Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Nitrogen containing other than solely as a nitrogen in an...
Reexamination Certificate
2000-09-18
2001-09-25
Fay, Zohreh (Department: 1614)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Nitrogen containing other than solely as a nitrogen in an...
C514S478000, C514S482000
Reexamination Certificate
active
06294581
ABSTRACT:
TECHNICAL FIELD
The present invention relates to suppression of IgA production, more specifically, to selective suppression of IgA production for preventing and treating immunological disorders caused by over-production of IgA antibodies in a human and an animal.
BACKGROUND ART
Immunoglobulins, which include an antibody and a protein structurally and functionally related therewith, are classified into five classes (IgA, IgD, IgE, IgM and IgG) based on their functional properties. Among these, IgAs are divided into two subclasses, i.e., serum IgA and secretory IgA (IgA1 and IgA2). The L-chains of the IgA1 are covalently bound to H-chains. On the other hand, the L-chains of the IgA2 are bound each other through S-S bonds instead of being bound to H-chains. 90% of the serum IgA is IgA1, whereas 60% of the secretory IgA is IgA2.
Sites of IgA production are present in submucosal plasma cells in, for example, a tunica propria of a mucous membrane of a digestive tract, in a salivary gland, in a mammary gland and the like. In a tunica propria of a mucous membrane of a digestive tract in a human, the number of IgA-producing cells is much greater than that of IgG-producing cells in the ratio about 20:1, in contrast to the ratio 1:3 (IgA:IgG) in a lymph node or a spleen. The IgA in mucosal secretions is produced as a dimer having one J-chain component and accompanied by a secretory piece (SC), which is only a little in the serum IgA. The secretory piece is added to the dimeric IgA molecule while it comes out from submucosal plasma cells in an intestine or a respiratory tract to mucosal secretions.
The production of an antibody in an organism is induced by stimulation with a certain antigen. For example, oral administration of a strain of an enterobacterium, Bifidobacterium longum, has been reported to increase the total amount of IgA in feces.
A substance capable of non-specifically stimulating antibody producing cells to deal with an antigen more effectively is often called an adjuvant. For example, cholera toxin, which is a causal toxin of diarrhea produced by Vibrio cholerae, is known to act on a mucous membrane of a small intestine and alter the ionic permeability of the membrane. The alteration results in an excretion of a large amount of electrolytes and water from the small intestine to cause diarrheal conditions. Cholera toxin B subunit, which is a detoxified component prepared by removing the substantial portion of the toxin, is known to be able to elicit an immune response which promotes IgA antibody production (to be able to induce IgA) after penetration into a mucosal membrane of a small intestine, and thus serve as an adjuvant.
IgG, which is about 65% of serum immunoglobulins (Ig) in humans, consists of antibodies against almost all of the antigens and plays an important role in systemic protective immunity. On the other hand, IgA plays an important role in local immune reaction. The secretory IgA in mucosal secretions inhibits the binding of a highly pathogenic microorganism or an allergen to a mucous membrane. Therefore, IgA not only prevents an infection but also prevents a component in foods that may act as an allergen from passing through a digestive tract wall by binding to it.
For example, in case where an extracellular toxin is secreted from microbial cells, the biological defense by antibodies depends on the direct action of antibodies bound to the surface of the microorganism. Thus, antibodies can exert various effects by direct binding to a microorganism.
However, the IgA is also known to act pathologically on a living body. For example, IgA nephropathy is an immunological disorder that is caused by excess immune reactions of IgA in response to an antigen and by deposition of immune complexes mainly containing IgA onto a glomerulus of a kidney. It is believed that the onset of the nephropathy is caused by long-term high IgA antibody titers. The titer of IgA antibody in blood from a patient with IgA nephropathy is quite higher than that in a healthy and normal individual. However, it has not been demonstrated whether the IgA involved in the formation of the immune complex is of the serum type from sites other than a mucous membrane (spleen, bone marrow, peripheral blood, etc.) or of the secretory type from a mucous membrane (digestive tract, respiratory apparatus, etc.).
It is suspected that the causal agent of the immune reaction is an antigenic stimulus mainly in an upper airway and a digestive tract. Candidate antigens include foods (e.g., gluten, milk, soybean), bacteria (e.g., Haemophilus parainfluenzae), viruses (e.g., Cytomegalovirus, Adenovirus, Epstein-Barr (EB) virus) [Tomino, Y., Bio. Clinica, 12(6):375-379 (1997)]. For example, it has been demonstrated that a component of Haemophilus parainfluenzae (HP) and an IgA-type anti-HP antibody are present in the glomerulus and serum in a patient with IgA nephropathy [Suzuki, S., Nakatomi, Y., Sato, H. et al., Journal of Allergy Clinical Immunology, 96:1152-1160 (1995)].
Although hypotheses concerning the cause of the IgA nephropathy and the mechanism of its development have been proposed as described above, many of them are still unclear. There is currently no specific therapy for the IgA nephropathy. Thus, a dietetic therapy or a pharmacotherapy is used. The dietetic therapy uses a low salt diet or a low protein diet. The pharmacotherapy uses an antiplatelet for suppressing blood coagulation in the glomerulus, an angiotensin converting enzyme inhibitor or a calcium antagonist for suppressing a rise in blood pressure, or an adrenocorticoid [Sakai, H., Bio. Clinica, 16:372-374 (1997)].
Effects of several immunosuppressive agents are currently examined by parenteral administration. However, since many of them systemically suppress immunological mechanisms such as IgG production and cellular immunity in addition to the suppression of the over-production of IgA, there is the high risk of causing a severe side effect. Therefore, such immunosuppressive agents have not been widely used clinically yet.
Examples of the immunosuppressive agents include 15-deoxyspergualin (designated as DSG hereinbelow) of formula 1:
Gu—(CH
2
)
6
—CONHCH(OH)CONH(CH
2
)
4
NH(CH
2
)
3
—NH
2
wherein Gu represents a guanidino group. DSG is clinically used as an immunosuppressive agent in an injectable form for renal transplantation.
Alternatively, an effect of suppressing antibody production by parenterally administered DSG has been reported in JP-A 8-40887, JP-A 5-238932, Okubo, M. et al., Nephron, 60:336-341 (1992), Makino, M. et al., Immunopharmacology, 14:107-114 (1987), Inoue, K. et al., Proceedings Japanese Society Nephrology 30th Annual Meeting, pp. 191 (1987). The suppression of the production of antibodies of IgE, IgG, IgM and the like has been confirmed therein. However, DSG has not been reported to selectively suppress IgA.
On the other hand, the use of DSG in an oral composition has been described in Japanese Patent 2610621 and JP-A 8-40887. However, selective suppression of a specified class of antibody has not been disclosed.
OBJECTS OF INVENTION
One object of the present invention is to provide a useful and novel means for preventing and treating immunological disorders caused by over-production of IgA antibodies in a human and an animal.
The other objects a nd advantages of the present invention will be apparent from the description below.
SUMMARY OF INVENTION
The present inventors have confirmed that orally administered DSG effectively suppresses the production of secretory IgA and serum IgA by using an animal experimental model which has been made to produce IgA in mucosal tissues due to stimulation by an antigen. Surprisingly, it has further proved that strong systemic immunosuppressive effects which are observed upon parenteral administration (e.g., intravenous administration) of DSG such as significant effects of suppressing IgG production at the same level as that of effects of suppressing IgA production, is not observed. In addition, the present inventors have demonstrated that the oral ad
Kato Ikunoshin
Saito Hideharu
Takesako Kazutoh
Browdy and Neimark
Fay Zohreh
Kwon Brian-Yong
Takara Shuzo Co. Ltd.
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