The present invention relates to an adsorbent for removing or recovering autoantibodies or immune complexes produced by combining an autoantibody with their homologous antigens, from body fluid and to an apparatus for removing autoantibodies or immune complexes thereof using the same. And, the present invention relates to a method for removing autoantibodies or immune complexes thereof from body fluid by passing body fluid through the above-mentioned removing apparatus.
Autoimmune disease is a disease which is caused by being formed antibodies to the components of tissue in one's body (hereinafter referred to as "autoantibodies"), and as a typical autoimmune disease, there is exemplified systemic lupus erythematosus (SLE) or rheumatoid arthritis (RA).
In SLE, it is known that the immune system produces immunoglobulins capable of binding to the components of nucleus in cells, particularly, deoxyribonucleic acid (DNA), or that the immune system produces immunoglobulins capable of biding to phospholipid in cell membrane, and the antibodies against DNA (anti-DNA antibodies; anti-dsDNA) or the antibodies against phospholipid (anti-phospholipid antibody) appear in body fluid, which are closely related to the pathogenesis of SLE. Also, it is known that complexes are produced by combining autoantibodies with their homologous antigens (hereinafter referred to as "immune complexes"), and the immune complexes thereof with their homologous antigens appearing in body fluid are closely related to the pathogenesis of SLE.
On the other hand, in RA, it is known that the immune system produces immunoglobulins which form complexes with autologous Immunoglobulin G (IgG) as the reactant, and these immunoglobulins against IgG (rheumatoid factor, RF) appear in body fluid, which are also closely related to the pathogenesis of RA. Also complexes produced by combining RF with their homologous antigens, namely, immune complexes, appearing in body fluid, are closely related to the pathogenesis of RA.
The mechanism that the produced autoantibodies or immune complexes thereof with their homologous antigens lead to the above-mentioned diseases is not completely clarified. However, there are reported the mechanisms such that autoantibodies give damage to cells, and that autoantibodies form complexes with antigens and immune complexes are deposited in tissue, which results in disorder in the tissues.
In SLE, it is known that the produced anti-DNA antibodies are combined with DNA originated in cells, which is outflowed into blood, to form an immune complex, and immune complexes are deposited around blood vessels or in the glomerulus, which results in angiitis or lupus nephritis. Also, it is known that the produced anti-phospholipid antibodies are combined with phospholipid in cell membrane, outflowed into blood, to form immune complexes, and immune complexes are deposited around blood vessels or in the glomerulus, which results in thrombosis or thrombocytopenia. Actually, renal insufficiency is the main cause of death in SLE.
Also with respect to RF, it is known that the produced RF is combined with an IgG in blood to form an immune complex, and immune complexes are deposited around blood vessels, which results in angiitis, or immune complexes are deposited on synovial membranes, which results in arthritis.
As aforementioned, various symptoms of diseases are caused by the produced anti-DNA antibodies or immune complexes thereof with DNA, the produced anti-phospholipid antibodies or immune complexes thereof with phospholipid, or the produced RF or immune complexes thereof with IgG in blood, and the like. Accordingly, it is very important to control autoantibodies such as the anti-DNA antibody, the anti-phospholipid antibody and RF in the treatments of the autoimmune diseases such as SLE and RA.
Hitherto, there have been widely used in the treatment of the autoimmune diseases such as SLE and RA, steroid, an immunosuppressor, immuno modulator, an anti-inflammatory agent, and the like, for the purpose of controlling the production of autoantibodies such as the anti-DNA antibody, the anti-phospholipid antibody, and RF and immune complexes thereof with their homologous antigens. Among them, corticosteroids are most popularly used. For example, there is often conducted a treatment in which an extremely large dose of oral corticosteroids is administered intermittently to the patient in a short term, what is called pulse therapy. However, steroids are apt to produce side effects by even its small amount of administration. Therefore, more serious side effects cannot be avoided when the administration of steroid is administered in an extremely large amount and in a short term. Further, since the above-mentioned agents are rather frequently used in a long-term administration, side effects are produced more easily. Furthermore, there occurs very often a case that the dose of the agents must be increased more and more due to drug resistance. As the result, it become impossible to use these agents or to exhibit the effects of the agents satisfactorily, depending on the patient's condition. Particularly, although it is most necessary to control anti-DNA antibodies, anti-phospholipid antibodies and immune complexes thereof with their homologous antigens during the period that a patient of active SLE, there happen quite often cases where pulse therapy or the effective treatment using the agents such as the immunosuppressor cannot be adopted because of the above-mentioned reasons.
Also, in the treatment of RA, it is known that steroid shows a dramatic effect for controlling the production of RF and immune complexes thereof. However, some patients suffering from RA for several years suddenly show symptoms of malignant rheumatoid arthritis, which is more malignant than RA, accompanied by a rise in the body temperature, and, most of them had been administered steroid in the past. Accordingly, there is still a strong suspicion that steroids act at least partially in triggering the onset of malignant rheumatoid arthritis.
Then, as an another treatment besides the drug therapy, there is attempted an extracorporeal circulation treatment, in which autoantibodies existing in body fluid such as the anti-DNA antibody, the anti-phospholipid antibody or RF, and immune complexes thereof with their homologous antigens are directly removed. It is the most simple method to replace the partient's plasma containing autoantibodies such as the anti-DNA antibody, the anti-phospholipid antibody and RF, and immune complexes thereof with their homologous antigens, with plasma obtained from a healthy body, what is called plasma exchange. By means of the plasma exchange, autoantibodies such as the anti-DNA antibody, the anti-phospholipid antibody and RF, and immune complexes thereof are remarkably decreased, and the symptoms are alleviated. However, this treatment is costly because a large quantity of plasma obtained from healthy bodies is required, in addition, it involves the danger that the transfused blood is infected with serum hepatitis or HIV during the treatment. Accordingly, the plasma exchange is not widely employed for the present.
In the plasma exchange, plasma of a patient including all components of the plasma is replaced with plasma obtained from healthy bodies. On the other hand, there is developed a method for the separation of blood plasma component using a membrane in order to selectively remove pathogenic substances, i.e. autoantibodies such as the anti-DNA antibody, the anti-phospholipid antibody and RF, and immune complexes thereof with their homologous antigens. In the method, based on the volume of molecules, high molecular weight components including the pathogenic substances are removed from the plasma using a membrane, and the plasma having low molecular components including the main protein, i.e. albumin is returned into the patient's body. However, autoantibodies are composed of IgG (immunoglobulin G) having a molecular weight of about 1.6.times.10.sup.5 or IgM (immunoglobulin M) having a molecular weight of about 9.times.10.sup.5, besides, immune complexes produced by combining autoantibody with its homologous antigen has a wide range of molecular weight. Therefore, not all of the autoantibodies and the immune complexes cannot be separated from albumin having a molecular weight of about 60,000, or normal IgG and IgM according to the volume of the molecule. As the result, there occur problems such that a large amount of albumin is also removed when autoantibodies and immune complexes are removed, and further, all proteins having a molecular weight equal to, or larger than that of the pathogenic substances are removed during the separation.
From the above-mentioned problems, there has been desired a method for more selectively removing the pathogenic substances, i.e. autoantibodies such as the anti-DNA antibody, the anti-phospholipid antibody and RF, and immune complexes thereof with their homologous antigens, and yet, the useful components are not removed from the body fluid.
It is an object of the present invention to provide a means for selectively removing only autoantibodies such as the anti-DNA antibody, the anti-phospholipid antibody and RF, and immune complexes thereof with their homologous antigens from body fluid without losing the useful components in the body fluid.
This and other objects of the present invention will become apparent from the description hereinafter.