KR20110067407A - Treatment for lupus and lupus nephritis - Google Patents
Treatment for lupus and lupus nephritis Download PDFInfo
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- KR20110067407A KR20110067407A KR1020090123985A KR20090123985A KR20110067407A KR 20110067407 A KR20110067407 A KR 20110067407A KR 1020090123985 A KR1020090123985 A KR 1020090123985A KR 20090123985 A KR20090123985 A KR 20090123985A KR 20110067407 A KR20110067407 A KR 20110067407A
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Abstract
Description
The present invention relates to a pharmaceutical composition for treating lupus and lupus nephritis, and more particularly, to activate specific cells capable of inhibiting the development of lupus and lupus nephritis, and bee venom improves the therapeutic efficacy and proteinuria for lupus and lupus nephritis. It relates to a natural substance that is effective in.
Systemic lupus erythematosus (SLE) is a chronic autoimmune inflammatory disease with a complex clinical symptom called lupus, caused by excessive antibody production of hyper-activated B and T cells. It is an autoimmune disease considered to be pathogenic autoantibodies and immunocomplexes.
Lupus nephritis is a serious complication of systemic lupus erythematosus that occurs frequently in patients with systemic lupus erythematosus, which not only directly contributes to morbidity and mortality, but also indirectly leads to kidney failure (Agrawal). et al., 2006).
Although many other immune and non-immune factors contribute to the development of lupus nephritis, the production of autoantibodies against the nucleat and endogenous antigens and the formation of glomerular immune deposits Plays an important role in the development of lupus nephritis (Deocharan et al., 2002; Lefkowith and Gilkeson, 1996).
In many studies, anti-DNA antibodies are important diagnostic markers that bind cell surface antigens or directly cross-reactive antigen (s) or inflammatory processes in the kidneys. The ability to indirectly bind glomerular basal membrane components through starting chromatin materials has been reported to be associated with the development of lupus nephritis (Yung and Chan, 2008).
Furthermore, cytokines and chemoattractants induced by renal cells and invasive immune cells exacerbate immunocomplex mediated renal imjury (Aringer and Smolen, 2005; Kulkarni, 2005; Kulkarni). and Anders, 2008).
Lupus treatment is currently focused on immunosuppressants such as corticosteroids, cyclophosphamide, azathioprine, and mycophenolate mofetil (Waldman and Appel, 2006). . However, these drugs carry dangerous side effects that are susceptible to infectious diseases and cancer (Radis et al., 1995).
This raises interest in the development of molecules that directly counter inflammatory responses, as well as low-toxic drugs for controlling immune complex formation and deposition.
Early nephritis in systemic lupus erythematosus has been reported to be due to the generation of pathogenic autoantibodies, deposition of immune complexes, and activation of multistage complement (Cabral and Alarcon-Segovia, 1998; Lefkowith and Gilkeson, 1996). However, it is known that invasion of macrophages and lymphocytes (primarily T cells) in the kidney plays an important role in the pathogenesis of the kidneys (Kuroiwa and Lee, 1998). Therefore, it is important to reduce pathogenic autoantibody mediators and immune cell mediators that affect the treatment of lupus nephritis.
Bee venom (BV), on the other hand, is one of the oriental medicine therapies that have been widely used for the treatment of several immune-related diseases, especially rheumatoid arthritis (RA) (Suh et al., 2006).
In many studies bee venom has been shown to reduce rheumatoid arthritis in human and animal studies and to have an anti-inflammatory effect (Yoon et al., 2008). In addition, Zusanli acupoint injection of bee venom has been known to have anti-inflammatory and anti-pain effects on the Freund's adjuvant-induced arthritis in rats. Many studies have been conducted to demonstrate its effectiveness.
Bee venom is a bee stored by honey bees in their own sac for self-defense. Bee venom contains melittin, apamin, aolapin and mast cell degranulation peptides. It consists of a variety of peptides, including MCD-peptide, as well as various enzymes such as phospholipase A2 and non-peptide components such as histamines, carbonhydrates and lipids. kwon et al., 2001).
Among them, melittin is the main ingredient that accounts for about 50% of bee venom, and Hartman et al. (1991) reported that melittin injection reduces rat edema, and melittin is the main ingredient of bee venom. It has been reported to inhibit the enzymatic activity of phospholipase A2 (Saini et al., 1997).
Therefore, the present inventors have studied whether the bee venom is effective in the treatment of lupus and lupus glomerulonephritis, and found that bee venom is involved in the activation of specific cells that are effective in suppressing the development of lupus and lupus nephritis. The invention came to the following.
The present invention is to solve the above problems,
The purpose of the present invention is to confirm that bee venom is involved in activating specific cells capable of inhibiting the development of lupus and lupus nephritis, and to provide natural substances with therapeutic efficacy against lupus and lupus nephritis.
According to an aspect of the present invention,
It provides a pharmaceutical composition for treating lupus and lupus nephritis, comprising bee venom as an active ingredient.
In addition, the bee venom is characterized by inhibiting the expression of lupus or lupus nephritis by activating CD4 + CD25 + regulatory T cells.
The bee venom is characterized by activating CD4 + CD25 + regulatory T cells, reducing the production of IgG and IgG2, anti-ds-DNA, and inhibiting IgG1 and IgG2a deposition.
The bee venom is characterized by reducing the production of TNF-α and IL-6, which are inflammatory molecules of nephritis by activating CD4 + CD25 + regulatory T cells.
In addition, the present invention provides a therapeutic or adjuvant for treating lupus and lupus nephritis symptoms due to inactivation of CD4 + CD25 + regulatory T cells containing bee venom as an active ingredient.
As described above, the pharmaceutical composition for treating lupus and lupus nephritis using bee venom according to the present invention is an anti-DNA antibody and IL-6, which are the etiology of lupus and lupus nephritis by activating CD4 + CD25 + regulatory T cells. Inhibition of the etiology associated with lupus and lupus nephritis, such as inhibiting production, can be usefully developed and used as pharmaceuticals and proteinuria therapeutics for inhibiting the development and progression of lupus and lupus nephritis.
Hereinafter, the present invention will be described in more detail.
The present invention provides a new use of bee venom. Bee venom is known to have anti-inflammatory activity and is used to treat arthritis. Inflammation can be caused by a variety of causes and progresses through a complex mechanism in which a myriad of substances act in vivo.
The inventors have found that bee venom is effective in improving lupus and lupus nephritis and, to elucidate its mechanism, genetically engineered New Zealand Black / white (NZB / W) that inhibited expression to resemble human systemic lupus erythematosus. Experiments using the F1 mice confirmed that bee venom had significant effects and efficacy in improving lupus and lupus nephritis.
As a result of examining the effect of bee venom according to the present invention on the symptoms of proteinuria, which is a symptom of lupus and lupus nephritis, it showed an effect of reducing proteinuria production.
In addition, the anti-DNA antibody, which is the etiology of lupus and lupus nephritis, and serum levels circulating IgG, IgG1, IgG2a, and reduced deposition.
In addition, it showed an effect of reducing TNF-α, IL-6, which affects the production of anti-DNA antibodies, which is the cause of lupus and lupus nephritis.
In addition, it showed an effect of activating CD4 + CD25 + regulatory T cells known as immune cells suppressing autoimmune disease expression.
Therefore, the present invention directly confirmed the effect of bee venom on immune cells that suppress the etiology and expression of lupus and lupus nephritis.
Specifically, after treatment with bee venom in NZB / W F1 rats with systemic lupus erythematosus, it was measured whether the symptoms of proteinuria in the rat, the pathogenesis of lupus and lupus nephritis as described above, and the increase of immune suppressor immune cells.
CD4 + CD25 + regulatory T cells are known to play a pivotal role in maintaining tolerance in rodents such as mice, squirrels, and humans (Sakaguchi et al., 1995). In addition, many studies have shown that CD4 + CD25 + regulatory T cells can reestablish autoimmunity and prevent autoimmune diseases such as multiple sclerosis and colitis (Sakaguchi et al., 2003). The famous Wolf et al. Have provided evidence that CD4 + CD25 + regulatory T cells are important inhibitory immune cells of anti-glomerular membrane glomerulonephritis in mice. Activation of anti-dsDNA-producing autoreactive B cells in lupus rats leads to overcoming inhibition of CD4 + helper T cell populations and CD4 + CD25 + regulatory T cells Ask for help. Activated CD4 + helper T cell populations produce high amounts of cytokines and form immunocomplexes that can remain bound or trapped in tissues with subsequent inflammation and organ damage. Help B cells secrete autoantibodies (La Cava, 2009).
Recent studies have shown that the transcription factor gene Foxp3 is specifically expressed by CD4 + CD25 + regulatory T cells and programs their development and function (Fortenot et al., 2003.).
Therefore, the present invention verified that bee venom activates the expression of CD4 + CD25 + regulatory T cells, as shown in FIG. 9, through the pharmaceutical composition for treating lupus and lupus nephritis including bee venom as an active ingredient, lupus nephritis and lupus It was confirmed that the expression of can be suppressed or improved.
In addition, in many studies, cytokines not only produce mutations in immune regulation, but also cause local inflammation, which ultimately leads to tissue destruction in autoimmune diseases (Aringer and Smolen, 2005). Recent investigations suggest that TNF blocking treatment may improve lupus nephritis (Segal et al., 2001). TNF stimulates IL-6 production (Feldmann and Maini, 2001), and IL-6 production affects both anti-DNA antibody production and the pathogenesis of nephritis in NZB / W in mice (Finck et al., 1994). .
Infitrating monocytes / macrophages, expressed as proinflammtory cytokines, are known to be important mediators of injury in most forms of kidney disease (Wang et al., 2008). Recently, CD4 + CD25 + T cells have demonstrated that they can exert direct inhibitory effects on monocytes / macrophages (Taams et al., 2005).
Accordingly, the present invention is activated by the bee venom of the CD4 + CD25 + regulatory T cells, the production of IL-6 affecting the production of anti-DNA antibody and anti-DNA antibody affecting the pathogenesis of nephritis is inhibited in Table 2 and Proven through the results of FIGS. 3 to 8.
Based on the above results, the pharmaceutical composition for treating lupus and lupus nephritis using bee venom according to the present invention as an active ingredient is an anti-DNA antibody and IL-, which is the pathogenesis of lupus and lupus nephritis by activating CD4 + CD25 + regulatory T cells. Inhibition of the etiology associated with lupus and lupus nephritis, such as inhibiting the production of 6, and a pharmaceutical composition comprising such bee venom as an active ingredient has been developed and useful as a medicine for inhibiting the development and progression of lupus and lupus nephritis Can be.
Hereinafter, the present invention will be described in detail by examples. The following examples are provided to illustrate the present invention, but the content of the present invention is not limited thereto.
-Experiment Preparation-
NZB / WF1 rats (6 years old) purchased from SLC Inc., Japan (Shizuoka, Japan) were used to carry out the experiment, and the specific pathogen-free status was maintained during the experiment. In addition, experiments are conducted in accordance with the ethical laws and guidelines established by Kyung Hee University for the protection and use of laboratory animals. The NZB / WF1 rats developed autoimmune disease, which shows immune complex glomerulonephritis, proteinuria and renal failure progression, suggesting human systemic lupus erythematosus (SLB), and almost all mice die within one year (Foster, 1999).
The mice were initially included in two groups of 10 animals, one group was treated with saline, and the other group was treated with bee venom. Bee venom was provided by Sigma (St. Louis, Mo, USA), and the bee venom was diluted in 0.5 mg / ml of normal saline, and the bee venom solution (3 mg / kg body wt) was once a week Each rat in the treatment group (Bee venom) was allowed to be injected subcutaneously.
In addition, the rats in the control group (Saline) are treated with the same dosing method as in the bee venom treatment group.
Experimental Example 1 Rats Survival and Weight Change after 32 Weeks
Three mice in the control group and two mice in the bee venom group died during the experiment. In addition, as a result of measuring and comparing the average body weight of the rats of the control group and the bee venom treatment group, it was confirmed that the average body weight of the rats belonging to the bee venom treatment group and the control group is not significantly different.
Experimental Example 2 Proteinuria Measurement
After the bee venom treatment and saline treatment in the bee venom treatment group and control group, respectively, proteinuria was measured from 18 weeks. Proteinuria was measured semiquantitatively by infiltrating the urine of each group of rats with woolpaper test strips (URiSCAN; Youngdong Pharmaceutical Co., Seoul, Korea).
The color change of the strip penetrated by the urine sample is visually judged compared to the standard strip according to the manufacturer's criteria and scored from 0 to 4+. Urinary protein is graded according to the following score.
0 = <15 mg / dL, 1 + = 30mg / dL, 2 + = 100mg / dL, 3 + = 300mg / dL, 4 + = 1000mg / dL.
Table 1 shows the average level of proteinuria and Figure 2 shows the effect of bee venom treatment on proteinuria, before the saline and bee venom treatment from Table 1 and Figure 2 100% rats of the control group and the bee venom group Significant proteinuria (≥ 1+ = 30mg / dL) was detected, and the mean level of urinary protein was not significantly different between the two groups until 26 weeks. However, at 30 weeks, the control group developed severe proteinuria. In contrast, the average level of urine protein in the bee venom group began to decrease. Upon completion of the study, the rats in the control group continued to degrade kidney function, whereas the rats in the bee venom control group significantly reduced amplification of urinary protein production. It can be seen that bee venom is effective in improving proteinuria.
(The above values are expressed as mean ± SEM, and statistics were used by Student's t-test; * P <0.05)
Experimental Example 3 Bee Venom Effect in IgG, IgG1, IgG2a and Anti-DNA Antibodies
-Serum Collection and Autoantibody Measurement-
After 32 weeks, blood was collected from the retro-orbital sinus with isofluorane anesthesia inhaled in each group of rats. Serum immunoglobulin (Ig) class-specific anti-DNA antibody assays were performed using mouse whole IgG, IgG1, IgG2a enzyme-linked immunosorbent assay (ELISA) kit (Bethyl Laboratories Inc., Montgomery, Tx, USA). Serum IgG antibodies that react with anti-double-stranded DNA (anti-dsDNA) are determined by ELISA purchased from Alpha Diagnostic Internationa (San Antonio, TX, USA). All ELISAs are performed according to the manufacturer's instructions.
-Measurement result
Serum levels of circulating IgG, IgG1, IgG2a and anti-DNA antibodies were measured at 16 and 32 weeks and the results are shown in Table 2 and FIG. 3 below. Table 2 shows the standard levels of the anti-DNA antibodies, Figure 3 is a view showing the production effect of IgG, IgG1, IgG2a during bee venom treatment, respectively. It was confirmed that the levels of IgG and IgG2a antibodies in the bee venom group were significantly reduced in the bee venom group compared to the control group.
(The above values are expressed as mean ± SEM.)
In addition, the serum level of anti-dsDNA was measured after 32 weeks, and the results are shown in FIG. 4. 4 is a diagram showing the effect of anti-double-stranded DNA production during bee venom treatment, as shown in the anti-dsDNA antibody formation generated at the same time as the anti-DNA antibody production is confirmed that the growth in the bee venom group significantly reduced Could.
These results suggest that bee venom can inhibit the formation of IgG, IgG2a, anti-ds-DNA associated with the development of lupus and lupus nephritis.
Experimental Example 4 Effect of Bee Venom in Kidney Pathology
-Immunofluorescence staining of autoantibodies
Kidneys are embedded in Tissue-Tek OCT compounds (Sakura, CA, USA), quickly frozen with Freezer Spray, and cut through cryostats in 20-μm-thick sections. The section was permeablized for 20 minutes in PBS containing 0.5% Triton X-100 and then blocked for non-specific reactions and the sample was rhodamine-conjugated goat anti-mouse IgG1 (Santa) at the optimal concentration (pretreatment, concentration). cruz, CA, USA) and FITC-hybrid goat anti-mouse IgG2a (Santa cruz, CA, USA) antibodies. Finally, the fluorescence intensity in the glomeruli was detected with a confocal laser scannig microscope system (
Organizational structure and morphometric evaluation
After sacrifice for pathological evaluation of 32 week old mice, a portion of the kidney is mixed in 4% paraformaldehyde solution and embedded in paraffin. The elongate block is cut into 5 μm sections and stained with periodic acid-Schiff (PAS) reagents.
-Results of Bee Venom Treatment in Renal Pathology-
5 is a diagram showing the effect of bee venom treatment for glomerulonephritis, kidney section in the control group was confirmed that the glomerulonephritis appeared in comparison with the bee venom group. It was also found that IgG1 and IgG2a deposition was detected by immunofluorescence.
6 and 7 show the results, FIG. 6 shows a confocal image of immunological deposition, and FIG. 7 compares immunodeposition. Here, A and C (red) of Figure 6 represents IgG1 in the renal glomeruli, B and D (green) represents the immunodeposition of IgG2a in the renal glomeruli, A and B in the kidney of the control group Glomeruli, C and D are rat kidney glomeruli of the bee venom group.
As can be seen, the symbolic deposition of IgG1 and IgG2a was observed in the renal glomeruli of the control group, while the IgG1 and IgG2a were less detected in the bee venom treated mice. In other words, bee venom inhibits IgG1 and IgG2a deposition and prevents the exacerbation of immune-mediated renal trauma.
Experimental Example 5 Effect of Bee Venom on Renal Cytokine
Renal Cytokine Analysis
Rat kidneys were measured using ELISA (BD Biosciences, San Jose, CA, USA) to test pre-inflammatory molecules caused by nephritis, TNF-α, IL-6, IL-10, and IFN-γ. In short, snap-frozen kidney pieces are homogenized in PRO-PREP protein extract (iNtRON Biotechnology Inc., Seoul, Korea), incubated for 20 minutes in ice, and centrifuged for 15 minutes at 13000 rpm, 4 ° C. Supernatants are used for kidney proinflammatory cytokine arrays. Protein concentration in each supernatant is measured in the BCATM Protein Assay Kit (Thermo Fisher Scientific Inc. Rockford, IL, USA). Protein levels of cytokines are being corrected by the total amount of protein. The result is expressed as pg / mg.
Effect of Bee Venom on Renal Cytokines
Rat kidneys were measured to test pre-inflammatory molecules caused by nephritis, TNF-α, IL-6, IL-10 and IFN-γ, and the results are shown in FIG. 8. FIG. 8A shows TNF-α cytokine production, FIG. 8B shows IL-6 cytokine analysis, in which mice in the bee venom group had significantly reduced increases in TNF-α and IL-6 compared to the control group. Confirmed.
FIG. 8C shows an IL-10 cytokine assay, and FIG. 8D shows an IFN-γ cytokine assay, showing no significant difference between IFN-γ and IL-10 in rats of the control group and the bee venom group. there was.
Experimental Example 6 Effect of Bee Venom in CD4 + CD25 + Regulatory T Cells
Flow cytometric
Using flow cytometry, antibodies include FITC-hybrid anti-mouse CD4, phycoerythrin (PE) -hybrid anti-mouse Foxp3, allophycocyanin (APC) -hybridized
Statistical analysis
Statistical analysis of the data was performed using Prism 4.02 software (GraphicPad Software Inc., San Die Sea, CA, USA). Statistics were performed using Student's t-test.
Measurement and Results
All rats in each group received bee venom (3.0 mg / kg bod y wt) or saline once weekly for 14 weeks starting at 18 weeks. T cell subset profiles in CD4 + CD25 + (lymphocyte gated) and Foxp3 (CD4 + T cell gated) in splenocytes of 32-week-old cancer NZB / W F1 mice were measured using FACS analysis, and the results are shown in FIG. 9. It was.
Figure 9A is a diagram showing the results of FACS analysis of splenic regulatory T cells, Figure 9B is a view showing the FACS analysis of Foxp3 expression, as shown in the CD4 + CD25 + regulatory T cell population of the bee venom group rat control group It can be seen that the increase considerably. In addition, Foxp3 expression in CD4 + CD25 + regulatory T cells was also improved in the bee venom group. In addition, the results are statistically significant with a p-value <0.05.
Through the above results, it can be seen that bee venom according to the present invention improves lupus and lupus nephritis by activating the expression of CD4 + CD25 + regulatory T cells, which are autoimmune diseases suppressing immune cells, and thereby enhancing the expression of Foxp3 expressed therein. Reduce the TNF-α, IL-6, IgG, IgG1 and IgG2a, anti-DNA antibodies, which are the pathogenesis of lupus and lupus nephritis, have the effect of improving proteinuria, and thus bee venom expresses lupus and lupus nephritis And progression can be suppressed.
1 is a view showing the average body weight of the control group (saline) and bee venom group (Bee venom).
2 is a view showing the bee venom treatment effect on proteinuria.
Figure 3a is a diagram showing the effect of the production of bee venom treatment.
Figure 3b is a view showing the production effect of IgG1 during bee venom treatment.
Figure 3c is a view showing the production effect of IgG2a during bee venom treatment.
Figure 4 shows the effect of anti-double-stranded DNA production during bee venom treatment.
Figure 5 shows the effect of bee venom treatment for glomerulonephritis.
6 shows a confosal image of immune deposition.
Figure 7 is a comparison of the immunodeposition of the control group and the bee venom group ( * P <0.01, *** P <0.001).
8A shows the production of TNF-α cytokines ( * P <0.05).
FIG. 8B shows IL-6 cytokine analysis ** P <0.01).
8C shows IL-10 cytokine analysis.
8D shows IFN-γ cytokine analysis.
Figure 9a is a diagram showing the results of FACS analysis of splenic regulatory T cells of each group of 32 weeks old ( *** P <0.001).
Figure 9b is a diagram showing the results of FACS analysis of Foxp3 expression in each group of 32 weeks old ( * P <0.05).
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101469167B1 (en) * | 2012-02-27 | 2014-12-04 | 경희대학교 산학협력단 | Composition for preventing or treating diseases related to abnormal suppression of regulatory T cell activation comprising bee venom-derived PLA2 |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR101469167B1 (en) * | 2012-02-27 | 2014-12-04 | 경희대학교 산학협력단 | Composition for preventing or treating diseases related to abnormal suppression of regulatory T cell activation comprising bee venom-derived PLA2 |
| US9526767B2 (en) | 2012-02-27 | 2016-12-27 | University-Industry Cooperation Group Of Kyung Hee University | Pharmaceutical composition comprising bee venom-phospholipase A2 (BV-PLA2) for treating or preventing diseases related to degradation of abnormal regulatory T cell activity |
| US9919035B2 (en) | 2012-02-27 | 2018-03-20 | Inist St Co., Ltd. | Pharmaceutical composition comprising bee venom-phospholipase A2 (bv-PLA2) for treating or preventing diseases related to degradation of abnormal regulatory T cell activity |
| US9956270B2 (en) | 2012-02-27 | 2018-05-01 | Inist St Co., Ltd. | Pharmaceutical composition comprising bee venom-phospholipase A2 (BV-PLA2) for treating or preventing diseases related to degradation of abnormal regulatory T cell activity |
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