CN114990206B - Application of Common gamma-chain receptor as drug target in preparation of drug for treating lupus nephritis - Google Patents

Application of Common gamma-chain receptor as drug target in preparation of drug for treating lupus nephritis Download PDF

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CN114990206B
CN114990206B CN202210624820.2A CN202210624820A CN114990206B CN 114990206 B CN114990206 B CN 114990206B CN 202210624820 A CN202210624820 A CN 202210624820A CN 114990206 B CN114990206 B CN 114990206B
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陆前进
印慧琪
李黎明
赵俊鹏
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Abstract

The invention discloses application of a common gamma-chain receptor as a drug target in preparing a drug for treating lupus nephritis, and the common gamma-chain receptor can be used for treating the lupus nephritis by inhibiting the function of the common gamma-chain receptor. The antibody targeting common gamma-chain receptor is used for treating lupus nephritis, and has strong specificity and small toxic and side effects. The invention shows that the function of the common gamma-chain receptor for inhibiting has certain potential in treating lupus nephritis for the first time, the utility and the mechanism of the common gamma-chain receptor as a drug target in treating lupus nephritis are explored for the first time, the influence of anti-common gamma-chain on Treg and Tfh cell differentiation and B cell autoantibody secretion is studied, and an experimental basis and a new treatment target are provided for treating lupus nephritis.

Description

Application of Common gamma-chain receptor as drug target in preparation of drug for treating lupus nephritis
Technical Field
The invention belongs to the field of biological medicine, and relates to application of a common gamma-chain receptor as a medicine target in preparation of a medicine for treating lupus nephritis.
Background
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by disorders of T and B lymphocytes, the production of multiple autoantibodies, and involvement of multiple systems and organs. When a large amount of autoantibodies, such as anti-dsDNA, are deposited on the kidney, the proliferative lesion of the whole or local glomerulus is caused, and further the kidney is damaged to different degrees, so that immune complex Nephritis is formed, and the disease is clinically called Lupus Nephritis (LN). LN is hidden and easy to ignore, the morbidity of SLE patients is as high as 50-60%, the labor force and the life quality of the patients are greatly influenced, even the lives of the patients are threatened, heavy burdens are caused to the patients and families and society of the patients, and the SLE patients are mainly caused to die.
The exact etiology and specific pathogenesis of LN is not clear, and its clinical treatment faces challenges. Currently, LN clinical treatment mainly depends on glucocorticoids and immunosuppressants, but only can make patients in stable or low-activity state, and can not completely cure the disease. In addition, part of patients have low reactivity and no response to the medicine, and need to take the medicine for a long time, so the toxic and side effects are great. Therefore, the further exploration of the pathogenesis of LN and the development of biological agents aiming at specific targets and the opening of new treatment modes are the problems to be solved urgently in LN clinical treatment.
Disclosure of Invention
The invention aims to solve the technical problem that the traditional LN treatment medicine has large side effect, and provides a common gamma-chain receptor as a new medicine target point, so that the effect of the common gamma-chain receptor on LN treatment is clarified, and an experimental basis and a new treatment means are provided for LN treatment.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
the application of the Common gamma-chain receptor as a drug target in preparing the drug for treating lupus nephritis is within the protection scope of the invention. Lupus nephritis is treated by inhibiting common gamma-chain receptor function. Preferably, common gamma-chain receptor function is inhibited by a common gamma-chain receptor monoclonal antibody.
Wherein, the common gamma-chain acceptor monoclonal antibody is InVivoMAb anti-mouse CD132 (common gamma chain) (anti-common gamma chain for short).
Wherein, the compound inhibits the function of common gamma-chain receptor and prevents proinflammatory factors IL4, IL7, IL9, IL21, IL15 and IL13 from playing an inflammation role.
The application of the Common gamma-chain receptor monoclonal antibody in preparing the medicine for treating lupus nephritis is also within the protection scope of the invention.
Wherein, the monoclonal gamma-chain receptor monoclonal antibody can be combined with a pharmaceutically acceptable carrier.
The invention selects anti-common gamma-chain as the acting medicine of the target spot, inhibits the function of common gamma-chain receptor, and selects the international recognition lupus erythematosus model MRL/lpr mouse to carry out animal experiments. The research finds that the common gamma-chain receptor is highly expressed in spleen and kidney of MRL/lpr mice (P < 0.001), the anti-common gamma-chain can reduce the Tfh cell ratio in peripheral blood of the mice (P < 0.001) and up-regulate the Treg cell ratio (P < 0.01); the content of anti-dsDNA antibody in the plasma of the mouse (P < 0.01) and the secretion of B cell IgM antibody (P < 0.001) are obviously reduced, the ratio of urine protein/urine creatinine of the mouse (P < 0.05) is reduced, and the survival rate of the mouse (P < 0.05) is improved. In conclusion, the common gamma-chain receptor function inhibition can improve the lupus nephritis phenotype of MRL/lpr mice, improve the survival rate (P is less than 0.05) and play a therapeutic role on LN through the ways of Tfh inhibition, treg cell differentiation promotion, B cell autoantibody generation reduction and the like. The research result provides a new therapeutic target for LN diseases.
Has the advantages that: the monoclonal antibody anti-common gamma-chain of the targeting common gamma-chain receptor is used for the first time, the MRL/Lpr mouse is subjected to intraperitoneal injection treatment, and the anti-common gamma-chain can target the common gamma-chain receptor, so that the proportion of Treg cells is up-regulated by down-regulating the Tfh cell proportion of the mouse, the content of anti-dsDNA antibodies and IgM antibody secretion in peripheral blood of the mouse are obviously reduced, and the deposition of autoantibodies in the kidney of the mouse is reduced, so that the kidney damage is improved, the urine protein/urine creatinine ratio of the mouse is reduced, the treatment effect is exerted, LN disease symptoms are relieved, and the survival rate of the mouse is improved.
At present, LN clinical treatment still depends on glucocorticoids and immunosuppressants, the disease conditions of most patients are in a stable or low-activity state, and can not be completely cured, and partial patients have the problems of low responsiveness and no response to the drugs, need to take the drugs for a long time, and further cause large toxic and side effects and the like. And the treatment of LN by targeting the common gamma-chain receptor with the antibody has strong specificity and small toxic and side effects. The invention takes the common gamma-chain receptor as a target point for the first time, researches the utility and the mechanism of the monoclonal antibody anti-common gamma-chain for treating LN, researches the influence of the anti-common gamma-chain on Tfh and Treg cell induced differentiation and B cell antibody secretion, and provides an experimental basis for developing new LN targeted treatment medicines.
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The foregoing and/or other advantages of the invention will become further apparent from the following detailed description of the invention when taken in conjunction with the accompanying drawings.
FIG. 1 shows mRNA expression levels of common gamma-chain receptor in spleen and kidney of MRL/lpr mice.
FIG. 2 shows the improvement of anti-common gamma-chain on nephritis and survival rate of MRL/lpr mice.
FIG. 3 shows kidney histopathology and immunofluorescence analysis of MRL/lpr mice.
FIG. 4 shows that anti-common gamma-chain can reduce the content of autoantibody anti-dsDNA in the plasma of MRL/lpr mice.
FIG. 5 is the control of anti-common gamma-chain targeting common gamma-chain receptor on the ratio of Tfh and Treg cells in peripheral blood of MRL/lpr mice.
FIG. 6 shows the effect of anti-common gamma-chain on Tfh and Treg cell differentiation in MRL/lpr mice.
FIG. 7 shows that anti-common gamma-chain can inhibit antibody secretion by B cells in vitro.
Detailed Description
Example 1
1. Experimental materials
1.1 drugs and reagents for experiments anti-common gamma-chain antibody (Bio X Cell), igG antibody (Bio X Cell), cyclophosphamide (Sigma-Aldrich), anti-dsDNA ELISA kit (Jianglaibio), urine protein kit (Nanjing constructed organism) and urine creatinine kit (Nanjing constructed organism).
1.2 flow antibody (BD pharmingen, biolegend, eBioscience), cell sorting reagent (biolenged).
1.3 Experimental animals
The experiment adopted MRL/lpr mice, aged about 10 weeks, and had a body weight of 30-40g, provided by Beijing Sibefu Biotechnology, inc. C57 mice, aged about 8-12 weeks, weighed 20-25g, were provided by Jiangsu Jiejiaokang Biotech, inc. Feeding conditions are as follows: room temperature is 18-20 ℃, humidity is 50-60%, light and shade are alternated (12 h), luminosity is moderate, and ventilation and cleanness are good. All experiments were approved and conducted as directed by the ethical committee of the dermatologic hospital, national academy of medicine (the institute of dermatology, national academy of medicine).
2. Experimental methods
2.1 real-time fluorescent quantitative PCR (qPCR) technology for detecting mRNA expression level of common gamma-chain receptor in mouse kidney and spleen
Total RNA from kidney and spleen was extracted from C57 mice and MRL/lpr mice using Trizol (Invitrogen) according to the instructions and Homezapine was used
Figure BDA0003676597430000041
III RT Supermix for qPCR (+ gDNA wiper) -RNA reverse transcription reagent reverse transcription to cDNA. The expression of common gamma-chain receptor was detected by qPCR using the ChamQ Universal SYBR qPCR Master Mix and primers in Roche Light Cycler 96. The primer sequences are as follows: common gamma-chain acceptor upstream primer: 5 'CTCAGGCAACCTACTCCAC-3', downstream primer: 5 'GCTGGAC AACAAATGTCTGGTAG-3'.
2.2 Improvement of Anti-common gamma-chain on MRL/lpr mouse nephritis and survival rate
We required MRL/lpr mice to be grouped as follows according to this study: igG group (10 mg/kg, negative control group, 11), cyclophosphamide group (PC-Cyclophosphamide, 25mg/kg, positive control group, 10), anti-common gamma-chain group (10 mg/kg, experimental group, 12). Administration was started at 11 weeks of age of mice (28 days 2 months at 2022), mice in the positive control group were intraperitoneally injected with cyclophophamide once a week, mice in the negative control group and the experimental group were intraperitoneally injected with IgG and anti-common γ -chain antibody 2 times a week, respectively, and the body weight, urine protein, urine creatinine, anti-dsDNA and other indicators of the mice were monitored during administration.
2.3 Kidney histopathology and immunofluorescence analysis in MRL/lpr mice
To analyze the kidney inflammatory cell infiltration and pathological injury, mice 20 weeks after administration were sacrificed after anesthesia, kidney tissues were collected and fixed in 4% paraformaldehyde, HE staining was performed, and inflammatory cell infiltration was analyzed. Frozen kidney sections were directly immunofluorescent stained with IgG2a (Abcam) and indirectly immunofluorescent stained with C3 (Abcam) and corresponding fluorescent secondary antibodies.
2.4 Anti-common gamma-chain can reduce the content of autoantibody Anti-dsDNA in the plasma of MRL/lpr mice
At 8 weeks after administration of the mice, 2 mice in the negative control group died of severe renal injury (urinary protein >300 mg/dL), and we measured the peripheral serum levels of autoantibody anti-dsDNA (jianglaibo) in the peripheral blood plasma of the negative control group (11 mice) at 3 months of 2022 and 21 days of anti-common γ -chain group (12 mice), and in the peripheral blood plasma of the negative control group (9 mice) at 5 months of 2022 and 6 days of anti-common γ -chain group (12 mice).
2.5 Anti-common gamma-chain targeting common gamma-chain receptor for regulating Tfh and Treg cell ratio in MRL/lpr mouse peripheral blood
To investigate the regulatory effect of anti-common gamma-chain on Tfh and Treg cells, we isolated peripheral blood of mice in a negative control group, a positive control group and an anti-common gamma-chain group, and detected the Tfh and Treg cell ratio in the peripheral blood by a flow cytometer.
2.6 Effect of Anti-common gamma-chain on induced differentiation of MRL/lpr mice Tfh and Treg cells
To study the anti-common gamma-chain pair
Figure BDA0003676597430000051
Effects of directed differentiation of CD4+ T cells into Tfh and Treg cells. In this experiment, ficoll (Cytiva) density gradient method was used to separate C57 mouse Peripheral Blood Mononuclear Cells (PBMC) and EasySep was used TM Human />
Figure BDA0003676597430000053
CD4T Cell Iso Kit (Stemcell) extraction->
Figure BDA0003676597430000052
CD4+ T cells, classified into Tfh and Treg groups. Tfh group: 5ng/L TGF-beta (Peprotatin), 20ng/mL IL-6 (Peprotatin), 10ng/mL IL-12 (Peprotatin) and 20ng/mL IL-21 (Peprotatin) are added after 5 mug/mL anti-CD3 and 2 mug/mL anti-CD28 are stimulated and activated to perform Tfh induced differentiation; treg group: 5 μ g/mL anti-CD3 (R)&D Systems) and 2. Mu.g/mL anti-CD28 (R)&D Systems) after stimulation and activation, 5ng/mL TGF-beta (Peprotatin) and 10ng/mL IL-2 (Peprotatin) are added for Treg induced differentiation. After IgG (control group) and anti-common gamma-chain (experimental group) are added, tfh and Treg directional induced differentiation are respectively carried out in vitro, and the Tfh and Treg cell proportion is detected by a flow cytometer after 66 h.
2.7 Anti-common gamma-chain can inhibit antibody secretion of B cell in vitro
C57 mice are approximately 8-12 weeks old, sacrificed after anesthesia, spleens are removed under aseptic conditions, ground and filtered to prepare single cell suspensions, CD19+ B cells are sorted using the easy Sep Mouse CD19 positive Selection Kit II (Stemcell), and the sorted CD19+ B cell pellets are resuspended using DMEM complete medium (10% FBS +1% penicillin/streptomycin + 55. Mu.M. Beta. -mercaptoethanol) and added to cell culture plates at 1X 10 6 Individual cells/well. In addition, 100ng/mL R848 (Sigma) and 30ng/mL IL-4 (Peprotitin) per well induced the initial B cell differentiation into plasma cells and antibody secretion. A blank control group (without adding R848 and IL-4), a negative control group (with adding R848, IL-4 and IgG antibodies) and an anti-common gamma-chain drug group (80 ug/mL) were set, and cell supernatants were collected after 66h and LEGENDplex was used TM Mouse Immunoglobulin Isotyping Panel (6-plex) (Biolegend) measures IgG1, igG2a, igG2b, igG3, igA, igM antibody content.
3. Results of the experiment
3.1 The mRNA expression level of the Common gamma-chain receptor in MRL/lpr spleen and kidney of a lupus nephritis model mouse. As shown in FIG. 1, the mRNA expression of common gamma-chain receptor in kidney and spleen of MRL/lpr mice is significantly higher than that of C57 mice (P < 0.001), which indicates that the common gamma-chain receptor can promote the generation and development of LN, and the antagonism of the function of common gamma-chain receptor can have therapeutic effect on LN.
3.2 And Anti-common gamma-chain improves the nephritis and survival rate of MRL/lpr mice. At 8 weeks and 11 weeks after administration, 2 mice in each of the negative control groups died of severe renal injury (urinary protein >300 mg/dL), and as shown in fig. 2, anti-common γ -chain decreased the amount of urinary protein (a), inhibited the ratio of urinary protein/urinary creatinine (P < 0.05) (B) in MRL/lpr mice, and significantly increased the survival rate (P < 0.05) (C) of mice, while having no significant effect on the body weight of mice, compared to the negative control group (D). The result shows that the inhibition of the common gamma-chain receptor function can relieve the symptoms of lupus nephritis of the mice and prolong the service life of the mice to a certain extent.
3.3 Anti-common gamma-chain reduces the deposition of the kidney IgG2a and C3 immune complex in MRL/lpr mice. As shown in fig. 3, the pathological HE staining and immunofluorescence staining results of mouse kidney tissues show that the kidney lymphocyte infiltration of Anti-common gamma-chain drug group MRL/lpr mice is obviously reduced, the swelling hyperplasia degree of glomeruli is reduced (a), and the deposition of immune complexes of kidney IgG2a (B) and C3 (C) is reduced. This indicates that inhibition of common gamma-chain receptor function can improve the renal damage condition of MRL/lpr mice.
3.4 Effect of Anti-common gamma-chain on the level of autoantibody Anti-dsDNA in the plasma of MRL/lpr mice. As shown in FIG. 4, anti-common gamma-chain significantly reduced the anti-dsDNA content (P < 0.01) in the plasma of MRL/lpr mice 65 days after administration as compared to the negative control group. It is shown that the inhibition of the function of the common gamma-chain receptor can inhibit the generation of the mouse autoantibody and reduce the kidney injury.
3.5 Anti-common gamma-chain targeting common gamma-chain receptor to MRL/lpr mice peripheral blood Tfh, treg cell ratio regulation. As shown in fig. 5, the anti-common gamma-chain can significantly reduce the Tfh cell ratio (P < 0.001) and increase the Treg cell ratio (P < 0.01) in the peripheral blood of the mice compared with the negative control group, and the result shows that the inhibition of the common gamma-chain receptor function can reduce the Tfh/Treg cell ratio, thereby relieving the occurrence and development of LN.
3.6 The influence of Anti-common gamma-chain on the Naive CD4+ Tfh and Treg cells of a C57 mouse in vitro induced differentiation. As shown in fig. 6, anti-common γ -chain significantly inhibited Tfh cell differentiation (P < 0.001) compared to the negative control group, suggesting that common γ -chain receptor may be involved in the development of LN by affecting Tfh cell function.
3.7 The effect of Anti-common γ -chain on B cell antibody secretion. As shown in FIG. 7, R848 (100 ng/mL) and IL-4 (30 ng/mL) can promote secretion of B cell antibodies, and anti-common gamma-chain can reduce secretion of IgM to a significant extent (P < 0.001) compared with a blank control group. The results suggest that inhibition of common gamma-chain receptor function can alleviate autoantibody secretion and improve LN disease progression.
The invention provides application of a common gamma-chain receptor as a drug target in preparing a drug for treating lupus nephritis, particularly a plurality of methods for inhibiting the function of the common gamma-chain receptor, and a plurality of ways for realizing LN treatment targeting the target. All the components not specified in the present embodiment can be realized by the prior art.

Claims (2)

  1. Application of Common gamma-chain receptor monoclonal antibody in preparing medicine for treating lupus nephritis; wherein the Common gamma-chain receptor monoclonal antibody inhibits the function of Common gamma-chain receptor to block proinflammatory factors IL4, IL7, IL9, IL21, IL15 and IL13 from playing an inflammation role.
  2. 2. The use of claim 1, wherein said monoclonal gamma-chain receptor monoclonal antibody is conjugated to a pharmaceutically acceptable carrier.
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