JP2023178240A - Autoimmune disease inhibitory pharmaceutical composition, autoantibody production inhibitor, and abnormal immunity modulator - Google Patents

Abstract

To prepare a pharmaceutical composition capable of inhibiting autoimmune diseases, particularly autoimmune arthritis, as existing arthritis therapeutics often cause side effects from excessive immunosuppression; hence, there is a demand for an agent with reduced immunosuppression to inhibit autoimmune diseases such as arthritis.SOLUTION: An autoimmune disease inhibitory pharmaceutical composition is prepared that includes dantrolene or a pharmaceutically acceptable salt thereof or a hydrate thereof as an active ingredient and is formulated as an injection, infusion, oral administration, inhalation, or suppository.SELECTED DRAWING: Figure 1

Description

The present invention relates to a pharmaceutical composition for suppressing autoimmune diseases, an agent for suppressing the production of autoantibodies, and an agent for regulating abnormal immunity.

Rheumatoid arthritis is an autoimmune disease that causes arthritis, and is one of the frequently occurring physical symptoms. The prevalence of rheumatoid arthritis in Japan is about 0.5%, and the number of patients is about 700,000. The immune system's function due to lifestyle habits, genetic factors, and infectious diseases are involved, but the detailed onset mechanism is unknown. Currently, rheumatoid arthritis is commonly treated by administering drugs with immunosuppressive effects such as methotrexate (MTX) and biological preparations. However, immunosuppression may lead to the development of susceptible infections such as pneumonia and urinary tract infections.

In recent years, it has been reported that endoplasmic reticulum stress is one of the factors contributing to the onset of rheumatoid arthritis. Many molecular chaperones in the endoplasmic reticulum are Ca ²⁺ -dependent, and it is known that if the Ca ²⁺ concentration within the endoplasmic reticulum is not maintained, the function of the endoplasmic reticulum is significantly reduced, resulting in endoplasmic reticulum stress. However, the mechanism by which rheumatoid arthritis develops due to endoplasmic reticulum stress has not been fully elucidated.

By the way, dantrolene is a compound that belongs to hydantoin derivatives, and can suppress the release of Ca ²⁺ from the sarcoplasmic reticulum by blocking the ryanodine receptor and blocking the transmission process of excitement from the transverse tubules to the sarcoplasmic reticulum. Are known. In addition to being widely used as a muscle relaxant, dantrolene has the effect of suppressing liver fibrosis as shown in Patent Document 1, and has the effect of inhibiting Ras activity or suppressing cancer cells as shown in Patent Document 2. It is known that it has an effect of inhibiting the growth of , and as shown in Patent Document 3, that it is effective for spasm after nerve damage.

The present inventors have reported that oral administration of dantrolene to disease model mice significantly reduces endoplasmic reticulum stress in hepatocytes when loaded with a high-fat diet and sarcoplasmic reticulum in neurons in Alzheimer's disease. (See Non-Patent Document 1).

Further, an external skin preparation containing a drug having a muscle relaxing effect such as dantrolene as an active ingredient has been disclosed (see Patent Document 4). In this document, the term rheumatoid arthritis is used, and application to rheumatoid arthritis is also mentioned. However, rheumatoid arthritis is used here to mean ``edema and inflammation of local joint tissues caused by local lymph flow due to chronic skeletal muscle tension due to various reasons'', and in recent years rheumatoid arthritis The cause of the disease is different from the common causes, and it is unknown whether there is autoantibody production or abnormalities in immune cells. Additionally, this document states that dantrolene is a drug for external use on the skin, that it is a drug that only acts on skeletal muscles, that it targets local tissues, and that it has a muscle relaxing effect. Since the topical skin preparations in this document are described as being used in combination with other oral drugs, they are intended only for local inflammation caused by contraction and tension of skeletal muscles, and systemic pathological conditions are not considered at all. do not have. In addition, a method for treating or inhibiting the progression of T cell-mediated autoimmune diseases such as multiple sclerosis using a ryanodine receptor inhibitor such as dantrolene has been disclosed (see Patent Document 5). However, the focus is on overexpression of ryanodine receptors in activated T cells, regulation of calcium signals, and proliferation of activated T cells, and no consideration is given to the production of autoantibodies.

JP 2020-7237 Publication International Publication No. 2015/182625 pamphlet Japanese Patent Application Publication No. 2016-539167 Japanese Patent Application Publication No. 2007-308403 US Publication No. 2014/0135385

Tamitani Masaki et.al., Biochem Biophys Rep.2020;23:100787

Conventional arthritis treatment drugs have problems with side effects due to excessive immunosuppressive effects. Therefore, there has been a need for a drug that has less excessive immunosuppressive effect and can suppress autoimmune diseases such as autoimmune arthritis in which autoantibodies are produced. Therefore, an object of the present invention is to provide a new pharmaceutical composition capable of suppressing autoimmune diseases in which autoantibodies are produced, particularly autoimmune arthritis.

In the course of intensive study to solve the above problems, the present inventors focused on dantrolene, which has effects such as muscle relaxation, as a drug that has the effect of suppressing autoimmune diseases. Furthermore, it was surprisingly found that dantrolene has an inhibitory effect on collagen-induced arthritis, which is a typical mouse model of rheumatoid arthritis. Furthermore, they discovered that dantrolene has an effect of suppressing the production of autoantibodies and an immunomodulatory effect that acts only on abnormal immune cells, rather than an immunosuppressive effect that acts on all immune cells, and completed the present invention.

That is, the present invention is as follows.
[1] A self-administered drug containing dantrolene, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, and the dosage form is an injection, an infusion, an oral preparation, an inhalation agent, or a suppository. A pharmaceutical composition for suppressing autoimmune diseases in which antibodies are produced.
[2] The pharmaceutical composition according to [1] above, wherein the autoimmune disease in which autoantibodies are produced is autoimmune arthritis.
[3] The pharmaceutical composition according to [1] or [2] above, wherein the pharmaceutically acceptable salt is a sodium salt.
[4] The pharmaceutical composition according to [1] or [2] above, which is administered to a subject in which autoantibodies are produced at a predetermined threshold or higher.
[5] An autoantibody production inhibitor containing dantrolene, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.
[6] An agent for regulating abnormal immunity, which contains dantrolene, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.

In addition, as another aspect of the present invention, (I) an autoimmune disease in which autoantibodies are produced, which comprises administering to a subject an effective amount of dantrolene or a pharmaceutically acceptable salt thereof, or a hydrate thereof; (II) Use of dantrolene or a pharmaceutically acceptable salt thereof or a hydrate thereof for the production of a pharmaceutical composition for suppressing autoimmune diseases in which autoantibodies are produced; ) Dantrolene or a pharmaceutically acceptable salt thereof or a hydrate thereof for use in suppressing autoimmune diseases in which autoantibodies are produced. In addition, the "effective amount" in the above (I) means an amount effective for suppressing autoimmune diseases in which autoantibodies are produced.

The pharmaceutical composition of the present invention for suppressing autoimmune diseases in which autoantibodies are produced makes it possible to suppress autoimmune diseases in which autoantibodies are produced, particularly autoimmune arthritis, in a subject. Furthermore, the autoantibody production inhibitor of the present invention makes it possible to suppress autoantibody production in a subject.

These are the results of evaluating the arthritis scores of the limbs of arthritis model mice (CIA mice) in Example 2. This is the result of bone micro-CT analysis of ankle joints in dantrolene-administered CIA mice or CIA mice in Example 3. These are the results of HE staining of ankle joints in dantrolene-administered CIA mice or CIA mice in Example 4. FIG. 6 is a diagram showing the results of examining the anti-bovine type II collagen antibody concentration in blood serum collected from dantrolene-administered CIA mice or CIA mice (Day 63) in Example 5. FIG. 5 is a diagram showing the correlation between anti-bovine type II collagen antibody concentration in blood serum collected from dantrolene-administered CIA mice or CIA mice (Day 63) and arthritis score in Example 5. FIG. 5 is a diagram showing the total IgG concentration (mg/mL) in blood serum collected from Day 63 in dantrolene administration group or non-administration group in CIA mice or control mice in Example 5.

The pharmaceutical composition for suppressing autoimmune diseases in which autoantibodies are produced according to the present invention contains dantrolene, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, and the dosage form is injection, drip, or internal administration. There are no particular restrictions on the pharmaceutical composition for suppressing autoimmune diseases, which is characterized in that it is a drug, an inhalant, or a suppository, and is also referred to hereinafter as the "present pharmaceutical composition." Further, the autoantibody production inhibitor of the present invention is not particularly limited as long as it contains dantrolene, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, and the following: It is also referred to as "the autoantibody production inhibitor". Further, the abnormal immunity regulator of the present invention is not particularly limited as long as it contains dantrolene, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. It is also called a "modulator of abnormal immunity."

Dantrolene (1-[[[5-(4-Nitrophenyl)-2-furanyl]methylene]amino]-2,4-imidazolidinedione) in this specification has a molecular formula of C ₁₄ H ₁₀ N ₄ O ₅ and a molecular weight of 314.257. It is a compound with CAS number 7261-97-4 and is represented by the following chemical formula (I). Dantrolene can be produced by a known method, or a commercially available compound can be used.

As used herein, "pharmaceutically acceptable salts" of dantrolene or its pharmaceutically acceptable salts include, for example, alkali metal salts such as sodium salts and potassium salts, and alkaline earth metal salts such as calcium salts and magnesium salts. salts, transition metal salts such as ammonium salts and zinc salts, cyclic amine salts, mono-, di- or tri-lower alkyl amine salts, mono-, di- or trihydroxy-lower alkyl amine salts, Examples include hydroxy-lower alkylamine salts such as polyhydroxy-lower alkylamine salts, and hydroxy-lower alkyl-lower alkylamine salts, with sodium salts being preferred.

Furthermore, dantrolene or a pharmaceutically acceptable salt thereof may be a solvate of these with water, alcohol, etc. ]-3-sodio-2,4-imidazolidinedione). Such a hydrate of dantrolene sodium is commercially available under the trade name "Dantrium (registered trademark)." Dantrium is used as a muscle relaxant because it inhibits the release of Ca ²⁺ from the sarcoplasmic reticulum by blocking ryanodine receptors and blocking the transmission of excitement from the transverse tubules to the sarcoplasmic reticulum. There is.

As used herein, autoantibody refers to an antibody directed against a component of one's own body.

As used herein, autoimmune diseases in which autoantibodies are produced include diseases that occur due to autoantibody abnormalities associated with autoimmune abnormalities. These autoimmune diseases include autoimmune arthritis in which autoantibodies are produced, specifically rheumatoid arthritis; Sjögren's syndrome; systemic lupus erythematosus; mixed connective tissue disease; dermatomyositis/polymyositis; and systemic scleroderma. ; Vasculitis syndrome can be mentioned, and rheumatoid arthritis can be preferably mentioned, but it is not limited thereto.

In this specification, suppression of autoimmune diseases in which autoantibodies are produced refers to prevention of the onset and recurrence of autoimmune diseases in which autoantibodies are produced, as well as autoimmune diseases that have already developed and in which autoantibodies are produced. It means to reduce the severity of, inhibit the progression of, or alleviate symptoms.

Suppression of autoantibody production in the present autoantibody production inhibitor means suppression of production of the above-mentioned autoantibodies by autoantibody-producing cells, such as B cells. The present autoantibody production inhibitor particularly suppresses the production of autoantibodies associated with autoimmune diseases in which the autoantibodies are produced. Specifically, autoantibodies related to autoimmune arthritis include suppression of production of anti-type II collagen antibodies, and autoantibodies related to systemic lupus erythematosus include suppression of production of anti-ds-DNA antibodies.

The term "abnormal immunity regulator" as used herein refers to an agent that does not affect normal immune function but regulates and stabilizes the abnormal immune function. Here, "regulating and stabilizing abnormal immune function without affecting normal immune function" means, for example, that it does not affect the production of antibodies such as IgG antibodies against antigens such as viruses and bacteria. Examples include suppressing the production of antibodies involved in autoimmune diseases, such as suppressing the production of anti-type II collagen antibodies in autoimmune arthritis.

The dosage form of the pharmaceutical composition, the autoantibody production inhibitor, or the abnormal immunity regulator can be an injection, an infusion, an oral solution, an inhalation, or a suppository, and the route of administration is intravenous. It can be administered parenterally or orally.

The present pharmaceutical composition, the present autoantibody production inhibitor, or the present abnormal immunity regulator may contain appropriate carriers, excipients, and diluents that are commonly used in the manufacture of drugs or pharmaceutical compositions. The carriers, excipients and diluents include mannitol, polyvinyl alcohol, lactose, dextrose, sucrose, sorbitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Mention may be made of amorphous cellulose, polyvinylpyrrolidone, water, methyl hydroxybenzoate, propyl hydroxybenzoate, talc, magnesium stearate and mineral oil.

The preferred dosage of the present pharmaceutical composition, the present autoantibody production inhibitor, or the present abnormal immunity modulator can be determined by those skilled in the art in light of various related factors such as the age, sex, and weight of the patient, health condition, and disease severity. It can be determined as appropriate. In the case of oral administration, when administered to adults (60 kg) as a pharmaceutical composition for suppressing autoimmune diseases, a production inhibitor of the subject autoantibodies, or a regulator of the subject abnormal immunity, in terms of dantrolene sodium hydrate; The daily dose of the active ingredient is in the range of 0.01 to 0.3 g, preferably 0.02 to 0.2 g, and can be administered once or in several divided doses. Dosing intervals can include 1 week, 6 days, 5 days, 4 days, 3 days, 2 days, 1 day, 12 hours, 8 hours, 4 hours, 2 hours, 1 hour or 30 minutes. Specifically, as a pharmaceutical composition for suppressing autoimmune diseases, as an agent for suppressing the production of autoantibodies, or as an agent for regulating abnormal immunity, 25 mg of dantrolene sodium hydrate is administered to adults (60 kg) once a day. An example of this method is to increase the dose by 25 mg every week (divided administration 2 to 3 times a day) and determine the maintenance dose. On the other hand, in the case of parenteral administration such as intravenous administration, the pharmaceutical composition for suppressing autoimmune diseases in terms of dantrolene sodium hydrate, the production inhibitor of the autoantibodies in question, or the regulator of abnormal immunity in adults ( 60 kg), the daily dose of the active ingredient is in the range of 0.01 to 0.3 g, preferably 0.1 to 0.2 g, and can be administered once or in several doses. .

The present pharmaceutical composition, the present autoantibody production inhibitor, or the present abnormal immunity regulator may be used in subjects who have not developed an autoimmune disease in which autoantibodies are produced but are likely to develop one in the future, or who have already It can be administered to subjects who have developed an autoimmune disease. Whether or not you have not developed an autoimmune disease but are likely to develop one in the future, and whether you have already developed an autoimmune disease, can be determined using known methods for diagnosing the presence or absence of an autoimmune disease. Examples include a method of measuring the presence or absence of autoantibodies or marker peptides in a biological sample obtained from a subject. For example, in the case of rheumatoid arthritis, a method of measuring the presence or absence of anti-cyclic citrullinated peptide (CCP) antibodies or rheumatoid factor in a subject can be mentioned.

The present pharmaceutical composition, the present autoantibody production inhibitor, or the present abnormal immunity regulator is preferably administered to a patient in which autoantibodies are produced at a predetermined threshold value or more. Here, the predetermined threshold value or higher for autoantibodies refers to autoantibodies confirmed to be present in healthy individuals who do not suffer from a predetermined autoimmune disease, plus one standard deviation of the average value of autoantibodies in the healthy individuals ( SD), +2SD, +1 standard deviation (SD) of the median, +2SD, etc. In addition, for autoantibodies that are not confirmed to be present in healthy individuals who do not suffer from a specific autoimmune disease as being above a predetermined threshold of autoantibodies, if the autoantibodies are detected or if the autoantibodies at a predetermined concentration are It can be done if detected.

The present pharmaceutical composition, the present autoantibody production inhibitor, or the present abnormal immunity modulator include a package insert stating that autoimmune diseases are suppressed by administration of dantrolene, a pharmaceutically acceptable salt thereof, or a hydrate thereof. May contain.

EXAMPLES Hereinafter, the present invention will be explained in more detail with reference to Examples, but the technical scope of the present invention is not limited to these examples.

[Example 1] Preparation of autoimmune arthritis model mouse A collagen-induced arthritis (CIA) model mouse was prepared using wild-type DBA1 mice by the method shown below. First, on Day 0, 50 μL of complete Freund's adjuvant (Cat 231131: BD Biosciences) supplemented with 200 μg of killed tuberculosis bacteria was added to one 7- to 8-week-old wild-type DBA1 (male, female) mouse. A reagent (100 μL/mouse) mixed with 50 μL (100 μg) of type II collagen (Catalog No. 2032: Condrex) was subcutaneously injected into the tail of each mouse. Then, on Day 21, a reagent containing 50 μL of incomplete Freund's adjuvant (Cat 263910: BD Biosciences) mixed with 200 μg of killed tuberculosis bacteria and 50 μL (100 μg) of the bovine type II collagen described above was added to each mouse. 100 μL/mouse) was subcutaneously injected again into the tail of the mouse. Mice were bred until Day 63, euthanized on Day 63, and analyzed as described below (micro-CT, histological evaluation, antibody production amount measurement). For the dantrolene group, dantrolene sodium (355-44503: Fujifilm Wako Pure Chemical Industries, Ltd.) was administered at 100 mg/kg/day from Day-7 (7 days ago) to Day 63 in the production of the collagen-induced arthritis (CIA) model mice. A CIA model mouse was prepared by mixing it with commercially available experimental mouse feed and administering it continuously until Day 63. As a control group, the above CIA model mice without dantrolene administration were used. In addition, arthritis is induced in mice by administering type II collagen to mice and inducing the production of antibodies against type II collagen in the mice.

[Example 2] Evaluation of arthritis score by dantrolene administration in arthritis model mice The arthritis scores of the limbs of the arthritis model mice prepared in Example 1 were recorded every week. The arthritis score was calculated as follows, as described in a previous paper (Protection against peroxynitrite-induced fibroblast injury and arthritis development by inhibition of poly(ADP-ribose) synthase, Proc. Natl Acad. Sci. USA, 95 (1998) 3867-3872). Each limb was evaluated as 0-4 points based on the criteria, and each animal was evaluated as a total of 0-16 points for both limbs. Figure 1 shows the total evaluation scores for both limbs per individual. The evaluation criteria for each limb are as follows.
Score 0: Normal limbs Score 1: Swelling of one toe Score 2: Swelling of two limbs Score 3: Swelling of three or more limbs Score 4: Severe swelling of the entire limb

From FIG. 1, in both male and female mice, the arthritis score in the control group increased after the 35th day, reaching an average of 2 to 2.5 on the 56th day and 4 on the 63rd day. On the other hand, in the dantrolene group, the arthritis score remained 0 until day 56, and was less than 1 on average even on day 63. Therefore, it was confirmed that the onset of arthritis can be suppressed by administering dantrolene. Although various factors are involved in endoplasmic reticulum stress, it was surprising that arthritis could be controlled simply with dantrolene.

[Example 3] Microstructural evaluation by dantrolene administration in arthritis model mice After the ankle joints of the CIA mice produced in Example 1 (dantrolene-administered CIA mice and dantrolene-nonadministered control CIA mice: both female mice) were removed on Day 63. After removing as much soft tissue as possible, bone micro-CT analysis was performed by immersing the tissue in 70% ethanol 10 to 25 times the volume of the tissue. The results are shown in Figure 2.

From FIG. 2, in the control CIA mice, bones were destroyed and dissolved in many parts, but in the dantrolene-treated CIA mice, no bone destruction or dissolution was observed. Therefore, it was confirmed that dantrolene administration inhibits bone destruction and dissolution.

[Example 4] Histological evaluation by dantrolene administration in arthritis model mice The ankle joints of the CIA mice produced in Example 1 (dantrolene-administered CIA mice and dantrolene-nonadministered control CIA mice: both female mice) were removed on Day 63. After that, as much soft tissue as possible was removed, and the tissue was immersed in 70% ethanol in an amount 10 to 25 times the volume of the tissue and fixed. Thereafter, a resin-embedded specimen (non-decalcified sliced specimen) was prepared, and hematoxylin and eosin staining (HE staining) was performed. The results are shown in Figure 3.

From FIG. 3, cartilage destruction and bone lysis were observed in the control CIA mice, but no cartilage destruction and bone lysis were observed in the dantrolene-treated CIA mice. Therefore, it was confirmed that dantrolene administration inhibits cartilage destruction and bone dissolution.

[Example 5] Evaluation of antibody production amount The amount of anti-bovine type II collagen antibody in the serum collected from the CIA mice prepared in Example 1 and control mice on Day 63 was measured using an enzyme-linked immunosorbent assay (mouse anti-bovine type II collagen IgG antibody assay kit, catalog number 2032: Chondrex). The results are shown in Figure 4.

As is clear from FIG. 4, the concentration of anti-type II collagen antibody in serum was statistically significantly lower in the dantrolene-treated group than in the control group. Therefore, it was confirmed that the production of anti-type II collagen antibodies in serum was suppressed by administration of dantrolene. In addition, in wild-type DBA1 mice to which collagen was not administered, anti-type II collagen antibodies were not produced in the serum (not shown).

Moreover, the correlation between the anti-bovine type II collagen antibody concentration in the serum of the CIA mice produced in Example 1 and the control at Day 63 and the arthritis score is shown in FIG. From FIG. 5, there was a positive correlation between the anti-bovine type II collagen antibody concentration and the arthritis score.

Furthermore, in order to confirm the presence or absence of an immunosuppressive state due to the administration of dantrolene to the arthritis model mouse CIA, the amount of total IgG antibody produced was measured. Measurement of total IgG antibody production is based on the fact that dantrolene suppresses the production of IgG antibodies using type II collagen as an antigen, and if the production of IgG antibodies against other antigens decreases, type II collagen is detected. This is because there is a concern that antibody reactions to other antigens, such as viruses, may also be suppressed, which may have a disadvantageous effect on living organisms.

The arthritis model mouse CIA (CIA+) produced in Example 1 and the wild type DBA1 mouse (CIA-) (both female mice) as control mice were incubated from Day-7 (7 days ago) to Day 63 in the same manner as in Example 1. They were divided into a group that received dantrolene sodium and a group that did not receive dantrolene sodium. The total IgG concentration (mg/mL) in serum at each day 63 was examined by ELISA method. Total IgG measurement was performed using Mouse Total IgG Antibody Detection Kit (catalog. no. 3022: Chondrex). The results are shown in FIG.

First, from the results shown in FIGS. 4 and 5, arthritis occurred in the prepared CIA mice in a dose-dependent manner of anti-type II collagen antibody in the serum. In addition, dantrolene, a ryanodine receptor structure-stabilizing drug, was thought to act on immune cells, reduce the production of pathological antibodies that trigger arthritis, and as a result suppress the onset of arthritis. Furthermore, from FIG. 6, no effect on the total IgG production amount was observed by dantrolene administration in both the arthritis model mouse (CIA+) and the control mouse (CIA-) ("n.s": no significant difference). From Figure 4-6 above, conventional arthritis treatment drugs have an immunosuppressive effect, but using dantrolene reduces excessive immunosuppression and increases the risk of infection, which is a problem with conventional arthritis treatment drugs. It is expected to suppress arthritis without causing symptoms. That is, dantrolene is not an immunosuppressant that acts on all immune cells, but can also be used as an immunomodulatory agent that acts only on abnormal immune cells.

Claims (6)

An autoantibody-producing agent characterized by containing dantrolene, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient, and having a dosage form of an injection, an infusion, an oral preparation, an inhalation agent, or a suppository. A pharmaceutical composition for suppressing autoimmune diseases. The pharmaceutical composition according to claim 1, wherein the autoimmune disease in which autoantibodies are produced is autoimmune arthritis. The pharmaceutical composition according to claim 1 or 2, characterized in that the pharmaceutically acceptable salt is a sodium salt. The pharmaceutical composition according to claim 1 or 2, which is administered to a subject in which autoantibodies are produced at a predetermined threshold value or more. An autoantibody production inhibitor containing dantrolene, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient. A modulator for abnormal immunity containing dantrolene, a pharmaceutically acceptable salt thereof, or a hydrate thereof as an active ingredient.