JPH06135836A - Inducer for contra-suppressor cell - Google Patents

Abstract

PURPOSE:To obtain an inducer for contra-suppressor cell and a therapeutic agent for low immunopathy. CONSTITUTION:Glycyrrhizin as an active ingredient is mixed with a base of medicine. When an inducer for contra-suppressor cell thus obtained is administered, a contra-suppressor cell is induced. The induced contra-suppressor cell suppresses eruption of inhibitory suppressor cell, a main cause for low immunopathy and its action and alleviates and treats opportunistic infective disease.

Description

Detailed Description of the Invention

[0001]

TECHNICAL FIELD The present invention relates to an inducer of contra suppressor cells and a therapeutic agent for hypoimmunity.

[0002]

2. Description of the Related Art It is known that hypoimmunity is often induced by basic diseases such as cancer, stress, serious injury or burn, use of transplant rejection agents after organ transplantation, or during aging. Surgery 156 , 233 (198
3), Immunology Today 11 , 17
0 (1990), Advances in Host defense Mechanisms
6 , 81 (1986), Transplantation Proceedings 23 , 2175 (19)
91) and Advances in Immunology (Advanc
es in Immunology) 29 , 287 (1980)).

Further, infection itself by microorganisms such as bacteria and viruses also contributes to hypoimmunity, and AIDS, which has become a big problem in recent years, is a prominent example in which hypoimmunity is induced. By the way, from the serum of patients with hypoimmune disease caused by cancer or burns, the amount of prostaglandin E ₂ (Archives of Surgery (Ar
chives of Surgery 123 , 293 (1988)), steroids (Journal of Burn Care Rehabilitation 5 , 143
(1984)), transforming growth factor-β (Journal of the
Journal of Clinical Immun
11 ), 95 (1991)), and various humoral immunosuppressive substances have been found, and it can be presumed that these contribute to the induction of hypoimmune disease.

Furthermore, in these hypoimmune patients, the interferon producing ability (The Journal of Immunology 129 , 1806 (198)
2)), interleukin 2 production (Clinical Experimental I
mmunology) 65 , 570 (1986)) or thymus-derived cell-dependent cell killing action (Transplantation (Trans
plantatation 33 , 422 (1982)), natural killer cell-dependent cell killing action (Cellu Immunology
lar Immunorogy) 86 , 551 (1984)) and the like, suppressor cells (suppressor macrophages, suppressor T lymphocytes, suppressor B lymphocytes) that have the function of reducing the immune response appear, and play an important role in inducing hypoimmunity. ing.

[0005] For example, the fact that suppressor cells remarkably suppress host tumor resistance is explained by North et al. (Journal of Experimental Medicine).
al Medicine) 159 , 1295 (1984)). That is, when Meth A tumor was used in a mouse allograft system, antitumor effector cells responsible for associated immunity were detected at a peak 9 days after transplantation, but after that, the appearance of suppressor cells eliminated the effector cell activity. As a result, more violent tumor growth progresses.

On the other hand, in the case of organ transplantation, in order to suppress the rejection reaction to the transplanted organ, cyclosporin A (transplantation procedures) is used.
(Transplantation Proceedings) 23 , 2180 (1991)), O
KT3 (The New England Journal of
Medicine (The New England Journal of Medicine) 31
3 , 337 (1985)) and other immunosuppressive agents have been developed and are now available in clinical settings, the survival days of organ transplant patients are steadily increasing.

However, with these immunosuppressive agents,
Suppression of T cells (The Journal of Immunology (T
he Journal of Immunology) 128 , 355 (1982)) and induction of suppressor T cells (Clinical and Experimental Immunolo
gy) 71 , 369 (1988)), resulting in a marked decrease in the cellular immunity of the patient, and eventually it becomes impossible to eliminate even indigenous bacteria and airborne bacteria, and in many cases patients die due to sepsis. .

In burns, direct death due to physical damage has almost been avoided by the progress of modern medical treatment including breath and water management, but it is caused by an opportunistic infection caused by hypoimmunity. Death due to sepsis and the like has become a major problem.

When the suppressor cells derived from the burned mouse are transferred to the non-burned mouse, the susceptibility of the transferred mouse to the herpes virus infection is significantly increased. It was confirmed to depend on suppressor T cells present in mouse spleen.

Kupper et al. (Journal of Surgical Research) 38 , 606
(1985)) conducted an animal experiment using a sepsis model,
Transfer of suppressor cells (Lyt2 ⁺ T cells) increased the average mortality rate in this model from 15% to 92%. Further, at this time, when a single antibody against a suppressor produced by suppressor cells was simultaneously administered, such an increase in mortality was not observed. This fact clarifies the importance of suppressor cells in attracting opportunistic infections, and by blocking the action of suppressor cells and their soluble factors, it is possible to restore the infection resistance of the burn host to a non-burn condition. Tell a story.

[0011]

In order to remove suppressor cells, which are one of the causes, from individuals with low immunity, X-ray irradiation (Cancer Immunology and Immunotherapy) has hitherto been performed.
y) 16 , 175 (1984)), Topical Cerium Nitrate (Surgery 99 , 53 (1986)), Melferran (Cancer Immunology and Immunotherapy) 20 ,
209 (1985)) and Cyclophosphamide (Nature)
(Nature) 262 , 77 (1976)) and other alkylating agents, cimetidine (The journal of trauma
of Tnauma) 25 , 131 (1985)) and ranitidine (The Journal of Immunoloi
gy) 132 , 3054 (1984)), a histamine type 2 receptor inhibitor, and indomethacin that inhibits prostaglandin E ₂ production (Journal of Biological Response Modifiers).
Response Modifiers 7 , 568 (1988)), Aspirin (British Journal of Cancer (Bri
tish Journal of Canser) 38 , 503 (1978)), ibuprofen (Surgery 97 , 721 (1985)) and other non-steroidal anti-inflammatory drugs, and other polymyxin B (Journal of Burn Care Rehabilitation ( Journal of Burn Care Rehabilitation) 10 , 213 (1
989)), aclacinomycin A (Immunopharmacology 10 , 19 (1985)), hepataminol AMP (Japan Journal of Pharmacology) 48 , 417 (198).
8)), Procainamide (Clinical and Inve
stigative of Medicine) 11 , 425 (1988)), lipid A
Derivatives (Infection and Immunity)
ton and Immunity) 56 , 1076 (1988)), OK-432
(International Journal of Cancer
(International Journal of Canser) 26 , 401 (1980))
Many methods and materials have been picked up in various experimental systems.

[0012] However, although the conventional methods developed for removing suppressor cells can be evaluated for their effects to some extent, they are still incomplete, and the development of other effective methods is strongly desired.

By the way, as a substance that effectively and absolutely suppresses the activity of suppressor cells, a contra suppressor cell that is a blocker cell of suppressor cells has been reported (Advances in Cancer Research (Advances in
Cancer Research) 42 , 277 (1984)). The contra-suppressor cells are highly effective against opportunistic infections of herpesvirus type 1 (HSV-1) induced by suppressor cells. For example, one day prior to intraperitoneal infection of burned mice with 10 LD ₅₀ of HSV-1 intratracheally transfected suppressor cells, 95% of the burned mice survived.

The present invention has been made from the above viewpoint, and is an inducer of a contra suppressor cell for the purpose of removing suppressor cells in order to effectively reduce and treat opportunistic infections and the like in patients with low immunity. It is an object of the present invention to provide a therapeutic agent for hypoimmune diseases, such as an agent for reducing opportunistic infections or a therapeutic agent.

[0015]

Means for Solving the Problems As a result of intensive studies to solve the above problems, the present inventor has found that glycyrrhizin has an action of inducing a contra suppressor cell, and the induced contra suppressor cell causes an opportunistic infection. The present invention has been completed by finding that it can be reduced and treated.

That is, the present invention is a contra-suppressor cell inducer containing glycyrrhizin as an active ingredient and a therapeutic agent for hypoimmunity containing glycyrrhizin as an active ingredient.

The present invention will be described in detail below. <1> Contra suppressor cell inducer, therapeutic agent for hypoimmune disease The contra suppressor cell inducer or the therapeutic agent for hypoimmune disease of the present invention contains glycyrrhizin as an active ingredient.

Glycyrrhizin is a licorice-derived saponin, which has a structure in which one molecule of glycyrrhetinic acid is bound to two molecules of glucuronic acid and is characterized by extremely low acute and chronic toxicity. Glycyrrhizin has an action of proliferating the host immune system such as interferon γ-producing ability, an antitumor effect and an antiviral effect which are expressed through host functions, and is currently widely used as a therapeutic drug for chronic hepatitis in clinical settings. in use.

In the present invention, as a dosage form, one or more pharmaceutically acceptable non-toxic excipients, for example,
Lactose, potato starch, sodium alginate, or powders, granules, dragees, and capsules containing aminoacetic acid, threonine, calcium carbonate and the like can be used. In the case of an injection, the solvent may be only distilled water for injection or physiological saline, or an amino acid such as detoxified aminoacetic acid.

Glycyrrhizin is known as an injectable preparation in a physiological saline solution containing cysteine and glycine, and can be suitably used in the present invention.

<2> Usage The dose of the inducer of the contra suppressor cells of the present invention is 200 to 400 m per day for an adult when orally administered.
For parenteral administration, the desired effect can be expected by using in the range of 10 to 200 mg per day for an adult.

In severe patients, effective administration of the contra suppressor cells may not be expected even if the contra suppressor cell inducer of the present invention or the therapeutic agent for hypoimmunity is administered. In such a case, a contra suppressor cell inducer is administered to a healthy person, blood containing induced contra suppressor cells is transfused to a patient with low immunity, or lymphocyte fraction is actively transferred to opportunistic The infection can be reduced and treated.

[0023]

The action of the inducer of contra suppressor cells and the therapeutic agent for hypoimmunity of the present invention will be described below.

<1> Contra suppressor cell-inducing effect of glycyrrhizin The effect of glycyrrhizin-inducing contra suppressor cells will be described in animal experiments.

The contra-suppressor cells have the property of specifically adhering to bicia virosa lectin (VV lectin) (European Journal of Immunology) 11 , 937 (1).
981)), changes in the number of VV lectin-adherent cells in glycyrrhizin-administered animals were examined.

48 hours after intraperitoneal (ip) administration of glycyrrhizin, splenic lymphocytes (5 × 10 ⁷ cells) derived from mouse, rat and guinea pig were treated with VV lectin (0.5 μg / ml, 2
(Hour) Add to a treated plastic petri dish having a diameter of 9 cm, and incubate at 37 ° C. for 45 minutes. After removing the lectin-nonadherent cells, N- acetyl-D-galactosamine (1 mg / ml) was added to the petri dish, and the VV lectin-adherent cells were detached from the plate by further culturing for 15 minutes. The number of viable cells was counted with a hemocytometer. The results are shown in Table 1.

[0027]

[Table 1]

As is clear from these results, a marked increase in VV lectin-adherent cells was observed in splenic lymphocytes derived from mice to which glycyrrhizin had been administered. In addition, VV lectin-adherent cells were hardly detected in the control saline-administered group. From this, it was confirmed that administration of glycyrrhizin induces contra suppressor cells in splenic lymphocytes.

Similar results were obtained by injecting 0.1 to 100 mg / kg in rats or guinea pigs intraperitoneally, sc (subcutaneously) or po.
It was also observed when administered (orally). Further, when continuous administration of glycyrrhizin was tried, it was found that the lectin-adherent cells increased depending on the number of times of administration of the drug.

<2> Glycyrrhizin-induced suppression of suppressor cells by contra suppressor cells (1) Effect on Con A-induced suppressor cells First, contra-suppressor cells suppress suppressor cells induced by Con A Were examined using a mixed lymphocyte culture (MLR) system.

1 × 1 splenic lymphocytes from BALB / c mice (H-2 ^d ).
0 ⁶ / ml, 24μg / ml concanavalin A (Con A)
Suppressed cells (Lyt2 T cells) were induced by culturing for 48 hours in (Acta Patholodica microbiologica immunologica Scandinavia).
gca, Microbiologica, et Immunoligica, Scandinavia, sec
tion C, 9 , 277 (1982)).

Unidirectional MLR of reaction cells (BALB / c mouse-derived lymphocytes, 1 × 10 ⁵ cells / well) and stimulator cells (C57BL / 6 mouse-derived lymphocytes) using a 96-well microplate.
To the obtained suppressor cells and glycyrrhizin administration (10 mg / k
g, ip) splenic lymphocytes (contra suppressor cells) obtained from BALB / c mice were added at a ratio of 2: 2: 1: 2 and cultured at 37 ° C. for 5 days in a 5% CO ₂ incubator. .

24 hours before the end of the culture, 1 μCi / well of tritiated thymidine ( ³ H-TdR) was added, and the uptake of ³ H-TdR into the reaction cells was measured by a liquid scintillation counter to suppress the inhibition. The inhibition of cell action was investigated. The suppression rate obtained by the following formula is shown in FIG.

Suppression rate (%) of suppressor cell activity = [1- (CPM of suppressor cell-added group / CPM of suppressor cells-added splenic lymphocytes derived from glycyrrhizin-administered mouse)] × 100

As a result, splenic lymphocytes obtained from the mice to which glycyrrhizin had been administered were M induced by ConA.
The inhibitory activity of LR was inhibited by 50 to 70%. Similar results were observed in liver lymphocytes derived from glycyrrhizin-administered mice or lymphocytes in undeveloped blood, and 0.1 to 100 mg / kg glycyrrhizin sc and iv were administered to rats and guinea pigs.
It was also confirmed when and po were administered.

(2) Inhibitory effect on burn-induced suppressor cells Next, the suppressive cells induced by burns were used to examine the effect of the contra suppressor cells to suppress suppressor cells.

Burns (30% of body surface area, 3 degrees)
Spleen lymphocytes from BALB / c mice (6 days after burn, 1x10 ⁶
Cells) and splenic lymphocytes from syngeneic mice (reactive cells, 1 × 1)
0 ⁵ ) and splenic lymphocytes (stimulator cells) derived from allogeneic mice (C57BL / 6) were subjected to one-way MLR to examine suppressor cell activity that regulates MLR (Immunology Letters (Immun
ology Letters) 19 , 33 (1988)). Furthermore, in order to measure the activity of the contra suppressor cells, glycyrrhizin administration (10 mg
/ kg, ip) 1: 1: 1 splenic lymphocytes obtained from mice
The mixture was added and cultured at a ratio of 0:10 :.

After culturing as described above, ³ H-
The inhibition of the action of burn-induced suppressor cells was measured by measuring the amount of TdR. The inhibition rate is shown in Table 2.

[0039]

[Table 2]

As a result, splenic lymphocytes obtained from mice to which glycyrrhizin had been administered inhibited the activity of burn-induced suppressive cells by 50-80%. That is, contra suppressor cells were induced in spleen cells derived from glycyrrhizin-administered mice, and the action of suppressor cells was suppressed by these contra suppressor cells.

From the above results, it was shown that the contra suppressor cells have an inhibitory effect on the suppressor cells induced by both Con A and burn.

<3> Inhibitory Cell Appearance Inhibitory Action by Glycyrrhizin (1) Inhibitory Cell Appearance Inhibitory Action in Burned Animals BALB / C mice were burned (30% of body surface area, 3 degrees) two days and four days later. Glycyrrhizin was intraperitoneally administered (10 mg / kg). Spleen lymphocytes obtained daily from glycyrrhizin-treated or non-glycyrrhizin-treated burn mice were derived from syngeneic mouse splenic lymphocytes (reactive cells).
One-way MLR was carried out with allogeneic mouse-derived lymphocytes (stimulator cells). MLR was prepared by mixing stimulator cells and splenic lymphocytes from burned mice administered with glycyrrhizin at a ratio of 1: 1: 10 to responding cells (1 × 10 ⁵ cells) and incubating at 37 ° C. for 5 days in a 5% CO ₂ incubator. went. The inhibition rate was calculated in the same manner as above and shown in FIG.

As a result, splenic lymphocytes (○) obtained from glycyrrhizin-non-administered burn mice over time showed burn 4
Beginning to significantly suppress MLR from day one, its activity is burn 6
It peaked on day (60-80% inhibition) and disappeared after 11 days. On the other hand, splenic lymphocytes (●) derived from burned mice administered with glycyrrhizin suppressed the same MLR by at most 30% (6 days after burns), and the burn-induced activity was markedly blocked by glycyrrhizin.

The effect of such splenic lymphocytes is
Since the V-lectin-adherent cells disappeared when they were removed, it was confirmed that the result that the activity of the suppressor cells in the glycyrrhizin-administered mice was low was due to the induction of the contra suppressor cells by glycyrrhizin.

(2) Suppressive cell inhibitory effect induced by alloantigen BALB / c (H-2 ^d ) mice were treated with 5 × 10 ⁷ EL-4 per mouse.
Immunization with tumor cells (H-2 ^d ) induces alloantigen-repressive cells. Glycyrrhizin administered (10 mg / kg,
Allo-lymphocytes were transferred to the ip) BALB / c mice in the same manner, and the resulting splenic lymphocytes were added to the MLR system. After culturing, the amount of alloantigen-reactive cells was measured by measuring the amount of ³ H-TdR in the reaction cells.

As a result, when allolymphocytes were transplanted, the activity of suppressor cells was detected from the third day after transfer (30-50%).
Suppression), peaking on day 5-7 (70-80% suppression),
It disappeared by the 9th day. When allolymphocytes were transplanted to mice treated with 10 mg / kg of glycyrrhizin by the same method, suppressor cell activity was not detected as described above, and the suppressor rate of suppressor cells was 20 to 40 even on the 5th day, which is seen as a peak. %
It was nothing more than

That is, it was confirmed that glycyrrhizin has an action of preventing the appearance not only of burns but also of suppressor cells induced by alloantigen. This fact has already been published in the magazine (Medical History, Volume 158, 1
35 (1991)), involvement of contra suppressor cells,
It is not described that the contra suppressor cells are induced by glycyrrhizin.

(3) Inhibitory action of suppressor cell appearance in tumor-bearing animals 1 × 10 ⁵ Meth A / mouse in the left abdomen of BALB / c mice
Even if the same amount of tumor cells is again transplanted to the right abdomen 7 to 10 days after the tumor cells are transplanted, the secondary transplanted tumor does not grow due to the associated immunity. On the other hand, when reimplantation of the tumor was attempted under the same condition 20 days after the transplantation, the associated immunity was destroyed by the action of suppressor cells that appeared with the growth of the tumor.
Growth of secondary transplanted tumor is observed (Journal of Experimental
al Medicine) 159 , 1295 (1984)).

In the same experimental system, 7 days after the primary transplantation of tumor cells, splenocytes obtained from another mouse to which glycyrrhizin (10 mg / kg, ip) was frequently administered were transferred, and 13 days later. After that, the activity of suppressor cells in splenic lymphocytes obtained from tumor-bearing mice was measured by MLR.

BALB / c tumor-bearing mice on the 7th day in which 1 × 10 ⁵ Meth A tumors were transplanted subcutaneously in the groin were administered with glycyrrhizin to syngeneic normal mice (10 mg / kg, ip, twice every other day). ) Splenocytes (1 × 10 ⁸ per mouse)
Individual) were transferred via vein. In the control group, spleen cells obtained from normal mice were similarly transferred to mice 7 days after tumor bearing. The suppressor cell activity of splenic lymphocytes derived from tumor-bearing mice obtained on day 20 of tumor transplantation was measured by unidirectional MLR for 5 days of culture, as in <3> (1) above. The results are shown in Table 3.

[0051]

[Table 3]

As a result, splenic lymphocytes derived from tumor-bearing mice not administered with glycyrrhizin suppressed MLR by 80%, whereas those of tumor-bearing mice transferred with splenocytes derived from glycyrrhizin-treated mice suppressed MLR by only 20%. Was not done.

That is, splenocytes derived from glycyrrhizin-administered mice have an action of eliminating suppressor cells induced by primary tumor transplantation. However, when the VV lectin-adherent cells were removed from the spleen cells, their activity was also lost. Therefore, it was confirmed that the inhibitory cell inhibitory action of glycyrrhizin was a phenomenon caused by the induction of contra suppressor cells.

<4> Effect of Glycyrrhizin-Induced Contra suppressor Cells on Infection Reduction The effect of glycyrrhizin on HSV-1 infection of burned animals was examined. Immediately after the burn, mice were infected with HSV-1 and at the same time glycyrrhizin (10 mg / kg, ip) Was administered or glycyrrhizin-induced contra suppressor cells were transferred to observe the survival of mice.

BALB / c mice were burned (30% of body surface area,
Glycyrrhizin was administered 2 hours after the treatment (3 times) (1
Contra suppressor cells (1 × 10 ⁸ cells / mouse) induced by 0 mg / kg × 2, ip) were intravenously transferred to burned mice. Burned mouse (○) and burned mouse (●) that received transfer of contra suppressor cells
Then, 95% of the burned mice were infected with HSV-1 in an amount that would kill the mice, and the mice were observed for 15 days. The results are shown in Fig. 3.

As a result, 90% of all burned mice were spared from HSV-1 infection by the administration of glycyrrhizin. When glycyrrhizin-induced contra suppressor cells were actively intravenously transferred to the same HSV-1-infected burned mice, the mortality rate was reduced to 10%. Since removal of the VV lectin-adherent cell fraction prior to active transfer of splenocytes abolishes such activity, glycyrrhizin-mediated protection of HSV-1-infected burned mice is mediated by glycyrrhizin-induced contra-suppressor cells. It was confirmed that this was a phenomenon that occurred.

As described above, glycyrrhizin has an action of inducing a contra suppressor cell, suppresses the action of a suppressor cell via the contra suppressor cell, and has an action of preventing the appearance of a suppressor cell, Further, as a result, it has an effect of preventing infection.

<5> Effect of Infection Treatment with Glycyrrhizin-Induced Contrasuppressor Cells Mice immediately after the burn were infected with HSV-1, and 24 hours after that, the survival of the mice was confirmed by transferring the glycyrrhizin-induced contrasuppressor cells.

Two hours after the BALB / c mice were burned, 95% of the burned mice were infected with HSV-1 in an amount intraperitoneally, and one day after that, glycyrrhizin was administered to the BALB / c normal mice ( Contra suppressor cells (1 × 10 ⁸ cells / mouse) induced by 10 mg / kg, ip) were intravenously transferred to HSV-1 infected burn mice,
The mice were observed for 15 days. The results are shown in Fig. 4.

The spleen and liver were removed 3, 4 and 5 days after the infection, and the virus amount in the organ was quantified by the plaque method using VERO cells. The results are shown in Fig. 5 (A: spleen, B: liver).

As a result, 80% of burned mice were infected with H by the transfer of glycyrrhizin-induced contra suppressor cells.
The death from infection by SV-1 was avoided (Fig. 4). Infected burned mice that had been transfected with glycyrrhizin-induced contra suppressor cells had significantly reduced viral load in the spleen and liver after infection as compared to the non-transfected group (Fig. 5).

As explained above, the contra suppressor cells induced by glycyrrhizin have the effect of suppressing the action of suppressor cells and consequently treating infection. It should be noted that when a physiological saline solution in which cysteine and glycine are added to glycyrrhizin is used, the same effect as above is obtained.

<6> Properties of glycyrrhizin-induced contra suppressor cells The properties of glycyrrhizin-induced contra suppressor cells were examined. Glycyrrhizin administration (10 mg / kg, i.
p. Twice every other day) splenic lymphocytes obtained from mice were treated with various single antibodies (4 ° C, 40 minutes) and complement (37 ° C, 40 minutes).
Processed in. The processing method is Immunology Letters (Im
Munology Letters 19 , page 33 (1988) was followed.

These treated cells (1 × 10 ⁶ cells) and burn-induced suppressive cells (1 × 10 ⁶ cells 6 days after burn injury) were treated with <2.
> ML of the one-way system for 5 days culture as in (1)
It was added to R and its properties were examined by using the inhibitory activity against the activity of suppressor cells as an index. As a result, it was revealed that glycyrrhizin-induced contra suppressor cells were sensitive to CD3 and L3T4 single antibodies, insensitive to Ly 2.2 single antibody, and were CD3 positive, CD4 positive, and CD8 negative T cells. (Table 4).

[0065]

[Table 4]

The same was true when a physiological saline solution prepared by adding cysteine and glycine to glycyrrhizin was used.

<7> Properties of Suppressor Cells Induced by Burns After treatment of splenic lymphocytes derived from mice on day 6 of burn with various single antibodies against cell surface markers and complement, the properties of suppressor cells were examined by MLR. investigated. As a result, burn-induced suppressor cells were sensitive to CD3 and Lyt 2.2 single antibody, and L3T4
It was found to be CD3 positive, CD4 negative, and CD8 positive T cells that are insensitive to a single antibody (Table 4). This is similar to the results already reported in magazines (Journal of Surgical R
esearch) 38 , 606 (1985)).

The same was true when a physiological saline solution prepared by adding cysteine and glycine to glycyrrhizin was used.

<8> Inhibitory ability of glycyrrhizin-induced contra suppressor cells against burn-induced suppressor cells Mice were treated with glycyrrhizin (10 mg / kg, ip, 1
(Twice administered every other day) Spleen contra suppressor cells derived from mice and burn-induced suppressor cells (6 days after burn injury) were mixed at various ratios (1: 0.1 to 1: 1), and then mixed by MLR. Suppressor activity was measured. As a result, the same amount of contra suppressor cells was required to completely remove the suppressive activity of the suppressor cells derived from the burned mouse (Table 5).

[0070]

[Table 5]

The same was true when a physiological saline solution prepared by adding cysteine and glycine to glycyrrhizin was used.

[0072]

EXAMPLES Examples of the present invention will be described below.

[0073]

[Formulation example]

 <Formulation Example 1> Tablets A mixture having the following composition is formed into tablets by a conventional method. Glycyrrhizin 25 mg Potato starch 220 mg Magnesium stearate 5 mg ───────────────────────── Total 300 mg

<Formulation Example 2> Sugar-coated tablet A mixture having the following composition is made into a sugar-coated tablet by a conventional method. Glycyrrhizin 25 mg Glycine 25 mg Methionine 25 mg Calcium carbonate Suitable amount Lactose Suitable amount Carboxymethyl cellulose Suitable amount ───────────────────────── Total 300 mg

<Formulation Example 3> Injectable solution 200 mg of glycyrrhizin was dissolved in physiological saline to prepare 10
Make up to 0 ml.

<Formulation Example 4> Injection: Glycyrrhizin 200 mg, glycine 2000 mg, and cysteine 100 mg were dissolved in physiological saline to prepare 100 ml.
And

[0077]

INDUSTRIAL APPLICABILITY According to the present invention, a contra suppressor cell that suppresses the action of a suppressor cell can be induced.
Further, by inducing the contra suppressor cells, opportunistic infections, sepsis, etc. of hypoimmune patients can be reduced and treated.

Furthermore, by transfecting the contra suppressor cells of the healthy subject induced by the present invention into a patient, opportunistic infections can be reduced and treated even in severe patients.

[Brief description of drawings]

FIG. 1 shows suppression of action of ConA-induced suppressor cells by glycyrrhizin-administered mouse-derived contra suppressor cells.

FIG. 2 shows the inhibitory effect of glycyrrhizin on the appearance of suppressor cells in burned mice.

FIG. 3 is a graph showing the protective effect against infection with HSV-1 in burned mice by glycyrrhizin-induced contra suppressor cells.

FIG. 4 is a graph showing the therapeutic effect of infection with glycyrrhizin-induced contra suppressor cells on HSV-1 infection of burned mice.

FIG. 5 is a graph showing the amount of HSV-1 in organs.

Front page continued (72) Inventor Makiko Kobayashi 77550 Galveston City, Texas, USA Ferry Road 500, # 414 (72) Inventor Tokuichiro Utsunomiya 77551 Galveston City, Texas United States Central City Boulevard 6315, # 117 (72) Invention Person Utsunomiya Kyozo 4260 Shimotsuruma, Yamato City, Kanagawa Prefecture

Claims (3)

[Claims] 1. An inducer of contra suppressor cells containing glycyrrhizin as an active ingredient. 2. A therapeutic agent for hypoimmunity, which contains glycyrrhizin as an active ingredient through induction of contra suppressor cells. 3. The contra suppressor cell according to claim 1, which is used for preventing or treating an opportunistic infection by inducing the contra suppressor cell in a healthy person, acquiring the contra suppressor cell, and transferring the contra suppressor cell to a patient. Inducer.