JPS5820632B2 - Artificial network system device - Google Patents

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 immunoglobulin, and aggregated immunoglobulin 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, by selectively removing only unnecessary or harmful substances contained in body fluids such as blood,
It is extremely difficult to remove this, and even if you try to remove only the target object, other useful components will also be removed.Therefore, even today, such selective removal devices are still not available. It has not been developed.

The present invention has been made in view of such circumstances, and
Selectively removes and purifies substances such as unnecessary or harmful antigen-antibody combinations, 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 erythrocytes, or their membrane components. Or a support to which the Fc'J receptor and/or C3b i receptor separated from these membrane components (hereinafter, these components are referred to as bonds) is fixed, or a mechanism that accommodates any of these. A container is provided, and blood, plasma, other blood components, other body fluids, or fluids obtained from these fluids by methods such as dialysis or filtration are intermittently or continuously introduced into the container. By causing the object to be removed to bind to the bond, the object to be removed is removed.

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. By contacting the bonds held by the means, they are selectively bound due to the biological affinity between them, while useful substances present in body fluids such as blood The substance is not removed by the bond and remains as it is in the body fluid flowing out from the container, thereby achieving effective removal of only the substance to be removed.

Of course, in addition to the above-mentioned exemplified objects to be removed, components (compounds) having binding properties on the bond, or complexes thereof, cells,
It goes without saying that cellular components and the like can also be advantageously removed by applying the apparatus of the present invention.

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 Fc receptors 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 are hollow fibers, fibrous materials such as membranes, tubular materials, or membrane materials (these materials generally include polymers such as cellulose, polyacrylonitrile, and polyvinylpyrrolidone). The target object to be removed can be removed by fixing the bonded hands to these and placing them in a container, through which body fluids such as blood can flow or come into contact with each other (through fiber walls or membranes, etc.). This makes it possible to effectively combine the bond with the bond.

Also, depending on the shape of the support to which the bond is fixed (
(for example, when the support is in the form of granules or powder), a filter, semipermeable membrane, etc. is provided at the entrance and exit of the container, and care is taken to prevent the support from being mixed in body fluids such as blood that are purified and returned to the body. There is.

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 inside of the container is covered with a semipermeable membrane or the like. A mechanism is preferably adopted in which body fluid is allowed to flow through the semipermeable membrane or the like by partitioning the body and accommodating the object having the bond in the partition, thereby purifying the body fluid.

A more specific apparatus of the present invention as described above is shown in Fig. 1.
Shown in Figure 2.

1 is a blood supply tube connected to an artery, and blood is sent to a plasma separation device 4 through a blood supply tube 3 when a blood pump 2 is operated.

Although not shown, a mechanism is provided for supplying an anticoagulant such as heparin into the blood in order to prevent coagulation of the blood during the blood feeding process.

The plasma separation device 4 has a large number of holes in the inner wall (fibrous wall) through which only plasma can pass, and the diameter of the holes is about 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 fibers in the plasma separation device 4, and during this time, the suppressed plasma (containing the object to be removed) in the blood flows through the hollow fibers. 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 that has leaked out from the hollow part of the hollow fiber through the semi-permeable wall to the outside of the fiber is collected, and the plasma is fed from the outlet 4a. The liquid is sent to the removal container 6 through the tube 5.

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 hollow capillary cellulose fibers 10 with a diameter of 500 microns and a length of 30 cm are arranged in a bundle in the removal container 6. Both ends 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 10 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 the hollow fibers 10 reaches the outlet 12 and is collected through the citron return tube 7 connected to the bottom of the removal container 6. It is taken out of the container 6, joins with the remaining replacement fluid 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 Ω.

Note that before storing the cellulose hollow fibers 10 in the removal container 6, cyanogen bromide is applied to the inner surface of the cellulose hollow fibers 10 (
treatment with a solution), and Fc receptors and C3b complement receptors separated from membrane components of neutrophils were covalently bonded and immobilized thereon.

Further, after the hollow fibers 10 subjected to such a bonding operation are housed in the removal container 6 by the above-mentioned method.

The inside of the container 6 is thoroughly washed with physiological saline to remove pyrogens,
It was confirmed that no harmful substances such as bacteria or cyanide remained.

The operation begins by forming an external shunt between the brachial artery and vein,
Blood was introduced from the brachial artery through a blood tube 1 by a blood pump 2 to a plasma separator 4 at a flow rate of 200 ml per minute.

The plasma separated by this plasma separator 4 is approximately 60r/min.
The plasma pumping liquid is passed through the tube 5 at a flow rate of ul to the removal container 6.
guided within.

Then, by circulating the hollow portion of the hollow fibers 10 in the container 6, the fixed FC resegmenter and the C
3b complement receptors were brought into contact with plasma, and the substance to be removed from the plasma was removed by binding to these receptors.

The thus purified plasma passed through the plasma return tube 7, merged with the remaining blood components in the return tube 8 from the plasma separator 4, and was returned to the arm vein.

A. For each case, extracorporeal circulation was performed for 4 hours, and antigen-antibody combinations in the serum before and after the test were tested using C1q deviation test C3OBEL, A, T, et al., rJ, Exq.

Med, J Vol. 142, pp. 139-150 (1975
)).

As a result, the average iC1q deviation value before implementation was 36%, but it was found that it decreased to 11% immediately after 4 hours of extracorporeal circulation. Reaction CAGNELLO1■
, et al., [Immunology J Vol. 19, No. 909
-919) page (1970) J found that 7 out of 8 cases were positive before the test, but all of them became negative after the test.

The results are summarized and shown in the table below.

In addition to such neutrophils, mononuclear cells and macrophages.

Since lymphocytes, platelets, eosinophils, basophils, and erythrocytic cells also contain Fc receptors and F3b receptors, similar tests were repeated for these receptors, and similar results were obtained. Obtained.

From these results, it was confirmed that the device of the present invention is highly effective in removing antigen-antibody combinations from blood.

Note that the above-described device is merely one 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 object to be removed is present in plasma, but there is no problem in using it as a device that processes the blood itself containing the object to be removed without separating the plasma. In addition, the artificial network system device according to the present invention is installed in the artificial dialysis machine so that the fluid such as dialysate that is circulated in the process of artificial dialysis is treated and the substances to be removed contained therein are combined and removed. Specifically, the removal container 6 can also be incorporated.

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 retained in the container, particles, powder, or membrane may be used. Supports of various shapes can be used, and in cases where 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 provided in the container to prevent the free mixing of the bond-containing material with the body fluid such as blood, thereby binding it to the body fluid. Needless to say, care must be taken to prevent contamination by hand-contaminated substances.

As described in detail above, the present invention retains the bond component that has a specific effect on the object to be removed, such as antigen-antibody conjugates, denatured immunoglobulins, and aggregated immunoglobulins present in body fluids such as blood. To provide an apparatus of the present invention, which selectively removes only the object to be removed by bonding the object to the component by flowing body fluid into the container, and which causes the object to be removed. The great significance of the present invention is that it has become possible to selectively remove unnecessary or harmful substances for the first time.

[Brief explanation of the drawing]

FIG. 1 shows an embodiment of the device according to the invention. ] This is a schematic diagram, and FIG. 2 is an enlarged model-like view of a vertical section of the removal container. 1: Blood supply tube, 2: Blood pump, 3: Blood feeding tube, 4: Plasma separation device, 5: Plasma feeding tube, 6:
Removal container, 7: plasma return tube, ) 8: return tube, 9: blood return tube, 10: hollow fiber.

Claims (1)

[Scope of Claims] 1. A device that removes and purifies antigen-antibody conjugates, denatured immunoglobulins, aggregated immunoglobulins, etc. present in blood, plasma, or other body fluids, and purifies neutrophils. , mononuclear cells, macrophages, lymphocytes, platelets, eosinophils,
Basophils or red blood cells or their membrane components or Fc receptors and/or C3b isolated from these membrane components
It has a support on which complement receptors are immobilized, or a container equipped with a mechanism for accommodating either of these, and blood, plasma, other blood components, or other body fluids, or dialysis from these fluids is placed in the container. The antigen-antibody conjugate, denatured immunoglobulin, aggregated immunoglobulin, etc. are bound and removed by distributing the solution obtained by a method such as filtration intermittently or continuously. An artificial network system device characterized by: 2. The device according to claim 1, wherein the support is a fibrous material, a tubular material, or a membrane material.