CN100572530C - Use the L-alpha-lysophosphatidylcholtoe toe to obtain differentiation of monocytes in mature dendritic cells in vivo - Google Patents
Use the L-alpha-lysophosphatidylcholtoe toe to obtain differentiation of monocytes in mature dendritic cells in vivo Download PDFInfo
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/66—Phosphorus compounds
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
- C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
- C12N5/00—Undifferentiated human, animal or plant cells, e.g. cell lines; Tissues; Cultivation or maintenance thereof; Culture media therefor
- C12N5/06—Animal cells or tissues; Human cells or tissues
- C12N5/0602—Vertebrate cells
- C12N5/0634—Cells from the blood or the immune system
- C12N5/0639—Dendritic cells, e.g. Langherhans cells in the epidermis
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K39/00—Medicinal preparations containing antigens or antibodies
- A61K2039/51—Medicinal preparations containing antigens or antibodies comprising whole cells, viruses or DNA/RNA
- A61K2039/515—Animal cells
- A61K2039/5154—Antigen presenting cells [APCs], e.g. dendritic cells or macrophages
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- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2500/00—Specific components of cell culture medium
- C12N2500/30—Organic components
- C12N2500/36—Lipids
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/30—Hormones
- C12N2501/38—Hormones with nuclear receptors
- C12N2501/385—Hormones with nuclear receptors of the family of the retinoic acid recptor, e.g. RAR, RXR; Peroxisome proliferator-activated receptor [PPAR]
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- C—CHEMISTRY; METALLURGY
- C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
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- C12N2501/00—Active agents used in cell culture processes, e.g. differentation
- C12N2501/999—Small molecules not provided for elsewhere
Abstract
The present invention relates to be divided in the monocyte body method of mature dendritic cell, wherein a) monocyte provides in appropriate culture medium, when b) having differentiation factor, monocyte is divided into dendritic cell, and c) the L-alpha-lysophosphatidylcholtoe toe adds substratum and obtains mature dendritic cell.Invention also relates to the inhibitor that uses at least a kind of L-alpha-lysophosphatidylcholtoe toe in drug manufacture, and medicine is used for preventing inflammation and/or anti-inflammatory disease and/or autoimmune disease.
Description
The present invention relates to the method that monocyte is divided into mature dendritic cell, monocyte provides in the substratum that is fit to its differentiation in view of the above, and the L-alpha-lysophosphatidylcholtoe toe adds described substratum.The inhibitor that the present invention also relates to use at least a kind of L-alpha-lysophosphatidylcholtoe toe is used to prevent inflammation and/or anti-inflammatory disease and/or autoimmune disease to produce medicament production.Dendritic cell participate in immunoreactive development and by identification, picked-up and antigen presentation come initial special T-lymphocyte reaction, particularly infectious agent (Steinman etc., 1997, Immuno.Rev., 156:25-37; Cella etc., 1997, Curr.Opin.Immunol., 9:10-16).Although the prematurity dendritic cell absorb and the antigen of digestion infectious agent is very effective, some signals such as bacteriocin or inflammatory cytokine can activate them by inducing ripening process, and this is the initial step that triggers in the adaptive immunity reaction.In fact, in this activated, dendritic cell obtained to move to the ability of finding the lymphocytic lymphoid organ of T-and the ability that transmits costimulatory signal, and the T-lymphocyte is essential to signal for activating originally.In this maturation, dendritic cell experience function and phenotype modify as:
The lymphocytic surface molecular increase of participation activation T-(as the molecule of CD40, CD80, CD83, CD86 and major histocompatibility complex (MHC) I type and II type,
Generate pro-inflammatory cytokine (as interleukin I L-12, IL-1 β, TNF α and IL-6),
They absorb and the ability of process antigen reduces.
Because the ability of mature dendritic cell development immune response and initial special T-lymphocyte reaction, they have specific treatment interest, especially at field (Austin.1998, the Curr.Opin.Hematol.5:3-15 of anti-infective, antineoplastic immune and immunotherapy; Reisa Sousa etc., 1999, Curr.Opin.Immunol.11:392-399).Because the ability of dendritic cell inducing immune tolerance, when needs suppressed patient's immune response, these dendritic cell also were favourable targets, are particularly useful for anti-autoimmunization or inflammatory disease.
Mature dendritic cell can the monocyte of external acquisition in cultivating.These monocytes are body-internal-circulation cells, influence the factor that they occur when passing the particular blood vessel endothelial cell wall around the contact, and its influence mode is not still known.3 kinds of possibilities are used for these monocytes concisely then:
Leave tissue and return lymphoglandula,
Be divided into scavenger cell,
Be divided into the prematurity dendritic cell.
The 1st step that obtains mature dendritic cell from monocyte is cultivated formed by inducing monocyte to be divided into the prematurity dendritic cell, especially uses interleukin I L-4 and factor GM-CSF (granular leukocyte macrophage-stimulating factor).After 6 days, 95% culturing cell is the prematurity dendritic cell.
The 2nd step is that mature dendritic cell is formed by inducing the prematurity dendritic cell maturation then, with exogenous agent such as bacterium or viral agent.Therefore, from the Kp OmpA albumen of klebsiella pneumoniae (Klebsiella pneumoniae) can induce these prematurity dendritic cell maturations be mature dendritic cell (P.Jeannin etc., NatureImmunology, 2000,1:502-509).Also mention by other exogenous molecules such as bacterial film lipopolysaccharides make the prematurity dendritic cell maturation be mature dendritic cell (Dichman etc., Journal of Cellular Physiology, 2000,185:394-400).Yet, use exogenous molecules to cause security and (the directly or indirectly side effect in the body of cost problem from infectious agent; Need very important etc. according to very strict legal and code requirement purifying), at the molecule that is difficult to use this type aspect vaccinology and the immunotherapy.
Nearest Perrin-Cocon etc. are at calendar year 2001 (The Journal of Immunolgy, 167:3785-3791) described from the monocyte that breaks up and to produce mature dendritic cell and can induce, as some oxidation plasma lipoproteins and Ox LDL (LDLs) more specifically with endogenous molecule.Yet oxidation LDLs is a composite particles, is made up of protein, triacylglycerol, phosphatide, free and esterified cholesterol, and the result is difficult to synthetic.
It is also important that and notice, stimulating monocyte to be divided into dendritic cell is essential in some treatment application (between duration of immunity, during the immune response stimulating), also must suppress the maturation that monocyte is divided into dendritic cell or more generally suppresses the prematurity dendritic cell in other treatment is used as autoimmunization or inflammatory disease.There is anti-inflammatory at present, as the treatment of taking adrenocortical hormone or taking Asprin.Problem is that this treatment has couple patient that very deleterious side effect is arranged when inflammation when being chronic.Prolong take adrenocortical hormone can the emerging syndrome in specific generation storehouse, during observe demineralize, spontaneous fracture and diabetes.The Asprin part is taken in prolongation can produce stomach ulcer.The present invention proposes to solve the shortcoming of prior art level, also proposes the anti-inflammatory molecule, and this molecule is synthetic and relatively cheap easily, the inhibition monocyte is divided into mature dendritic cell.
Therefore the present invention proposes to solve the shortcoming of prior art level, and by short scorching molecule, endogenous molecule are provided, molecule is synthetic easily and relatively cheap and irritate monocyte and be divided into mature dendritic cell.The present invention also relates to use liplid emulsions, comprise triglyceride level, phosphatide and glycerine such as specific I ntralipid
, be used to suppress monocyte and be divided into mature dendritic cell, by direct effect or through suppressing the indirect action of L-alpha-lysophosphatidylcholtoe toe effect.
Surprisingly, the present invention relates to use the L-alpha-lysophosphatidylcholtoe toe so that differentiation of monocytes in mature dendritic cells in vivo.
Term " L-alpha-lysophosphatidylcholtoe toe " is used in reference to the molecule of following formula:
Wherein,
Represent the long-chain of saturated fatty acid, lipid acid contains 12 to 20 carbon atoms, and preferably from 16 to 18.
In fact, one of bioactive molecule that produces in the LDL oxidation is the L-alpha-lysophosphatidylcholtoe toe, hereinafter is called LPC.Yet, having shown LPC in conjunction with the G2A acceptor, the G2A acceptor is the high-affinity receptor of LPC, especially suppresses lymphocytic propagation of T-and activation, the effect (Carson﹠amp of this prompting LPC in suppressing the immune response triggering; Lo, 2001, Science, 293:618-619).In addition, show that also high density LPC (50 μ M) suppresses the activity of transcription factor NF-KB (nf κ B), activates during dendritic cell maturation and NF-κ B is known.In addition, LPC is present in the blood plasma with high density, points out it not activate in blood plasma, it is not inclined to by the technician in the therepic use field selects.
Invention relates to the method for differentiation of monocytes in mature dendritic cells in vivo, in view of the above:
A. monocyte provides in suitable culture medium,
When B. differentiation factor exists, induce monocyte to be divided into dendritic cell,
The C.L-alpha-lysophosphatidylcholtoe toe adds described substratum and obtains mature dendritic cell.
Expression " suitable culture medium " is meant the substratum of all elements that comprises that cell survival is required.Mention RPMI 1640 substratum and its derivative and any substratum well known to those skilled in the art by example.This substratum is specific to comprise at least 1 factor that makes monocyte be divided into dendritic cell.The factor pair those skilled in the art that make monocyte be divided into dendritic cell know, especially do not have any implicit restriction and mention cytokine, as interleukin I L-4, factor GM-CSF (granular leukocyte macrophage-stimulating factor), IL-13 or TNF (tumour necrosis factor).
At step C) in, the described substratum of the specific adding of L-alpha-lysophosphatidylcholtoe toe, in the substratum final concentration between 10 and 80 μ M, preferably between about 20 and 60 μ M, favourable between 30 and 50 μ M.Still in step C, the L-alpha-lysophosphatidylcholtoe toe adds described substratum between the 3rd and the 6th day of monocyte differentiation, between the 4th and the 5th day of preferred monocyte differentiation.
According to the particular of invention, at least a kind of biological reagent also adds substratum in step C.Term " biological reagent " refers to a kind of molecule (or component), is that immunoreactive target maybe can synthesize this target.Therefore, this biological reagent can be selected from bacterium, virus, yeast, parasite or fungal antigen, tumour antigen, from the lysate of body and/or allos tumour cell.Term " autologous tumor cell " is meant the tumour cell that belongs to individual, the specific pharmaceutical prod of individual acceptance.Tumour cell can obtain by getting the cancerous tissue sample, particularly examination of living tissue or excision.Term " allos tumour cell " is meant the cell of acquisition from tumour, and tumour is derived from the individuality different with accepting specific pharmaceutical prod.Use the allos cell to be used for the treatment of the cancer patients by specific acquisition pharmaceutical prod, unlikelyly obtain the tumour cell sample from patient.This also might use the source of standard tumour antigen.Term " cell lysate " is meant in the born of the same parents and/or the mixture of membrane antigen, obtains by lysing cell according to those skilled in the art's known arrangement, as machinery, chemistry or enzymatic lysis.This biological reagent also can be a nucleic acid, at least a kind of antigen of encoding, and antigen is selected from bacterium, virus, yeast, parasite or fungal antigen and tumour antigen.Term " tumour antigen " is meant the antigen of acquisition from tumour cell, as tumor-associated peptides, specificly is with the interaction of molecules of I type and is and passs CD8T lymphocytic peptide.Mention following tumour antigen: MAGE-2 with known non-limited way, MAGE-3, MART, MUC-1, MUC-2, HER-2, GD2, carcinomebryonic antigen (CEA), TAG-72, ovary related antigen OV-TL3 and MOV18, TUAN, α-fetoprotein (AFP), OFP, CA-125, CA-50, CA-19-9, tumor of kidney related antigen G250, EGP-40 (or EpCAM), S100 (malignant melanoma related antigen), p53, tumor of prostate related antigen (as PSA and PSMA) and p21ras.
Therefore, add this biological reagent in the substratum and can obtain mature dendritic cell, they can activate the T lymphocyte of directed anti-specific antigen then.But injection again in the mature dendritic cell body of these external acquisitions then.
In another embodiment of invention, also can in step C, use the compound that is equal to the L-alpha-lysophosphatidylcholtoe toe, according to the cytosis mechanism identical with the L-alpha-lysophosphatidylcholtoe toe, promptly by the same film acceptor, specific is G albumen coupling membrane receptor such as acceptor G2A, GRP4 or PAF (platelet activation factor) acceptor, and/or it is the molecule of a kind of effect as the L-alpha-lysophosphatidylcholtoe toe through identical nuclear receptor such as PPAR acceptor (Pexoxisome proliferator-activated receptor).Thereby this compound of equal value can specific agonist as above-mentioned acceptor (as specific O-methyl-PAF, carbamyl-PAF or 2-O-methyl-PAF), also can be PAF itself.This compound is PPAR δ agent also, as specific L165041 (Merck Research), GW-5015616 (Glaxo) or card ripple prostacyclin (Cayman) or PPAR γ antagonist, for example specific bis-phenol a ethyl diglycidyl ether (Sigma) or Diclofenac
This compound is equal to the L-alpha-lysophosphatidylcholtoe toe, can use separately or with the L-alpha-lysophosphatidylcholtoe toe is collaborative.According to a preferable embodiment of invention, L-alpha-lysophosphatidylcholtoe toe and platelet activation factor (PAF) are collaborative to be used.
Invention also relates to the method for external activated T lymphocytes, in view of the above:
A. monocyte provides in suitable culture medium,
When B. differentiation factor exists, induce monocyte to be divided into dendritic cell,
The C.L-alpha-lysophosphatidylcholtoe toe adds described substratum and obtains mature dendritic cell,
D. biological reagent adds the directed anti-described biological reagent of gained mature dendritic cell among described substratum and the step B as defined above,
E. according to the mature dendritic cell contact T lymphocyte of the directed antibiont reagent of step C, obtain the T lymphocyte of directed antibiont reagent.
Completing steps C as mentioned above.Therefore, the T lymphocyte of the directed anti-particular organisms reagent of this method external acquisition of energy, but be expelled among the patient particularly immunosuppressant patient then in the cell body again.
Invention also relates to the external method that makes dendritic cell maturation, in view of the above:
A. the prematurity dendritic cell provide in suitable culture medium,
The B.L-alpha-lysophosphatidylcholtoe toe adds described substratum and obtains mature dendritic cell.
Those skilled in the art know the dendritic cell stage of maturity different with them.
In step B, the described substratum of the specific adding of L-alpha-lysophosphatidylcholtoe toe, in the substratum final concentration between about 10 and 80 μ M, preferably between about 20 and 60 μ M, favourable between 30 and 50 μ M.According to the particular of invention, at least a kind of biological reagent defined above also adds substratum in step B.
Invention also relates to a kind of substratum, it is characterized in that comprising L-alpha-lysophosphatidylcholtoe toe and at least a kind of differentiation factor defined above.
The invention a preferable embodiment in, in the substratum final concentration of L-alpha-lysophosphatidylcholtoe toe between about 10 and 80 μ M, preferably between about 20 and 60 μ M, favourable between 30 and 50 μ M.Particular according to invention, substratum also comprises biological reagent defined above, and reagent is specific to be bacterium, virus, yeast, parasite or fungal antigen, from the nucleic acid or the antigenic nucleic acid of codes for tumor of body and/or allos tumor cell lysate antigen, tumour antigen, coding bacterium, virus, yeast, parasite or fungal antigen.
Invention also relates to uses the L-alpha-lysophosphatidylcholtoe toe as immune activator.Term " activator " is meant a kind of molecule, causes effect of drugs or reinforcement or improve the effect of main medicine in pharmaceutical composition.In the situation of vaccine composition, the L-alpha-lysophosphatidylcholtoe toe is brought into play adjuvant effect then, the immune response of the anti-specific antigen of stimulation of host organism.Therefore, invention relates to vaccine composition, it is characterized in that comprising the L-alpha-lysophosphatidylcholtoe toe as immune activator, and it brings into play the effect of adjuvant then, the immune response that anti-biological reagent defined above need stimulate patient.
Preferable embodiment according to invention, the L-alpha-lysophosphatidylcholtoe toe is used to produce pharmaceutical prod to treat and/or prevent the infection that infect in bacterium, virus, fungi or parasite source or yeast causes and/or to produce pharmaceutical prod to treat and/or prevent cancer as immune activator.
For infectation of bacteria, specificly mention the infection that staphylococcus, mycobacterium, Neisseria bacterium, legionella, Salmonellas etc. cause.
For virus infection, the infection that the specific HIV of mentioning (human immunodeficiency virus), hepatitis virus, Measles virus, rubella virus, poliovirus, flavivirus etc. cause.
For fungi infestation, specific aspergillosis, the candidiasis etc. mentioned.
For parasitic infection, specific malaria, the leishmaniasis etc. mentioned.
Term " cancer " is meant all diseases that cellular abnormality propagation causes, especially be melanoma, lymphoma, leukemia in unrestriced mode, kidney, brain, colon, prostate gland, rectum, pancreas, ovary, lung, liver and breast cancer are selected from keracele (keratinomas), cancer and melanomatous skin carcinoma.
Pharmaceutical prod according to invention can pharmaceutical compositions provide, and unites at least a kind of pharmaceutically acceptable vehicle well known to those skilled in the art.In pharmaceutical composition according to invention, for in mouth, hypogloeeis, subcutaneous, intramuscular, intravenously, part, the tracheae, rectum or applied dermally, the L-alpha-lysophosphatidylcholtoe toe can the unit administration form or as using with the mixture of conventional medicine upholder, forms such as tablet, gel capsule, oral liquid for example, perhaps for rectal administration with suppository form, specific for parenteral administration with the Injectable solution form, particularly in the intravenously, skin or subcutaneous injection etc., according to routine operation well known to those skilled in the art.For topical application, the L-alpha-lysophosphatidylcholtoe toe can be used for emulsifiable paste, ointment, lotion or collyrium (eyelotion).
When solids composition prepared with tablet form, the L-alpha-lysophosphatidylcholtoe toe mixed pharmaceutically acceptable vehicle, and vehicle is also referred to as pharmaceutical carrier such as gelatin, starch, lactose, Magnesium Stearate, talcum, Sudan Gum-arabic etc.Tablet can be used sucrose, derivatived cellulose or other suitable substance dressing.Also can handle them and make its active L-alpha-lysophosphatidylcholtoe toe that prolongs or postpone and discharge continuously predetermined amount.Also may obtain the gel capsule goods, by mixing L-alpha-lysophosphatidylcholtoe toe and thinner and mixture being injected soft hard gel capsule.May obtain the goods of syrup form equally or use with the drops form, wherein the L-alpha-lysophosphatidylcholtoe toe exists with sweeting agent, sanitas such as specific methyl p-hydroxybenzoate (methylparaben) and Propyl Hydroxybenzoate and suitable spices toughener or dyestuff.Can be scattered in the powder of water or particle can comprise the L-alpha-lysophosphatidylcholtoe toe as with the mixture of dispersion agent or wetting agent or suspension agent, these are known those skilled in the art.For parenteral administration, use aqeous suspension, normal isotonic saline solution or aseptic and Injectable solution, solution comprises pharmaceutically-compatible dispersion agent or wetting agent, for example specific propylene glycol or butyleneglycol.
Invention also relates to the inhibitor of at least a kind of L-alpha-lysophosphatidylcholtoe toe of use to produce pharmaceutical prod, is used for preventing inflammation and/or anti-inflammatory disease and/or autoimmune disease.Term " inhibitor of L-alpha-lysophosphatidylcholtoe toe " is used in reference to a kind of molecule (or component), the inflammation and/or the immunostimulant activity of its blocking-up L-alpha-lysophosphatidylcholtoe toe are particularly by the differentiation of L-alpha-lysophosphatidylcholtoe toe blocking-up mature dendritic cell.It also refers to the module that effect is opposite with the L-alpha-lysophosphatidylcholtoe toe, by particular adjustments PPAR δ/PPAR γ ratio.Mention liplid emulsions by indication, comprise triglyceride level, phosphatide and glycerine such as specific I ntralipid
, lipoid E-80
, the PPAR gamma agonist.The PPAR gamma agonist is known those skilled in the art, can unrestriced mode mention the thiazolidinedione quasi-molecule, as specific ciglitazone, Tuo Lita azoles, pioglitazone, Rosiglitazone etc.Therefore this inhibitor can use to produce pharmaceutical prod in the body, is used to reduce inflammatory reaction, and specific is the inflammatory reaction in joint or especially between transplanting stage.According to the preferable embodiment of invention, the inhibitor of L-alpha-lysophosphatidylcholtoe toe is a liplid emulsions, comprises triglyceride level, phosphatide and glycerine.Tri-glyceride preferably extracts from vegetables oil, as specific soybean oil.Even more preferably liplid emulsions comprises 15 to 25% soybean oil, preferred 20% soybean oil, 0.5 to 1.5% Yelkin TTS, preferred 1.2%, 1.8 to 2.6% glycerine, preferred 2.2% glycerine.According to another preferable embodiment of invention, inhibitor is a PPAR gamma agonist defined above.
For inflammatory disease, specific sarcosis, lupus, rheumatoid arthritis, arthritis vertebralis, the uveitis etc. mentioned.
For autoimmune disease, specific type 1 diabetes, multiple sclerosis, psoriasis, contact supersensitivity, rheumatoid arthritis, the arthritis vertebralis etc. mentioned.
Fig. 1 shows titration curve, and absorbancy is diluted logarithmic function as the serum of a collection of mouse, gives mouse and has hen's egg-white lysozyme (HEL, LPC 1mg/ml) or independent HEL.
The following example provides by the example mode, in fact without any restriction.They might be more thorough to the understanding of invention.
The monocyte that embodiment 1-cultivates is divided into dendritic cell when L-alpha-lysophosphatidylcholtoe toe (LPC) exists or lack
Monocytic separation, cultivation and initial differentiation-monocyte separate from human peripheral, at first by density gradient centrifugation (620g in Ficoll-Hypaque; 20 minutes), follow secondary centrifuging (770g in 50%Percoll solution; 20 minutes).(Dynal, Oslo Norway) come purifying to monocyte by immunomagnetic isolation then, use anti-CD19 (hydridoma 4G7) (Becton Dickinson, Francklin Lakes, NJ, USA), anti-CD3 (OKT3, American Type Culture Collection, Rockville is MD) with anti-CD56 (NKH1, BeckmanCoulter, Fullerton, CA, USA) mixture of monoclonal antibody.Thus obtained monocyte is purified at least 90% then, as lacking the CD1a mark and existing shown in the CD14 mark.Be divided into dendritic cell with 40ng/ml recombinant human GM-CSF (granular leukocyte macrophage-stimulating factor) and the initial monocyte of 250U/ml recombination human interleukin IL-4.
Monocyte is incubated at RPMI 1640 substratum (Life Technologies, Rockville, MD, USA), substratum adds the foetal calf serum (LPDS that 2mM glutamine (Life Technologies), 10mM Hepes (Life Technologies), 40ng/ml gentamicin (Life Technologies) and 10% lipoprotein exhaust, Sigma, St Quentin-Fallavier, France).
Should notice that substratum shown in this example is the LPDS substratum.Comparative result can obtain with other substratum, promptly contains the foetal calf serum that 10% non-lipoprotein exhausts as the FCS substratum, or available any synthetic medium well known by persons skilled in the art obtains.
Handle monocyte-monocyte differentiation with LPC and began 40 μ M LPC (L-alpha-lysophosphatidylcholtoe toes back 5 days; Sigma, St Quentin Fallavier France) added substratum 24 hours.Control cells obtains when also lacking LPC in substratum.
Obtain " contrast " cell and " LPC " cell then.
The phenotype of the cell that embodiment 2-obtains according to embodiment 1
Used cell was to obtain according to embodiment 1 described the 6th day of operating in differentiation during this analyzed.
The phenotype of " contrast " and " LPC " cell is by FACSCalibur (Becton Dickinson, FrancklinLakes, NJ, USA) flow cytometry analysis on uses FITC (the fluorescein isothiocyanate)-anti-CD14 that puts together, anti-HLA-DR and anti-CD80 and PE (the phycoerythrin)-anti-CD1a that puts together, anti-CD83, anti-CD86 and anti-CD40 (Beckman Coulter).According to the prior art level, monocyte preferably has the CD14+CD1a-phenotype, and the prematurity dendritic cell preferably have the CD14-CD1a+CD86-phenotype, and mature dendritic cell preferably has in the middle of the CD14-CD1a-the CD86+ phenotype.
Gained is the result provide in table 1.
Table 1-LPC lacks (contrast) or the expression of CD83, HLA-DR and CD86 mark when existing
| CD83 | HLA-DR | CD86 | |
| Contrast | 5.79 | 78.76 | 117.77 |
| LPC | 11.74 | 146.31 | 759.69 |
When LPC existed, the phenotype of " LPC " cell performance that monocyte differentiation beginning back obtains can be compared with mature dendritic cell, especially by inducing such as the CD86 mark that increase proves with HLA-DR with the phenotype of " contrast " cell.
The internalization ability of the cell that embodiment 3-obtains according to embodiment 1
Used " contrast " and " LPC " cell were to obtain according to embodiment 1 described the 6th day of operating in differentiation during this analyzed.These cells are 37 ℃ of cultivations:
Use 1mg/ml FITC-T70-dextran (Sigma) 30 minutes estimating the ability of these cell internalizings by endocytosis,
Use 1mg/ml fluorescent yellow (with reference to L0259, Sigma, St Quentin-Fallavier, France) estimating the ability of these cell internalizings by pinocytosis,
Use yellowish green FluoSpheres (trade(brand)name, 0.45 μ m, Molecular Probes, Leiden, The Netherlands) that the carbonyl hydrochlorate modifies 3 hours to estimate the ability of these cell internalizings by big pinocytosis.
Internalization is stopping on ice with cold PBS damping fluid, and damping fluid contains 0.1%BSA (bovine serum albumin) and 0.05%NaN3." contrast " and " LPC " cell is washed with this same buffer and by FACSCalibur (trade(brand)name, Becton Dickinson) quantitative fluorescence at 4 ℃.
As shown in table 2, the control cells of breaking up when lacking LPC is compared, and the internalization ability by endocytosis, pinocytosis and big pinocytosis adds substratum by LPC the 5th day of monocyte differentiation and significantly reduces.
Table 2-LPC lack (contrast) or the monocyte of differentiation when existing by endocytosis, pinocytosis and greatly pinocytosis in
The change ability
| Endocytosis | Pinocytosis | Big pinocytosis | |
| Contrast | 100％ | 100％ | 100％ |
| LPC | 53％ | 49％ | 66％ |
It is one of feature of mature dendritic cell that the internalization ability reduces.These results show that the tendency that monocyte is divided into mature dendritic cell is strong when having LPC.
The lymphocytic ability of cytositimulation T that embodiment 4-obtains according to embodiment 1
Used " contrast " and " LPC " cell were to break up acquisition after the 6th day according to described the operating in of embodiment 1 during this analyzed.
Originally allotype T lymphocyte separates from human peripheral.Peripheral blood lymphocytes is passed through density gradient centrifugation (600g when Ficoll-Hypaque exists; 20 minutes) separate.After removing monocyte on the Percoll gradient, peripheral blood lymphocyte is found in tight section.The T lymphocyte comes purifying by immunomagnetic isolation, use anti-CD19 (antibody 4G7) (Becton Dickinson, Francklin Lakes, NJ, USA), the mixture of anti-CD16 (antibody 3G8), anti-CD56 (antibody NKH1), anti-glycophorin A (antibody 11E4B7.6) and anti-CD14 (antibody RMPO52), monoclonal antibody is sold by Beckman Coulter.
The T lymphocyte of purifying is incubated at flat 96 well culture plates of " contrast " or " LPC " cell.
2x10
5Individual T cell cultures exists or the monocyte of differentiation when lacking according to the LPC/T cell proportion (DC/LT ratio) of 1: 5,1: 10 or 1: 20 in 200 μ l substratum.After 4 days, 50 μ l culture supernatants are used for determining the secretion of IL-2 (interleukin-22) and γ IFN (IFN-), and use ELISA test kit (Endogen, Woburn, MA, USA).
As shown in table 3, compare with results of comparison (" contrast " cell), the cell that is derived from the monocyte differentiation by IL-2 and γ IFN according to the conventional T lymphocytic emiocytosis of expressing of dendritic cell/T percentage of lymphocyte (DC/LT ratio) significantly stimulates, and there was the LPC (" LPC " cell) that adds in back 5 days in monocyte differentiation beginning.
Table 3-LPC lack (contrast) or when existing by the monocyte inducer T lymphocyte that breaks up to IL-2
Stimulate with γ IFN excretory
| The DC/LT ratio | 0 | 0.05 | 0.1 | 0.2 | |
| Contrast | IL-2 | 0 | 6±8 | 15±6 | 35±11 |
| γIFN | 0 | 41±14 | 51±4 | 119±9 | |
| LPC | IL-2 | 0 | 23±1 | 47±26 | 173±31 |
| γIFN | 0 | 73±47 | 439±108 | 795±19 |
These results show that the monocyte that breaks up when having LPC stimulates the lymphocytic ability of allotype T to increase, and this is a feature of mature dendritic cell.Obtain comparable result by indication, wherein LPC is dissolved in ethanol or with the liplid emulsions form.
The character of the cell that embodiment 5-obtains according to embodiment 1: the mature dendritic cell that the monocyte of differentiation obtains when existing with oxidation LDLs relatively
The purpose of this example is that proof LPC participates in participating in when mechanism of action that monocyte is divided into mature dendritic cell may be different from oxidation LDLs and exists the mechanism of action (Perrin-Cocon etc. that monocyte is divided into mature dendritic cell when existing, The Journal of Immunology, 167:3785-3891,2001).
In this example, used cell is " LDLox " cell (Perrin-Cocon etc. that embodiment 1 obtains " contrast " and " LPC " cell and obtains described in the scientific publication thing, The Journal ofImmunology, 167:3785-3891,2001), when i.e. differentiation beginning existed oxidation LDLs to add substratum in back 5 days, after the monocyte differentiation of cultivation.
The inventor studies oxidation LDLs whether the inhibitor that monocyte is divided into the mature dendritic cell effect is also suppressed LPC is divided into mature dendritic cell to monocyte effect.
Therefore, Intralipid
Solution (50 μ g/ml phosphatide, Fresenius Kabi, Sevres, France) or come down to solution (the lipoid E-80 of the synthetic molecules of lipid
, lipoid Ag, Ludwigshafen, Germany, 50 μ g/ml phosphatide) and add substratum the 5th day of differentiation.These inhibitor pass through the CD86 of " LPC " and " LDLox " cell expressing according to embodiment 2 described operation analysis when existing, the result lists in table 4.
Table 4-is by LPC and LDLox cell, Intralipid
The inhibition of CD86 being expressed with lipoid E-80 (with
%)
Add Intralipid
Suppress monocyte and be divided into mature dendritic cell, in a similar fashion by oxidation LDLs and LPC method (changing 80% restraining effect into).
On the other hand, surprisingly, when monocyte is cultivated, add the expression that lipoid E-80 induces 81% inhibition CD86 when oxidation LDLs exists, although cultivate when LPC exists when monocyte, this inhibition only is 24%.
These results suggest, the mechanism of action that LPC is divided into mature dendritic cell to monocyte is different from the mechanism of action of oxidation LDLs.
When existing, embodiment 6-LPC participates in the cell mechanism that monocyte is divided into mature dendritic cell
Be divided into cytosis mechanism in the mature dendritic cell for further exploring LPC at monocyte, the inventor has studied the acceptor that may participate in.
Beginning is for determining that participating in LPC is divided into the family whether acceptor that acts in the mature dendritic cell belongs to g protein coupled receptor at monocyte, the proteic PTX (Toxins, pertussis of known blocking-up Gi; 100ng/ml) added substratum 3 hours.Change substratum then and as described in embodiment 1, add LPC.
Table 5 is listed result show, CD86 increases with the pre-incubated monocyte blocking-up of PTX LPC inductive, and the effect of prompting LPC comprises the Gi protein linked receptor.
Table 5-is with the inhibition of PTX to " LPC " cell expressing CD86
| Induce CD86 | |
| LPC | 100％ |
| LPC+PTX | 10％ |
These acceptors can specificly be following acceptors:
G2A acceptor (G2A-R): prove that recently LPC is the proteic high-affinity part of G2A, G2A albumen be with lymphocyte in reach the body link coupled G albumen that is subjected to.In addition, stimulate G2A to induce the outer kinases (ERK1/2: the phosphorylation extracellular signal associated kinase) of born of the same parents by LPC.In addition, can observe this phosphorylation when LPC adds substratum, prompting G2A acceptor participates in monocyte and is divided into mature dendritic cell by the LPC method,
Above-mentioned paf receptor (PAF-R); The effect of some LPC can comprise the paf receptor in the various kinds of cell type,
GPR4 acceptor: LPC also is the proteic part of GPR4, and GPR4 albumen is another kind of and acceptor link coupled G albumen, to sphingosine Phosphorylcholine affinity height.
Then, the inventor has studied and has participated in the transcription factor that LPC induces ripening process.For determining whether PPARs participates in LPC inductive maturation, the binding ability of 2 kinds of transcription factor PPAR γ and PPAR δ is with the gel technical Analysis that is shifted.The isotype that has 3 kinds of PPAR nuclear receptors: α, γ and δ.PPAR γ s is the target of thiazolidinedione quasi-molecule, as is used for the treatment of the ciglitazone of type ii diabetes.PPAR δ s has more wide expression and may be inhibition of PPAR γ s.The monocyte that breaks up is cultivated 2 hours (" LPC " cell) with LPC solution (40 μ M)." contrast " cell obtains when also lacking LPC in substratum.Behind the collecting cell, nucleoprotein extracts test kit (Sigma) with nuclear and extracts.Nucleoprotein contacts radiolabeled probe then, and probe contains the reactive element of being discerned by PPARs.After migration on the non-sex change glue, the doublet that contains the band of PPAR γ and contain PPAR δ with antibody by super displacement technical evaluation.PPAR determines by the intensity of measuring these bands in conjunction with activity.These activity are with the percentage expression with respect to " contrast " cell.
Table 6-regulates the activity of PPAR γ and PPAR δ by LPC
| PPARγ | PPARδ | |
| Contrast | 100％ | 100％ |
| LPC | 0％ | 263％ |
Induce significantly reducing in conjunction with activity of PPAR γ with the LPC processing, this can cause completely dissolve, and stimulates the activity of PPAR δ greatly.
The inventor uses PPAR gamma agonist ciglitazone then.Ciglitazone (Sigma, 50 μ M) solution breaks up at monocyte and added substratum on the 5th day, as described in embodiment 1, adds preceding 15 minutes at LPC (40 μ M, 2 hours) solution.The gained cell is " LPC+ ciglitazone " cell.But when lacking LPC, " ciglitazone " cell obtains according to same operation, and when lacking ciglitazone, as acquisition " LPC " cell as described in the embodiment 1.
The activity of PPAR γ and PPAR δ transcription factor is measured in these cells by above-mentioned gel displacement technology.
The inactivation of table 7-ciglitazone blocking-up PPAR γ also reduces LPC inductive PPAR δ increase
| PPARγ | PPARδ | |
| Contrast | 100％ | 100％ |
| Ciglitazone | 237％ | 106％ |
| The LPC+ ciglitazone | 115％ | 147％ |
These results show that the ciglitazone of activation PPAR γ suppresses the effect of LPC to PPAR γ and PPAR δ, and the result blocks LPC inductive dendritic cell maturation.
Analyzing these cells (" contrast ", " ciglitazone " and " LPC+ ciglitazone " cell) then stimulates the functional capabilities of T lymphocyte (LT).These cells are cultivated when the allotype T of purifying lymphocyte exists as described in embodiment 4.The secretion of γ IFN is as measurement as described in the embodiment 4.
Table 8-blended leukocytoreaction: the secretion of measuring dendritic cell inductive γ IFN by the T lymphocyte
| The DC/LT ratio | 0 | 0.05 | 0.1 | 0.2 |
| Contrast | 0 | 54±82 | 69±4 | 364±27 |
| LPC | 0 | 750±184 | 899±124 | 1326±248 |
| The LPC+ ciglitazone | 0 | 93±7 | 169±105 | 484±229 |
These results emphasize vital role and PPAR γ/PPAR δ ratio on systematic function the importance in sophisticated dendritic cell of PPARs in LPC inductive dendritic cell maturation.This ratio is regulated by LPC and ciglitazone.
Monocyte was divided into mature dendritic cell when the compound that embodiment 7-is equal to LPC existed
Whether the compound that the inventor determines to be equal to LPC promptly participates in the same cell mechanism of action through same film or intracellular receptor, also can induce monocyte to be divided into mature dendritic cell.
Whether for this reason, the inventor has studied PAF adding substratum can increase LPC is divided into mature dendritic cell to monocyte effect.
Therefore, PAF (Sigma, 5 μ M) solution is at the 5th day adding substratum of monocyte differentiation.The CD86 of gained " contrast " cell and " LPC " cell expresses according to embodiment 2 described operation analysis when PAF existence or shortage, and the result lists in table 9.
The expression of the CD86 mark of " contrast " and " LPC " cell when table 9-PAF existence or shortage
(meaning fluorescence intensity)
| CD86 | |
| Contrast | 49.02 |
| PAF | 102.88 |
| LPC | 287.11 |
| LPC+PAF | 676.88 |
These results suggest PAF induces the slight overexpression of CD86 separately, and unlike LPC, LPC induces the expression of CD86 to increase by 47% on the other hand, is important to note that PAT and LPC synergy, because the effect of 2 kinds of compounds induces the expression of CD86 to increase by 1200%.
Be to strengthen the idea that paf receptor participates in, the inventor has studied this receptor antagonist is divided into mature dendritic cell by the LPC method to monocyte effect.
Therefore, PAF antagonist BN52021 (Biomol, Plymouth Meeting, USA, 100 μ M) solution is at the 5th day adding substratum of monocyte differentiation.The CD86 of gained " contrast " and " LPC " cell expresses according to embodiment 2 described operation analysis when BN52021 existence or shortage, and the result lists in table 10.
The CD86 of " LPC " cell expresses when BN52021 existence of table 10-antagonist or shortage
| CD86 | |
| LPC | 100％ |
| LPC+BN52021 | 54％ |
These results suggest, the LPC effect obviously comprises paf receptor, hints that also the effect of LPC may comprise other acceptor.
By indication, the inventor also proves and add the effect that antagonist BN52021 induces 100% inhibited oxidation LDLs in the 5th day substratum that is divided into mature dendritic cell by oxidation LDLs inductive monocyte, points out LPC different with the mechanism of action of oxidation LDLs here once more.
Embodiment 8-is by the anti-antigenic immune response of LPC body internal stimulus
The purpose of this embodiment is to show that LPC is a kind of molecule, and it is immune adjuvant and can be used for immunology to increase anti-antigenic special T reaction.
LPC was that the inflammation product-in this example, 100 to 500nmol LPC solution are dissolved in 50 μ l PBS, injected the sole of the foot palmula of BALB/c mouse (Charles River Laboratories) at the 0th day.Sole of the foot palmula before injection and the back measure with micrometer, up to the 10th day, and compare with the sole of the foot palmula of injection PBS (50 μ l) gained " contrast " mouse.Inflammation intensity thickens reflection by foot.Maximum thickens injection in the 1st day and observed in back 24 hours.
Show to thicken sufficient inductive sole of the foot palmula inflammation (with mm) by LPC-after 11-24 hour
| Foot thickens (mm) | |
| PBS | 0.025 |
| LPC 100nmol | 0.35 |
| LPC 200nmol | 0.55 |
| LPC 300nmol | 0.725 |
| LPC 400nmol | 1.125 |
| LPC 500nmol | 1.075 |
These results show that LPC induces inflammation to depend on the dosage of injection.
For showing that LPC induces the lymphoglandula that moves to drainage in ripe and the dendritic cell body, 1.5%FITC (Sigma) solution is preceding 10 minutes in using 1: 1 dibutyl phthalate/acetone, and LPC solution (0.1M is in dibutyl phthalate) is applied to the ear skin of BALB/c mouse (Charles River Laboratories).This fluorescent mark is by the dendritic cell skin absorption of skin.After 24 hours, take out auricle and maxilla lymphoglandula and cell and place suspension.Cell suspending liquid is by the enrichment in dendritic cell of metrizamide (Sigma) gradient centrifugation.Cell with antibody (Pharmingen) mark of identification major histocompatibility complex (MHC) I type molecule and by flow cytometry analysis with can quantitative expression MHC II type molecule and contain the per-cent of the maxicell (dendritic cell) of FITC.These cells are to be delivery cell, absorb FITC and move to lymphoglandula in periphery.
Table 12-stimulates the dendritic cell migration by LPC
| FITC +Dendritic cell | |
| FITC | 7.1+1.7％ |
| LPC+FITC | 19.3+3.3％ |
These as a result the dendritic cell of display application LPC skin irritation move to the lymphoglandula of drainage.
LPC stimulates the T reaction that is specific to common injection soluble antigen.The LPC (250 or 500nmol in 50 μ l) that is dissolved in PBS mixes the sole of the foot palmula that hen's egg-white lysozyme (HEL, 50 μ g) and this mixture inject BALB/c mouse.After 7 days, taking out lymphoglandula and their cells in vitro stimulates three times again, in containing the antigenic substratum of 30 μ M HEL or do not have a HEL.After 3 days, the T lymphopoiesis mixed the ground thymidine by 16 hours and measures.
The propagation of the special T cell of table 13-HEL (is mixed the ground thymidine among the CPM; Three times mean value)
| Immune condition | Propagation when HEL lacks | Stimulate (30 μ M) again with HEL |
| HEL | 1315±275 | 5370±1983 |
| HEL+LPC 250nmol | 1608±7 | 10885±2861 |
| HEL+LPC 500nmol | 2101±87 | 23739±4265 |
These results show that LPC and antigen are injected altogether and promote that activation is specific to this antigenic T lymphocyte in the body.
LPC stimulates the anti-specific antibody of injecting soluble antigen altogether of generation.The LPC (350nmol is in 50 μ l) that is dissolved in PBS mix hen's egg-white lysozyme (HEL, 1mg/ml) and this mixture inject the sole of the foot palmula of BALB/c mouse.The a collection of mouse of " HEL+LPC " is accepted 50 these mixtures of μ l at the palmula of 2 metapedes.The a collection of mouse of " HEL " is accepted 50 μ l HEL solution (1mg/ml among the PBS) in 2 foots.After 15 days, give subcutaneous reinforcement injection at two flanks.The a collection of of " HEL+LPC " accepted HEL (1mg/ml) solution among 100 μ l LPC (5mM) solution and the PBS at each flank.The a collection of of " HEL " accepted HEL (1mg/ml) solution among the 100 μ l PBS at each flank.After 2 weeks, from mouse, get blood, measure by ELISA and be specific to the antigenic IgGs of HEL with respect to standard I gG solution scope.Light absorption ratio in the titration curve shown in Figure 1 (Abs) is diluted logarithmic function as serum.
These results suggest, LPC and antigen are injected altogether and are promoted immune activation and induce that to be specific to antigenic antibody synthetic, and injections of antigens induced reaction not separately.LPC induces anti-antigenic humoral response, proves its adjuvant ability.
But CD8+T lymphocyte reaction in the LPC inductor.In this example, the test of use is used for haptenic delay contact hypersensitivity.In this model, BALB/c mouse is come sensitization by using haptens DNFB (1-fluoro-2,0.5% solution in the 4-dinitrobenzene, 1: 1 sweet oil/acetone) to the back.After 5 days, the non-stimulating dose of DNFB (1: 1 0.2% solution in sweet oil/acetone) is applied to left ear, and auris dextra is accepted solvent.Bring out the stage at this, raised and be specific to the proteic CD8+T lymphocyte of haptens and permeate ear, secretion γ IFN and generate oedema.
The mouse that " contrast " criticized uses DNFB sensitization and another batch (" LPC " mouse) to accept 500nmol LPC separately, and this is by using the ethanolic soln of 20 μ l LPC before 10 minutes to skin of back at application DNFB.After 5 days, handle with the same procedure that is used to the stage of bringing out for 2 batches, this uses back 48 hours and measures ear with micrometer and thickens.
Table 14-measures dropsy of ear
| Auris dextra thickens (μ m) | Left side ear thickens (μ m) | |
| Contrast | 0±4 | 67±32 |
| LPC | 0±3 | 149±31 |
These results show, during the sensitization haptens used in preceding 10 minutes LPC increase use haptens (bringing out) the 2nd time during the inductive oedema.This means the reaction that LPC stimulates the CD8+T lymphocyte to postpone.
Embodiment 9-liplid emulsions such as Intralipid
Monocyte is divided into the effect of mature dendritic cell
Because embodiment 5 shows liplid emulsions such as Intralipid
The generation of blocking-up LPC inductive mature dendritic cell, the inventor also studied this blocking-up whether come liplid emulsions since then by suppressing the LPC effect indirect action and/or come the direct effect of liplid emulsions since then.
Intralipid
External adjusting PPARs.Beginning, Intralipid
Solution (50 μ g/ml phosphatide) adds substratum the 5th day of monocyte differentiation, according to can with the embodiment 6 described operations of comparing.Cell with Intralipid
Cultivate and collected in back 1 hour, 2 hours or 8 hours, extract the activity of nucleoprotein and PPAR γ and PPAR δ and as described in embodiment 6, determine.
Table 15-passes through Intralipid
Monocytic PPAR γ that adjusting is broken up and the activity of PPAR δ
| With the incubation time of Intralipid (hour) | PPARγ | PPARδ |
| 0 | 100％ | 100％ |
| 1 | 130％ | 94％ |
| 2 | 160％ | 94％ |
| 8 | 170％ | 77％ |
These results show Intralipid
The independent activity that activates PPAR γ and suppress PPAR δ.This Intralipid
Effect opposite with the effect of LPC.
The second, Intralipid
Solution (50 μ g/ml phosphatide) adds preceding 15 minutes (" LPC+Intralipid " cell) at the 5th day adding substratum of monocyte differentiation at LPC solution (40 μ M)." Intralipid " cell also obtains when LPC lacks." LPC " cell is at Intralipid
Obtain during shortage.Cell is collected after cultivating 2 hours, extracts the activity of nucleoprotein and PPAR γ and PPAR δ and determines as described in embodiment 6.
Table 16-Intralipid
Block LPC inductive adult tree by the activity of regulating PPAR γ and PPAR δ
The generation of prominent cell
| PPARγ | PPARδ | |
| Contrast | 100％ | 100％ |
| Intralipid | 156％ | 99％ |
| LPC | 1％ | 160％ |
| LPC+Intralipid | 40％ | 80％ |
Intralipid
Also block the effect of LPC by the activity of regulating PPAR γ and PPAR δ.
Intralipid
Blocking-up LPC inductive inflammation and immune response in the body.In this example, 3 batches of anti-hen's egg-white lysozyme of BALB/c mouse (HEL) antigen immune, immunity is by injecting 50 μ l solution to sole of the foot palmula." HEL " contrast crowd acceptance 50 μ g HEL, " HEL+Intralipid " criticizes and accepts Intralipid
The mixture of (45 μ l) and 50 μ g HEL (solution of 5 μ l 10mg/ml)." HEL+LPC " crowd acceptance 50 μ g HEL and the 350nmol LPC that is dissolved in PBS." HEL+LPC+Intralipid " crowd acceptance 50 μ g HEL, the HEL mixing is dissolved in 45 μ l Intralipid
350nmol LPC.After 24 hours, palmula thickness is measured with micrometer, and compares with the measurement carried out before the injection.Difference in thickness and inflammation intensity are proportional.
Table 17-Intralipid reduces inductive inflammation in the LPC body
| The mean thickness of foot (mm) in the time of 24 hours | |
| HEL+Intralipid | 0.19±0.04 |
| HEL+LPC | 1.07±0.19 |
| HEL+LPC+Intralipid | 0.45±0.04 |
These results show and the simultaneously injected Intralipid of LPC
Reduce 70%LPC inductive sole of the foot palmula inflammation.
Injected back 7 days, taking out lymphoglandula and their cells in vitro stimulates three times again, in the substratum that contains 10 μ M HEL or do not have a HEL.After 3 days, the special T lymphopoiesis of HEL mixed the ground thymidine by 16 hours and measures.
The propagation (mouse mean value) of the special T cell of table 18-HEL
| Immune condition | Propagation (cpm) when HEL lacks | Stimulate (10 μ M) again (cpm) with HEL |
| HEL | 370±212 | 738±408 |
| HEL+LPC | 2568±1570 | 11340±4426 |
| HEL+LPC+Intralipid | 1124±541 | 3959±2103 |
These results show and the simultaneously injected Intralipid of LPC
Blocking-up LPC inductive T response stimulus.
These results show Intralipid
Blocking-up LPC inductive mature dendritic cell produces, and passes through Intralipid
Through suppressing the indirect action of LPC effect, also pass through Intralipid
Direct effect to LPC antagonist PPARs.These results show Intralipid
Anti-inflammatory effect is arranged separately.
These results show PPAR γ/PPAR δ ratio importance in the sophisticated dendritic cell on producing function.This ratio is regulated by LPC, also by liplid emulsions such as Intralipid
Or ciglitazone is oppositely regulated.
Claims (14)
1. an external method that makes monocyte be divided into mature dendritic cell is characterized in that,
A. monocyte provides in suitable culture medium,
Induce monocyte to be divided into dendritic cell when B. differentiation factor exists,
The C.L-alpha-lysophosphatidylcholtoe toe adds described substratum and obtains mature dendritic cell.
2. the method for claim 1 is characterized in that, the L-alpha-lysophosphatidylcholtoe toe adds described substratum among the step C, and final concentration is between 10 and 80 μ M in the substratum.
3. method as claimed in claim 1 or 2 is characterized in that, the L-alpha-lysophosphatidylcholtoe toe adds described substratum among the step C between the 3rd and the 6th day of monocyte differentiation.
4. the method for claim 1, it is characterized in that, at least a biological reagent also adds substratum among the step C, and described biological reagent is bacterial antigens, virus antigen, yeast antigen, parasite antigen or fungal antigen, from the nucleic acid or the antigenic nucleic acid of codes for tumor of body and/or allos tumor cell lysate antigen, tumour antigen, coding bacterial antigens, virus antigen, yeast antigen, parasite antigen or fungal antigen.
5. the method for claim 1 is characterized in that, platelet activation factor also adds substratum among the step C.
6. the method for claim 1 is characterized in that, differentiation factor is selected from interleukin 4, GM-CSF, interleukin-11 3 and TNF.
7. the method for an external activated T lymphocytes is characterized in that,
A. monocyte provides in suitable culture medium,
Induce monocyte to be divided into dendritic cell when B. differentiation factor exists,
The C.L-alpha-lysophosphatidylcholtoe toe adds described substratum and obtains mature dendritic cell,
D. biological reagent adds the directed anti-described biological reagent of gained mature dendritic cell among described substratum and the step C,
E. according to the mature dendritic cell contact T lymphocyte of the directed antibiont reagent of step D, obtain the T lymphocyte of directed antibiont reagent,
Wherein, described biological reagent be bacterial antigens, virus antigen, yeast antigen, parasite antigen or fungal antigen, from the nucleic acid or the antigenic nucleic acid of codes for tumor of body and/or allos tumor cell lysate antigen, tumour antigen, coding bacterial antigens, virus antigen, yeast antigen, parasite antigen or fungal antigen.
8. an external method that makes dendritic cell maturation is characterized in that,
A. the prematurity dendritic cell provide in suitable culture medium,
The B.L-alpha-lysophosphatidylcholtoe toe adds described substratum and obtains mature dendritic cell.
9. a substratum is characterized in that, described substratum comprises the L-alpha-lysophosphatidylcholtoe toe and at least a factor that makes monocyte be divided into dendritic cell.
10. substratum as claimed in claim 9 is characterized in that, L-alpha-lysophosphatidylcholtoe toe final concentration in substratum is between 10 and 80 μ M.
11. as each described substratum in claim 9 or 10, it is characterized in that, it also comprises biological reagent, and described biological reagent is bacterial antigens, virus antigen, yeast antigen, parasite antigen or fungal antigen, from the nucleic acid or the antigenic nucleic acid of codes for tumor of body and/or allos tumor cell lysate antigen, tumour antigen, coding bacterial antigens, virus antigen, yeast antigen, parasite antigen or fungal antigen.
12. substratum as claimed in claim 9 is characterized in that, the described factor that makes monocyte be divided into dendritic cell is selected from interleukin 4, GM-CSF, interleukin-11 3 and TNF.
13. vaccine composition, it is characterized in that, described composition comprises as the L-alpha-lysophosphatidylcholtoe toe of immunity system activator and a kind of biological reagent, and described biological reagent is bacterial antigens, virus antigen, yeast antigen, parasite antigen or fungal antigen, from the nucleic acid or the antigenic nucleic acid of codes for tumor of body and/or allos tumor cell lysate antigen, tumour antigen, coding bacterial antigens, virus antigen, yeast antigen, parasite antigen or fungal antigen.
14. the purposes of the inhibitor of at least a L-alpha-lysophosphatidylcholtoe toe in the pharmaceutical prod of producing the prevention autoimmune disease, wherein, described inhibitor is a liplid emulsions, and described liplid emulsions comprises triglyceride level, phosphatide and glycerine.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| FR02/03499 | 2002-03-11 | ||
| FR0203499A FR2836828A1 (en) | 2002-03-11 | 2002-03-11 | Maturation of dendritic cells in vitro comprises adding L-alpha-lysophosphatidylcholine to a culture medium containing immature dendritic cells |
| FR03/01063 | 2003-01-30 |
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| Publication Number | Publication Date |
|---|---|
| CN1703504A CN1703504A (en) | 2005-11-30 |
| CN100572530C true CN100572530C (en) | 2009-12-23 |
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| CNB038053969A Expired - Fee Related CN100572530C (en) | 2002-03-11 | 2003-03-07 | Use the L-alpha-lysophosphatidylcholtoe toe to obtain differentiation of monocytes in mature dendritic cells in vivo |
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| CN (1) | CN100572530C (en) |
| FR (1) | FR2836828A1 (en) |
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| PL2841564T3 (en) | 2012-04-24 | 2018-08-31 | Stemlab, S.A. | Composition and method of stem cells for preservervation of cardiac tissue |
| KR101951933B1 (en) * | 2013-03-12 | 2019-02-25 | 주식회사 아리바이오 | Lipid nonomaterials comprising lysophosphatidylcholine or its derivative and Methods for preparing the same |
| CA2999691C (en) * | 2015-09-29 | 2020-07-14 | Osaka University | Leukocyte infiltration promoting agent and antitumor immunostimulatory agent |
| IL307508A (en) * | 2021-04-12 | 2023-12-01 | Corner Therapeutics Inc | Hyperactivators of mammalian dendritic cells |
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| US4746652A (en) * | 1986-11-18 | 1988-05-24 | Wake Forest University | Method of inducing diuresis with lysophospholipids |
| US5434182A (en) * | 1987-12-31 | 1995-07-18 | Isaacs; Charles E. | Antibacterial fatty acid compositions |
| CA2090738C (en) * | 1993-02-24 | 1996-05-21 | Hema-Quebec | Use of paf |
| FR2826975B1 (en) * | 2001-07-09 | 2004-06-04 | Bio Merieux | USE OF OXIDIZED LIPOPROTEINS FOR OBTAINING THE DIFFERENTIATION OF MONOCYTES IN MATURE DENDRITIC CELLS |
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Non-Patent Citations (5)
| Title |
|---|
| Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of peroxisome proliferator-activated receptor-γ. Masaaki Niino, Kazuya Iwabuchi, Seiji Kikuchi et al.Journal of Neuroimmunology,Vol.116 . 2001 |
| Amelioration of experimental autoimmune encephalomyelitis in C57BL/6 mice by an agonist of peroxisome proliferator-activated receptor-γ. Masaaki Niino, Kazuya Iwabuchi, Seiji Kikuchi et al.Journal of Neuroimmunology,Vol.116. 2001 * |
| Effects of parenteral lipid emulsions with different fatty acid composition on immune cell functions in vitro. Dominique Granato et al.Journal of Parenteral and Enteral Nutrition,Vol.24 No.2. 2000 |
| Oxidized low-density lipoprotein promotes mature dendritic cell transition from differentiating monocyte. Laure Perrin-Cocon, Frederic Coutant, Sophie Agaugue et al.The Journal of Immunology,Vol.167 No.7. 2001 |
| Troglitazone prevents insulin dependent diabetes in the non-obese diabetic mouse. Philip E. Beales, Roberto Liddi, Angela E. Giorgini et al.European Journal of Pharmacology,Vol.357 . 1998 |
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| FR2836828A1 (en) | 2003-09-12 |
| CN1703504A (en) | 2005-11-30 |
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