CN117883458A - Immune effect and application of cholesterol synthesis intermediate metabolite farnesyl diphosphate - Google Patents
Immune effect and application of cholesterol synthesis intermediate metabolite farnesyl diphosphate Download PDFInfo
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Abstract
The invention relates to the technical field of biology, in particular to an immune effect and application of cholesterol synthesis intermediate metabolite farnesyl diphosphate, and relates to application of farnesyl diphosphate or analogues, derivatives, synergists or inhibitors thereof in regulating dendritic cell chemotaxis and/or lymphocyte activation, or in preparing a medicament or a kit for regulating dendritic cell chemotaxis and/or lymphocyte activation, and a corresponding medicament or kit and a regulating method. The invention can be applied to regulating and controlling the chemotactic capacity of dendritic cells and/or lymphocyte activation, and/or further can be used for regulating and controlling the immune response and steady balance of organisms, preventing and controlling allergic diseases such as allergic rhinitis and the like, autoimmune diseases such as systemic lupus erythematosus and the like, selecting tumor immunotherapy scheme and/or performing prognosis evaluation, and has wide application prospect.
Description
Technical Field
The invention relates to the field of biotechnology and medicine, in particular to an application of cholesterol synthesis intermediate metabolite farnesyl diphosphate in regulating dendritic cell chemotaxis and/or lymphocyte activation, and further regulating and controlling organism immune response and immune related diseases.
Background
Dendritic cells are a key bridge connecting natural immunity and adaptive immunity, and play a key regulatory role in activating the immune response of an organism against pathogens and maintaining autoimmune tolerance. The functional regulation of dendritic cells determines the overall balance of immune responses. Dendritic cells are widely distributed in non-lymphoid and lymphoid tissues, and in vivo migration of dendritic cells is critical for their maturation activation and functional regulation. However, more and more studies have shown that disorders of dendritic cell migration may lead to excessive aggregation and activation of dendritic cells at the site of inflammation, resulting in excessive inflammation of the tissue and even triggering the onset of autoimmune disease. Dendritic cell-related chemokines and chemokine receptors have become potential diagnostic markers and therapeutic targets for autoimmune diseases.
DC migration is co-regulated by chemokines, cytokines, and other inflammatory mediators. Immature DCs distributed in the periphery sense danger signals through their surface pattern recognition receptors, mature activation upon uptake of pathogens, up-regulate chemokine receptor CCR7 expression. CCL19/CCL21 secreted by lymph node stromal cells acts on DCs expressed CCR7, promoting migration of DCs to T cell regions of secondary lymphoid organs, initiating and regulating T cell mediated adaptive immune responses. The glycolysis level is obviously increased in the DC chemotaxis process, and the activation enhancement of a transcription factor hypoxia-inducible factor 1alpha (HIF1α) is shown, so that the expression of the glycolytic enzyme lactate dehydrogenase LDHA is increased, and the lactic acid production is increased. CCL19/CCL21 has been shown to be closely related to the development of a variety of autoimmune diseases such as multiple sclerosis (multiple sclerosis, MS), rheumatoid arthritis (rheumatoid arthritis, RA), and inflammatory bowel disease (inflammatory bowel diseases, IBD). Experimental autoimmune encephalomyelitis, antigen-induced arthritis onset is significantly reduced in CCL19/CCL21 or gene-deleted mice for the receptor CCR7 thereof, and DC-mediated Th1 and Th17 cell activation is significantly reduced. Thus CCL19/CCL21 dependent DC migration and functional activation play a key role in maintaining the immune response and the homeostasis of immune regulation.
Cholesterol (Cholesterol) is a key lipid component of cell membranes and organelle membranes. Cholesterol synthesis and degradation is regulated by a range of cholesterol metabolizing enzymes and forms complex cholesterol metabolic pathways (fig. 1). The cholesterol synthesis pathway begins with Acetyl-CoA (Acetyl-CoA). Acetyl-coa synthesizes Mevalonate (Mevalonate) under the catalysis of hydroxymethylglutaryl-coa reductase (Hmgcr); mevalonic acid further synthesizes nivediphosphate (Farnesyl Diphosphate, FPP); FPP subsequently synthesizes cholesterol through a series of pathways.
The cholesterol pathway is found to play an important role in T cell anti-tumor immunity and is closely related to the occurrence and development of tumors. Statin drugs are commonly used cholesterol lowering drugs, and simvastatin can significantly inhibit cholesterol synthesis rate-limiting enzyme Hmgcr, and is widely used for clinical treatment of hypercholesterolemia and the like. Statins have also been reported to regulate T cell depletion and reduce tumor-related mortality in HIV-infected subjects. The above shows that the cholesterol pathway is a key regulatory component of the anti-tumor and anti-viral immune response of T cells, and blocking the cholesterol pathway may become an effective adjuvant for tumor immunotherapy.
Cholesterol pathways are also receiving increasing attention in innate immunity and anti-pathogenic inflammatory responses. The aggregation of cell membrane cholesterol can promote the formation of TLR4-MD2 and TLR4-CD14 complexes, thereby promoting LPS-induced natural immune response. Accordingly; abca1 and Abcg1 can promote cholesterol outflow in macrophages, destroy the formation of envelope and endosomal lipid valve structures, and further inhibit inflammatory responses in macrophages. In addition, cholesterol crystallization can induce activation of inflammatory bodies, thereby promoting atherosclerotic plaque formation.
However, the specific role and link for the specific cholesterol metabolites FPP and metabolic enzymes Hmgcr in the regulation of dendritic cell migration and its secondary lymphocyte activation, as well as autoimmune diseases, has not been known so far. For convenient clinical and scientific applications, there is an urgent need in the art to study and develop specific metabolic molecules that can regulate dendritic cell chemotactic ability and/or lymphocyte activation and/or autoimmune diseases.
Disclosure of Invention
The object of the present invention is to provide a substance which modulates the chemotactic ability of dendritic cells and/or the activation of lymphocytes: farnesyl diphosphate or an analogue, derivative, potentiator or inhibitor thereof. It is a further object of the present invention to provide the use of the above substances for the preparation of a medicament or kit for modulating dendritic cell chemotaxis and/or lymphocyte activation and the corresponding medicament or kit.
The present invention has found that simvastatin treatment or interference with Hmgcr expression inhibits chemotactic capacity and mitochondrial activation and fusion of dendritic cells under the stimulation of chemokines CCL19 and/or CCL21, T lymphocyte proliferation, differentiation, germinal center B cell production, and pathological injury and inflammatory response of systemic lupus erythematosus. Supplementation with FPP may enhance chemotactic capacity and mitochondrial activation and fusion of dendritic cells under stimulation by chemokines CCL19 and/or CCL21, T lymphocyte proliferation, differentiation and germinal center B cell production. The effect of inhibiting inflammatory diseases, preventing autoimmune diseases from progressing or enhancing dendritic cell tumor vaccines is achieved by realizing positive or negative regulation of immune response, thereby achieving the purpose of treating diseases. On this basis, the present invention has been completed.
In a first aspect of the invention there is provided the use of farnesyl diphosphate or an analogue, derivative, potentiator or inhibitor thereof to modulate dendritic cell chemotaxis and/or lymphocyte activation.
In a second aspect of the invention there is provided the use of farnesyl diphosphate or an analogue, derivative, potentiator or inhibitor thereof in the manufacture of a medicament or kit for modulating dendritic cell chemotaxis and/or lymphocyte activation.
Further, the farnesyl diphosphate is a metabolic molecule generated during cholesterol synthesis.
Further, the dendritic cells are derived from a mammal, preferably a mouse, a human, a rat, a dog, a monkey, an gorilla, a pig, a horse, a cow, or a sheep, more preferably a mouse.
Further, the dendritic cell chemotactic ability is selected from the group consisting of: chemotactic migration of dendritic cells (in vitro) under stimulation of chemokine CCR7 ligand (ccl19+ccl21, the same applies below), chemotactic migration of dendritic cells from peripheral skin tissue to stimulated lymph nodes (in vivo, induction with immune complex may be assisted), mitochondrial activation and fusion of dendritic cells under stimulation of CCR7L ligand; lymphocyte activation is selected from: t cells proliferate, differentiate into effector T cells (including Th1, th17, and Tfh cells), germinal center B cell formation, mediate inflammatory immune responses.
Further, the farnesyl diphosphate or an analog, derivative, or potentiator thereof promotes dendritic cell chemotactic ability and/or lymphocyte activation. Still further, farnesyl diphosphate or an analog, derivative, or potentiator thereof promotes dendritic cell chemotactic ability, mitochondrial activation and fusion, and lymphocyte activation as compared to control dendritic cells or lymphocytes that have not been contacted with farnesyl diphosphate or an analog, derivative, potentiator thereof.
Further, the inhibitor of farnesyl diphosphate inhibits dendritic cell chemotactic ability and/or lymphocyte activation. Still further, inhibitors of farnesyl diphosphate inhibit dendritic cell chemotactic ability, mitochondrial activation and fusion, lymphocyte activation, as compared to control dendritic cells or lymphocytes not contacted with an inhibitor of farnesyl diphosphate.
Further, the farnesyl diphosphate or analogue, derivative and synergist thereof are selected from the group consisting of: farnesyl diphosphate and its chemical structural analogues, derivatives, agents or drugs that increase the expression of farnesyl diphosphate; the inhibitor of farnesyl diphosphate is selected from the group consisting of: RNAi against farnesyl diphosphate and its upstream metabolizing enzyme Hmgcr (hydroxymethylglutaryl coa reductase), antisense oligonucleotides, interfering viruses, specific inhibitors (including but not limited to simvastatin) and/or molecular compounds for blocking or reducing farnesyl diphosphate and its upstream metabolizing enzyme Hmgcr expression and/or its function.
Further, the farnesyl diphosphate or analogues, derivatives, synergists or inhibitors thereof are further used for regulating and controlling the immune response and steady state balance of organisms, preventing and treating allergic diseases such as contact dermatitis, autoimmune diseases such as systemic lupus erythematosus, tumor immunotherapy scheme selection and/or prognosis evaluation.
In a preferred embodiment of the invention, the autoimmune disease is systemic lupus erythematosus.
In a third aspect of the invention, there is provided a medicament or kit for modulating dendritic cell chemotactic ability and/or lymphocyte activation comprising:
i) Farnesyl diphosphate or an analogue, derivative, potentiator or inhibitor thereof;
ii) pharmaceutically or immunologically acceptable carriers or adjuvants.
Further, the medicament or kit further comprises: immature or mature dendritic cells, chemotactic or non-chemotactic dendritic cells, chemokine CCL19 and/or CCL21, T lymphocytes, B lymphocytes.
In a fourth aspect of the invention, there is provided a method of modulating dendritic cell chemotactic capacity and/or lymphocyte activation comprising the step of contacting a dendritic cell and/or lymphocyte and/or mouse with farnesyl diphosphate or an analogue, derivative, potentiator or inhibitor thereof.
Further, the method further comprises:
before, at the same time as or after the contacting step, contacting the dendritic cells with a chemokine CCR7 ligand, contacting lymphocytes with dendritic cells, and contacting mice with the corresponding agent.
All numerical ranges provided herein are intended to expressly include all numbers and ranges of numbers that fall between the endpoints of the ranges. The features mentioned in the description or the features mentioned in the examples can be combined. All of the features disclosed in this specification may be combined with any combination of the features disclosed in this specification, and the various features disclosed in this specification may be substituted for any alternative feature serving the same, equivalent or similar purpose. Thus, unless expressly stated otherwise, the disclosed features are merely general examples of equivalent or similar features.
As used herein, "comprising," having, "or" including "includes" including, "" consisting essentially of … …, "" consisting essentially of … …, "and" consisting of … …; "consisting essentially of … …", "consisting essentially of … …" and "consisting of … …" are under the notion of "containing", "having" or "including".
Medicaments or kits
The invention also provides a medicine or a kit, which is used for regulating and controlling the chemotactic capacity of dendritic cells and/or lymphocyte activation, and/or is further used for regulating and controlling the immune response and steady state balance of an organism, preventing and controlling allergic diseases such as contact dermatitis, autoimmune diseases such as systemic lupus erythematosus, selecting a tumor immunotherapy scheme and/or performing prognosis evaluation. The medicament or the kit comprises an effective amount of the sequence selected from the following groups or the expression product thereof, or the inhibitor or the agonist thereof, and a pharmaceutically or immunologically acceptable carrier or auxiliary material.
The "pharmaceutically or immunologically acceptable" ingredients are substances that are suitable for use in humans and/or animals without undue adverse side effects (such as toxicity, irritation, and allergic response), i.e., a reasonable benefit/risk ratio. By "effective amount" is meant an amount that is functional or active in and acceptable to a human and/or animal.
The term "pharmaceutically or immunologically acceptable carrier" refers to a carrier for administration of a therapeutic agent or vaccine, and includes various excipients, diluents and adjuvants. The term refers to such agents or vaccine carriers: they are not per se essential active ingredients and are not overly toxic after administration. Suitable vectors are well known to those of ordinary skill in the art. A sufficient discussion of pharmaceutically acceptable excipients can be found in Remington's Pharmaceutical Sciences (Mack Pub.Co., N.J.1991).
Such vectors include (but are not limited to): saline, buffer, glucose, water, glycerol, ethanol, and combinations thereof. In general, the drug/vaccine formulation should be compatible with the mode of administration, and for example, the drug of the present invention may be prepared by conventional methods using physiological saline or an aqueous solution containing glucose and other adjuvants to prepare an injection form. The medicament is preferably manufactured under aseptic conditions. The preparation of the invention can also be prepared into a slow release preparation.
Reagents or reagent sets can be provided in the medicaments and kits of the invention as desired according to the principles and methods of control, prognosis. For example, the medicament or kit of the invention may further comprise: immature or mature dendritic cells, chemotactic or non-chemotactic dendritic cells, chemokine CCL19 and/or CCL21, T lymphocytes, B lymphocytes.
In addition, the kit of the present invention may further comprise, as required: containers, controls (including positive or negative controls), instructions for use, buffers, etc., which can be selected by one of skill in the art based on the particular situation.
The invention has the advantages that:
1. it is demonstrated that farnesyl diphosphate can regulate chemotactic capacity of dendritic cells and further regulate dendritic cell-dependent adaptive immune responses and inflammatory responses;
2. the invention can be used for regulating and controlling the chemotactic capacity of dendritic cells and/or lymphocyte activation, and/or further regulating and controlling the immune response and inflammatory response of organisms, preventing and controlling allergic diseases such as contact dermatitis and the like, autoimmune diseases such as systemic lupus erythematosus and the like, selecting tumor immunotherapy scheme and/or performing prognosis evaluation, and has wide application prospect.
Drawings
Fig. 1: intracellular cholesterol metabolic pathways.
Fig. 2: effect of simvastatin and farnesyl diphosphate treatment on the chemotactic capacity of dendritic cells in vitro;
simvastatin (SIM, supra) and farnesyl diphosphate (FPP) treatments affect flow cytometry detection of dendritic cell chemotactic ability in vitro. The results shown in the figures are mean ± standard deviation (n=4).
Fig. 3: interfering with the effects of Hmgcr and FPP treatment on chemotactic capacity of dendritic cells in vivo;
(A) Flow cytometer detection interfering with Hmgcr and FPP treatment affects chemotactic ability of dendritic cells in vivo.
(B) Fig. 3A shows the corresponding statistical result. The results shown in the figures are mean ± standard deviation (n=4).
Fig. 4: effect of simvastatin and FPP treatment on antigen complex-induced chemotactic capacity of dendritic cells in vivo;
(A) Immunofluorescence assays for the ability of simvastatin and FPP treatment to affect antigen complex-induced chemotactic ability in dendritic cells in vivo.
(B) Fig. 4A shows the corresponding statistical result. The results shown in the figures are mean ± standard deviation (n=6).
Fig. 5: effect of simvastatin and FPP treatment on antigen complex induced lymphocyte activation;
(A) Simvastatin and FPP treatment affected antigen complex induced Tfh cell and germinal center activation by flow cytometry.
(B) Fig. 5A shows the corresponding statistical result. The results shown in the figures are mean ± standard deviation (n=6 to 9).
Fig. 6: effect of simvastatin and FPP treatment on chemotactic dendritic cell mitochondrial activation;
(A) The method comprises the following steps Absolute numerical detection of the respiratory capacity of chemokine-stimulated dendritic cell line particles for use by simvastatin and FPP treatment. The results shown in the figures are mean ± standard deviation (n=3 to 4).
(B) Simvastatin and FPP treatment affects the percentage detection of chemokine stimulated dendritic cell line granule spare respiratory capacity. The results shown in the figures are mean ± standard deviation (n=3 to 4).
Fig. 7: interference of Hmgcr and FPP treatment on chemotactic dendritic cell mitochondrial fusion;
(A) Electron microscopy interfering with Hmgcr and FPP treatment affects mitochondrial fusion of chemokine-stimulated dendritic cells.
(B) Fig. 7A shows the corresponding statistical result. The results shown in the figures are mean ± standard deviation (n=25 to 30).
Fig. 8: effect of FPP treatment on chemotactic dendritic cells to stimulate T cell proliferation and activation capacity;
FPP treatment affects flow cytometry detection of the ability of chemotactic dendritic cells to stimulate T cell differentiation toward Th1, th17, and Tfh, as well as proliferation.
Fig. 9: influence of simvastatin treatment on pathological lesions and inflammatory response of systemic lupus erythematosus;
(A) Simvastatin treatment affected the detection of systemic lupus erythematosus mouse appearance.
(B) Simvastatin treatment affected HE staining detection of skin pathology in mice with systemic lupus erythematosus.
(C) Simvastatin treatment affected HE staining and immunofluorescence detection of systemic lupus erythematosus mouse kidney pathology.
(D) Simvastatin treatment affects flow cytometry detection of dendritic cell migration in systemic lupus erythematosus mice.
(E) Simvastatin treatment affects flow cytometry detection of lymph node Tfh cell and germinal center B cell activation in systemic lupus erythematosus mice.
Detailed Description
The following provides a detailed description of embodiments of the present invention with reference to examples.
It is to be understood that these examples are illustrative of the present invention and are not intended to limit the scope of the present invention. Appropriate modifications and variations of the invention may be made by those skilled in the art, and are within the scope of the invention.
The experimental procedures described in the following examples, which are not explicitly described in the specification, may be carried out by methods conventional in the art, for example, by reference to the molecular cloning laboratory Manual (third edition, new York, cold spring harbor laboratory Press, new York: cold Spring Harbor Laboratory Press, 1989) or according to the conditions suggested by the suppliers. Methods for sequencing DNA are routine in the art and can also be provided for testing by commercial companies.
Percentages and parts are by weight unless otherwise indicated. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In addition, any methods and materials similar or equivalent to those described herein can be used in the methods of the present invention. The preferred methods and materials described herein are presented for illustrative purposes only.
Example 1: culture process of dendritic cells
Mouse bone marrow cells were cultured in a 37℃cell culture medium [ RPMI-1640 (PAA) cell culture medium containing 10% (v/v) FCS (PAA) ] for six days with the addition of 100ng/mL mouse GM-CSF and 10ng/mL mouse IL-4 cytokine (R & D Systems, minneapolis, MN), and after 24 hours of stimulation with LPS (100 ng/mL, sigma), mature dendritic cells were induced and then subjected to anti-CD 11c magnetic bead (Miltenyi Biotech) sorting. Purified dendritic cells obtained by sorting are subjected to separation.
Example 2: effect of simvastatin and FPP treatment on chemotactic ability of dendritic cells in vitro.
Dendritic cells obtained in example 1 were stimulated with simvastatin (SIM, 50. Mu.M) alone or in combination with farnesyl diphosphate (FPP, 50. Mu.M) for 12h, followed by incubation in the upper layer (1X 10) of a 24-well transwell plate 5 The chemokines-containing CCL19 (50 ng/ml) and CCL21 (50 ng/ml) (R) were added to the bottom layer per well of cells, 100. Mu.l of medium, 8. Mu.m pore size, corning, life Science Co.)&D) The lower layer of cells was counted by flow cytometry for 6 hours, with the lower chemokine group minus the lower chemokine-free group, which is the number of cells chemotactic for chemokines, or the same volume of medium without chemokines. The detection results are shown in FIG. 2.
The data show that simvastatin inhibits dendritic cell chemotaxis and that anaplerotic FPP enhances dendritic cell chemotaxis.
Example 3: interfere with the effect of Hmgcr and FPP treatment on chemotactic capacity of dendritic cells in vivo.
Dendritic cells obtained in example 1 were treated with Hmgcr interfering RNA for 36 hours and then treated with FPP for 12 hours. Next, the sample was labeled with CFSE (0.5 mM)Recording for 10 min, and taking 2×10 6 Cells were subcutaneously injected into the unilateral footpads of mice. After 48h, the ipsilateral lymph node was taken and CFSE was detected + Cell occupancy of CD11c + The proportion of cells was used to represent the ability of CFSE-labeled DCs to chemotaxis towards lymph nodes in vivo. FIG. 3A shows flow cytometer data, and FIG. 3B shows statistics corresponding to FIG. 3A.
Thus, interfering with Hmgcr inhibits dendritic cell chemotaxis and recruiting FPP enhances dendritic cell chemotaxis.
The Hmgcr interfering RNA sequence is as follows:
Hmgcr SiRNA sense(5’-3’)：GGGAGUUCAAACUGUAUUATT
Hmgcr SiRNA antisense(5’-3’)：UAAUACAGUUUGAACUCCCTT。
example 4: effect of simvastatin and FPP treatment on antigen complex-induced chemotaxis and lymphocyte activation in vivo
Mice were subcutaneously injected with immune complexes formed by oral administration of SIM (20 mg/kg) or combined with oral administration of FPP (20 mg/kg) for 2h, followed by administration of A647-conjugated OVA-OVA antibodies. After 48h, immunofluorescence measures expression of CD3 (orange fluorescence), B220 (blue fluorescence), CD11c (red fluorescence) and OVA (green fluorescence) in lymph nodes to indicate the ability of dendritic cells carrying OVA antigen to migrate to lymph nodes. After 10 days, follicular helper T cells (Tfh cells: CD 4) were detected in the lymph nodes + CXCR5 hi PD-1 + ) Germinal center B cells (B220) + GL7 + ) Is a ratio of (2).
FIG. 4A shows that simvastatin orally administered inhibits the cell proportion of CD11c/OVA co-expression, i.e., inhibits antigen complex-induced migration of dendritic cells in vivo, while back-supplementing FPP enhances chemotactic capacity of dendritic cells in vivo; fig. 4B shows the statistics corresponding to fig. 4A.
Fig. 5A shows that simvastatin orally inhibits Tfh cell and germinal center B cell activation, while back-supplementation of FPP enhances Tfh cell and germinal center B cell activation; fig. 5B is a statistical result of fig. 5A.
Simvastatin is therefore able to inhibit chemotaxis and lymphocyte activation in dendritic cells, while anaplerotic FPP enhances chemotaxis and lymphocyte activation in dendritic cells.
Example 5: effect of simvastatin and FPP treatment on chemotactic dendritic cell mitochondrial activation
Dendritic cells obtained in example 1 were stimulated with simvastatin (SIM, 50 μm) alone or in combination with farnesyl diphosphate (FPP, 50 μm) for 12h and CCR7 ligands CCL19 and CCL21 (50 ng/ml) were given for 3h. The mitochondrial spare respiratory capacity (Spare Respiratory Capacity) was calculated using XF-96Extracellular Flux Analyzer (Seahorse Bioscience) to give Oxygen Consumption (OCR) measurements to cells to indicate mitochondrial activity of the cells. Fig. 6A and 6B show absolute values and percentages, respectively, of the spare call capability. The results show that simvastatin orally administered inhibits chemokine-stimulated dendritic cell mitochondrial activation, while the anaplerotic FPP enhances chemokine-stimulated dendritic cell mitochondrial activation
Thus, simvastatin inhibits mitochondrial activity of chemotactic dendritic cells and the replacement of FPP enhances mitochondrial activity of chemotactic dendritic cells.
Example 6: interference of Hmgcr and FPP treatment on chemotactic dendritic cell mitochondrial fusion
Dendritic cells obtained in example 1 were treated with Hmgcr interfering RNA for 36h, CCL19 and CCL21 (50 ng/ml) added with CCR7 ligand or combined farnesyl diphosphate (FPP, 50. Mu.M) for 6h. Mitochondrial fusion was then indicated by cryo-electron microscopy of mitochondrial length. Fig. 7A shows that interfering with Hmgcr can reduce mitochondrial fusion of chemokine-stimulated dendritic cells, while supplementing FPP can enhance mitochondrial fusion of chemokine-stimulated dendritic cells, and fig. 7B is a statistical result of fig. 7A.
Thus, interfering with Hmgcr can inhibit mitochondrial fusion of chemotactic dendritic cells while supplementing FPP can enhance mitochondrial fusion of chemotactic dendritic cells.
The Hmgcr interfering RNA sequence was as in example 3.
Example 7: effect of FPP treatment on chemotactic dendritic cells stimulating T cell proliferation and activation capacity.
The dendritic cells obtained in example 1 were taken and subjected to OVA 323-339 Pre-sensitization for 2h, followed by 1:10 ratio to CFSE-tagged OT-II mouse derived CD4 + T cells were subjected to a mixed lymphocyte reaction with CCL19 and CCL21 (50 ng/ml) or pooled farnesyl diphosphate (FPP, 50. Mu.M) treatment given simultaneously as CCR7 ligands. After 4d, IFN- γ, IL-17 and IL-21 were labeled to indicate Th1, th17 and Tfh cell differentiation, respectively, and CFSE dilution ratios were labeled to indicate T cell proliferation activation. The results in fig. 8 show that FPP is able to enhance the ability of chemotactic dendritic cells to stimulate T cells to differentiate towards Th1, th17 and Tfh, as well as proliferation.
Thus, FPP can enhance chemotactic dendritic cells' ability to stimulate T cell proliferation and activation.
Example 8 influence of simvastatin treatment on pathological lesions and inflammatory response of systemic lupus erythematosus
Mice were pretreated with simvastatin (20 mg/kg) for 3 weeks, and then a 500 μl pristate (Sigma) intraperitoneal injection was used to induce the systemic lupus erythematosus model. Mice were sacrificed 20 weeks after induction for analysis. Fig. 9A shows that simvastatin may reduce systemic lupus erythematosus skin injury, fig. 9B shows that simvastatin may reduce systemic lupus erythematosus skin inflammatory cell infiltration and tissue destruction, fig. 9C shows that simvastatin may reduce systemic lupus erythematosus glomerular swelling, i.e., renal complement C3C deposition, fig. 9D shows that simvastatin may reduce systemic lupus erythematosus dendritic cell migration, fig. 9E shows that simvastatin may reduce systemic lupus erythematosus lymph node Tfh cell and germinal center B cell activation.
Thus, simvastatin treatment inhibits pathological damage and inflammatory response in systemic lupus erythematosus.
In conclusion, simvastatin treatment or interference with Hmgcr expression can inhibit chemotactic capacity and mitochondrial activation and fusion of dendritic cells under the stimulation of chemokines CCL19 and/or CCL21, T lymphocyte proliferation, differentiation, germinal center B cell production, and pathological damage of systemic lupus erythematosus. Supplementing farnesyl diphosphate can enhance the chemotactic capacity and mitochondrial activation and fusion of dendritic cells under the stimulation of chemokines CCL19 and/or CCL21, T lymphocyte proliferation, differentiation, and germinal center B cell production. The positive or negative regulation of the immune response can be realized by regulating and controlling the farnesyl diphosphate, the effects of inhibiting inflammatory injury of inflammatory diseases, blocking autoimmune disease progression or enhancing dendritic cell tumor vaccines are exerted, and thus the purpose of treating diseases is achieved.
While the preferred embodiments of the present invention have been illustrated and described, the present invention is not limited to the embodiments, and various equivalent modifications and substitutions can be made by one skilled in the art without departing from the spirit of the present invention, and these equivalent modifications and substitutions are intended to be included in the scope of the present invention as defined in the appended claims.
Claims (10)
1. Use of farnesyl diphosphate or an analogue, derivative, potentiator or inhibitor thereof in the manufacture of a medicament or kit for modulating dendritic cell chemotaxis and/or lymphocyte activation.
2. The use according to claim 1, wherein the dendritic cells are of mammalian origin.
3. The use according to claim 1, wherein the dendritic cell chemotactic capacity is selected from the group consisting of: chemotactic (in vitro) of dendritic cells under stimulation of chemokine CCR7 ligand CCL19+CCL21, chemotactic migration of dendritic cells from peripheral skin tissue to stimulated lymph nodes, mitochondrial activation and fusion of dendritic cells under stimulation of CCR7 ligand; lymphocyte activation is selected from: t cells proliferate, differentiate into effector T cells, including Th1, th17, and Tfh cells, germinal center B cells form/activate, mediating inflammatory immune responses.
4. The use according to claim 1, wherein said farnesyl diphosphate or an analogue, derivative, potentiator thereof promotes dendritic cell chemotactic ability and/or lymphocyte activation; the inhibitors of farnesyl diphosphate inhibit dendritic cell chemotactic ability and/or lymphocyte activation.
5. Use according to claim 1, characterized in that the farnesyl diphosphate or analogues, derivatives, synergists thereof are chosen from: farnesyl diphosphate and its chemical structural analogues, derivatives, agents or drugs that increase the expression of farnesyl diphosphate; the inhibitor of farnesyl diphosphate is selected from the group consisting of: RNAi against farnesyl diphosphate and its upstream metabolic enzyme Hmgcr, antisense oligonucleotides, interfering viruses, specific inhibitors and/or molecular compounds for blocking or reducing farnesyl diphosphate and its upstream metabolic enzyme Hmgcr expression and/or its function.
6. The use according to claim 1, wherein said farnesyl diphosphate or an analogue, derivative, booster or inhibitor thereof is used for modulating the immune response and homeostasis of the body, for controlling allergic diseases, autoimmune diseases, tumor immunotherapy regimen selection and/or prognosis evaluation.
7. A medicament or kit for modulating dendritic cell chemotactic ability and/or lymphocyte activation comprising:
i) Farnesyl diphosphate or an analogue, derivative, potentiator or inhibitor thereof;
ii) pharmaceutically or immunologically acceptable carriers or adjuvants.
8. The medicament or kit of claim 7, further comprising: immature or mature dendritic cells, chemotactic or non-chemotactic dendritic cells, chemokine CCL19 and/or CCL21, T lymphocytes, B lymphocytes.
9. A method of modulating dendritic cell chemotactic ability and/or lymphocyte activation, comprising the step of contacting a farnesyl diphosphate or an analog, derivative, potentiator or inhibitor thereof with a dendritic cell and/or lymphocyte and/or mouse.
10. The method of claim 9, wherein the dendritic cells are contacted with a chemokine CCR7 ligand, lymphocytes are contacted with dendritic cells, or mice are contacted with a corresponding agent prior to, at the time of, or after the contacting step.
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