Blood contains a variety of components such as blood cells, cytokines and other humoral factors. These blood components play important roles on regulating immunity balance in a living body.
Endotoxin typified by lipopolysaccharide is a factor which exhibits a variety of biological activities involved in fever, blood pressure decrease, intravascular coagulation, and activation of Hageman factor in the blood. Particularly in clinical practice, for example, the blood of a patient after surgical operation is sometimes contaminated with such endotoxin to cause severe sepsis. It is known that leukocytes stimulated with the contaminant endotoxin in the blood of the patient, particularly of the severe patient, release a variety of cytokines such as tumor necrosis factor, interleukin-1, interleukin-6 and interferon, and acid peroxides. It is also known that these excessive cytokines give physiologically harmful effects.
Columns for removing a variety of components in the blood have been developed so far. As example thereof, there are a column intending to remove leukocytes and granulocytes (Patent Documents 1 and 2), a column intending to absorb the cytokine (Patent Documents 3 and 4), and a column intending to absorb leukocytes and toxin simultaneously (Patent Documents 5 and 6). However, none of them can simultaneously remove the humoral factor to which the blood cells respond. There has also been reported a filter for removing the leukocytes, whose main body is a certain filter element having a zeta potential of 0 mV or more (Patent Document 7). However the report merely discloses the removal of blood cells. Therefore, with any of these conventional columns, remaining cells have been insufficiently normalized.
Meanwhile, it has been reported that, among the blood components, a variety of substances, particularly latent transforming growth factor-beta (TGF-β), immunosuppressive acidic protein, interleukin-10, tumor necrosis factor (TNF) and prostaglandin E2, and cells such as B cells and macrophages abnormally increase or grow in patients with advanced cancer, and suppress immune functions by, e.g., inhibiting induction and functional expression of cancer specific killer cells (Non-patent Document 1, “Shuyo Men-ekigaku (Tumor Immunology)” pages 89 to 112, 1998 written by Hiromi Fujiwara, published by Chugai Igakusha). Thus, particularly aiming at the patients with cancer, there have been developed procedures to enhance an immune system in the patient by removing these immunosuppressive substances, leading to involution of the tumor and inhibition of tumor growth.
As a technology for removing these immunosuppressive substances efficiently and safely, there are disclosed the technologies intending to absorb TGF-β (Patent Documents 8 and 9), carcinoembryonic antigen (Patent Document 10), and immunosuppressive acidic protein (Patent Document 11). However, the technology to efficiently remove these immunosuppressive substances using one absorbent has not been developed yet.
The column described above typically has a filtering element or an absorbent (absorbent carrier) for removing or absorbing each target substance inside the column, and a variety of substances and shapes are used. For example, in Patent Document 1, a nonwoven fabric obtained by mixing fibers having a plurality of fiber diameters for preventing clogging with blood cells is used. However, the nonwoven fabric itself has a high bulk density, and insufficiently controls the removal of blood cells. Thus, the increase of pressure loss upon blood circulation is still concerned.
In the absorbent carrier composed of cellulose acetate beads having diameters of about 2 mm (Patent Document 2), pressure loss is not much concerned. However, it is impossible to enlarge an absorption surface area of the carrier, and this carrier is thus inefficient as the absorbent carrier. Reduction of particle diameter, however, leads to the increase of pressure loss, and thus such a reduction of diameter is not adoptable.
In Patent Document 6, it is disclosed that the bulk density of the absorbent carrier is adjusted to 0.05 to 0.15 g/cm3 for clogging prevention and keeping its configuration. However, this absorbent carrier is poor in practicability, and particularly morphological stability is insufficient.
Nonpatent Document 1: “Shuyo Men-ekigaku (Tumor Immunology)” pages 89 to 112, 1998 written by Hiromi Fujiwara, published by Chugai Igakusha.
Patent Document 1: JP Sho-60-193468-A
Patent Document 2: JP Hei-5-168706-A
Patent Document 3: JP Hei-10-225515-A
Patent Document 4: JP 2000-237585-A
Patent Document 5: JP 2002-113097-A
Patent Document 6: JP 2002-172163-A
Patent Document 7: JP Hei-6-142196-A
Patent Document 8: JP 2003-339854-A
Patent Document 9: JP 2004-248950-A
Patent Document 10: JP 2003-310751-A
Patent Document 11: JP 2003-111834-A