fixed by covalent bonding.Furthermore, the hollow fibers 10 subjected to such a bonding operation were stored in the removal container 6r (7) using the above-described method, and then the inside of the container 6 was heated under physiological conditions. Wash thoroughly with salt water,
It was confirmed that no harmful substances such as pyrogens, bacteria, and cyanide remained.

The operation begins by forming an external shunt between the brachial artery and vein,
Blood was introduced from the brachial artery through the blood tube 1 into the plasma separator 4 by the blood pump 2 at a flow rate of 200 ml per minute. The plasma separated by this plasma separator 4 is approximately 60 mj/min? The plasma was introduced into the removal container 6° through the plasma feeding tube 5 at a flow rate of . Then, the hollow fiber 1 in the container 6
By flowing through the hollow part, the immobilized Fc receptor and C3b complement receptor are brought into contact with plasma, and the object to be removed in the plasma is removed by binding to these receptors. The thus purified plasma passes through the plasma return tube 7 and is transferred to the plasma separation device 4.
It merged with the remaining blood components in the return tube 8 and was returned to the arm vein.

For each case, extracorporeal circulation was performed for 4 hours, and antigen-antibody combinations in the serum before and after the test were measured using a C1q deviation test [80, BEL, A, T. et al., [J, Exp', M
ed, J Vol. 142, pp. 139-150 (1975
)] was measured. As a result, the C1q deviation value before the experiment was 36% on average, but it was found to have decreased to 11% immediately after 4 hours of extracorporeal circulation.

In addition, the precipitation reaction with 'C7q' by immunodiffusion method 'AG
NELLO, V. et al., “Immunology J No. 19
Vol. 909-91.9 (1970) 11 summarizes the results in which 7 out of 8 cases were positive before the test, but all became negative after the test, and the results are summarized in the table below. show.

019 Explosion C1qme Takana John Test N. 0゜ Female 47 42 38 '9
+ -T, Ho Female 25 51 4
5 15 + -H, U, Female 81
54 38 8 +-, W.
Female 2'l 48 39 7
+-Y, M. Female 84 58 41
12 + -8, Ho male 29
60 26 9--A, 8゜ Male 42
62 38 15 → -M, B,
Female 38 51 29 10 → −
In addition to these neutrophils, mononuclear cells, macrophages, lymphocytes, platelets, eosinophils, basophils, and red blood cells were also detected.From these results, it was found that the device of the present invention can detect antigens in the blood. It was confirmed that this method is highly effective in removing antibody-conjugated substances.

The above-described device is merely an example of the artificial network system device according to the present invention, and various changes can be made according to the knowledge of those skilled in the art without departing from the gist of the present invention. For example, the above-mentioned device is suitable for use when the substance to be removed is present in plasma, but there are several devices that can process the blood itself containing the substance to be removed without separating the plasma. There is no problem, and the artificial network system according to the present invention may be installed in an artificial dialysis machine in order to treat a fluid such as a dialysate that is circulated in the process of artificial dialysis, and to bind and remove substances to be removed contained therein. It is also possible to incorporate the device, specifically the removal container 6. Of course, the support for fixing the bond is not limited to the above-mentioned hollow fibers, and as mentioned above, as long as the bond is held in the container, it may be granular, powdery, or Supports of various shapes such as membranes can be used, and if the bond is fixed to cells, polymeric substances, etc., the compartments containing these can be made semi-permeable. A membrane (made of a material similar to hollow fibers) is used in the container to prevent the free mixing of the bond-containing substance with the blood or other body fluid being passed, thereby preventing Needless to say, it is necessary to prevent substances containing bonds from being mixed in.

As described in detail above, the present invention retains the bond component that has a specific effect on the target for removal of antigen-antibody conjugates, denatured immunoglobulins, and aggregated immunoglobulins present in body fluids such as blood. By providing a container in which the body fluid flows through the container, only the object to be removed is bound to the imaginary component, and this is selectively removed. Alternatively, the present invention has a major drawback in that selective removal of harmful substances has become possible.

[Brief explanation of drawings]

FIG. 1 is a schematic view showing an embodiment of the apparatus according to the present invention, and FIG. 2 is an enlarged model-like view of a longitudinal section of a removal container. 1: Blood supply tube 23 Blood pump 3: Blood feeding tube 4: Plasma separation device 5: Plasma feeding tube 6:
Removal container 7: Plasma return tube i3: Return tube 9: Blood return tube 10: Hollow fiber applicant Rimitsu Niwa Medex Co., Ltd.

Claims (2)

[Claims] (1) A device that removes and purifies antigen-antibody combinations, denatured immunoglobulins, aggregated immunoglobulins, etc. present in blood, plasma, or other body fluids,
Neutrophils, mononuclear cells, macrophages, lymphocytes, platelets, eosinophils, basophils or red blood cells or their membrane components or Fc receptors and/or C3 isolated from these membrane components
b. A container equipped with a support on which the complement receptor is immobilized or a mechanism for accommodating any of these, and in the container,
By distributing blood, plasma, other blood components, other body fluids, or fluids obtained from these fluids by methods such as dialysis or filtration, intermittently or continuously,
An artificial reticuloendothelial system device, characterized in that it binds and removes the antigen-antibody conjugate, denatured immunoglobulins, aggregated immunoglobulins, and the like. (2) The device according to claim 1, wherein the support is a fibrous material, a tubular material, or a membrane material.