WO2008016118A1 - Agent ciblant le récepteur dopaminergique et procédé de criblage pour le rechercher - Google Patents

Agent ciblant le récepteur dopaminergique et procédé de criblage pour le rechercher Download PDF

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Publication number
WO2008016118A1
WO2008016118A1 PCT/JP2007/065197 JP2007065197W WO2008016118A1 WO 2008016118 A1 WO2008016118 A1 WO 2008016118A1 JP 2007065197 W JP2007065197 W JP 2007065197W WO 2008016118 A1 WO2008016118 A1 WO 2008016118A1
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dopamine
receptor
thl
cells
drug
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PCT/JP2007/065197
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English (en)
Japanese (ja)
Inventor
Sho Matsushita
Kazuhisa Nakano
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Immno, Inc.
Saitama Medical University
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Priority to JP2008527793A priority Critical patent/JP5442256B2/ja
Publication of WO2008016118A1 publication Critical patent/WO2008016118A1/fr

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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
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/55—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having seven-membered rings, e.g. azelastine, pentylenetetrazole
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/16—Drugs for disorders of the alimentary tract or the digestive system for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/12—Drugs for disorders of the urinary system of the kidneys
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P17/00—Drugs for dermatological disorders
    • A61P17/06—Antipsoriatics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • 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]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • A61P37/06—Immunosuppressants, e.g. drugs for graft rejection
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/08—Antiallergic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P5/00—Drugs for disorders of the endocrine system
    • A61P5/14—Drugs for disorders of the endocrine system of the thyroid hormones, e.g. T3, T4
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/04—Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P7/00—Drugs for disorders of the blood or the extracellular fluid
    • A61P7/06—Antianaemics

Definitions

  • the present invention relates to a medicament for immune-related diseases such as multiple sclerosis, and a screening method for the medicament, utilizing new knowledge about the Thl / Th2 / Thl7 differentiation induction mechanism via dendritic cells.
  • the present invention also relates to various drugs for controlling the Thl / Th2 / Thl 7 differentiation induction mechanism via dendritic cells.
  • helper T cells which play a central role in acquired immunity, are divided into Thl (type 1 helper T cells) that promote cellular immunity and Th2 ( Type 2 helper T cells).
  • DC Dendritic cells
  • DC1 Thl induction
  • DC2 Th2 induction
  • Thl / Th2 balance abnormalities are thought to be involved in the development of various immune-related diseases.
  • balance bias to Thl cells is a chronic inflammatory disease such as rheumatoid arthritis and , Organ-specific autoimmune diseases (e.g., multiple sclerosis, type 1 diabetes, inflammatory bowel disease, glomerulonephritis, hepatitis, liver damage, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, demyelination Disease, Hashimoto's thyroiditis, pernicious anemia, psoriasis) and the balance bias to Th2 cells is thought to be involved in allergic diseases and many systemic autoimmune diseases.
  • Organ-specific autoimmune diseases e.g., multiple sclerosis, type 1 diabetes, inflammatory bowel disease, glomerulonephritis, hepatitis, liver damage, autoimmune hemolytic anemia, leukopenia, thrombocytopenia, demyelination Disease, Hashimoto's thyroid
  • Thl 7 a new Th subfraction. These cells are involved in exacerbating autoimmune inflammation by producing tangle IL-17.
  • Thl 7 bias! / but it is considered to be strong! /, (Batten, M et al .; Interleukin 27 limits autoimmune encephalomyelitis by s uppressing the development of interleukin 17 — Producing T cells. N at Immunol. 2006. 7: 929—936.
  • Thl 7 interacts with Thl in a mutually ft manner and with Th2 in a mutually reinforcing manner.
  • a method for effectively treating or preventing various immune-related diseases as described above many methods for adjusting an abnormal Thl / Th2 balance as desired have been proposed.
  • a method for treating a Thl-mediated disease by administering a TCCR (T cell site force-in-receptor) polypeptide antagonist (JP 2003-512824); excess caused by autoimmune diseases such as multiple sclerosis Method for suppressing Thl cell-mediated immune response by use of xanthophyll (Japanese Patent Publication No. 2003-510353); a pharmaceutical composition comprising a specific benzhydryl derivative for treating or preventing organ-specific autoimmune diseases, etc. 2003-300881)) and the like have been proposed.
  • TCCR T cell site force-in-receptor
  • a pharmaceutical composition comprising a specific benzhydryl derivative for treating
  • An object of the present invention is to solve the conventional problems and achieve the following objects. That is, the present invention obtains new knowledge regarding the Thl / Th2 / Thl 7 differentiation induction mechanism via dendritic cells, and uses the knowledge to screen an effective drug for immune-related diseases and screening of the drug. It is an object of the present invention to provide a method and an effective drug for controlling a Thl / Th2 / Th17 differentiation induction mechanism via dendritic cells.
  • the present inventors diligently studied and as a result, obtained the following knowledge. That is, the first is the finding that the action of dopamine (DA) is greatly involved in the mechanism of inducing differentiation of Thl / Th2 / Thl 7 through dendritic cells. Second, the conventional Thl deflection Various organ-specific autoimmune diseases and chronic inflammatory diseases, including those that have been attributed to the treatment of TM7 and Th2 differentiation, or induction of Thl differentiation through modification of dopamine receptor activity This is a finding that it can be effectively treated or prevented.
  • DA dopamine
  • Th2 differentiation was promoted when life was dominant, and 13 ⁇ 417 differentiation was promoted when production of 1-6 ⁇ 0? / 3 was dominant.
  • the present invention is based on the above findings by the present inventors, and more specifically includes the following invention.
  • a medicament for treating or preventing a disease caused by Th imbalance comprising a compound that modifies the activity of a dopamine receptor as an active ingredient.
  • the disease caused by Th imbalance is a disease caused by excessive reaction of TM7 or Th2, and the compound that modifies the activity of dopamine receptor is dopamine D1-like receptor antagonist.
  • the medicament according to 1. [3] The medicament according to [2], wherein the dopamine Dl-like receptor antagonist is SCH23390.
  • a screening method for a drug for the treatment or prevention of a disease caused by Th imbalance wherein the screening method uses a modification of the activity of a donomin receptor as an index.
  • the disease caused by Th imbalance is a disease caused by excessive reaction of TM7 or Th2, and the modification of the activity of the dopamine receptor is inhibition of the activity of the dopamine D1-like receptor. Screening method.
  • a drug that inhibits the synthesis or storage of donomin in dendritic cells and contains a dopamine D1-like receptor antagonist as an active ingredient contains a dopamine D1-like receptor antagonist as an active ingredient.
  • a drug that promotes the synthesis or storage of donomin in dendritic cells and contains a dopamine D2-like receptor antagonist as an active ingredient contains a dopamine D2-like receptor antagonist as an active ingredient.
  • FIG. 1A shows that the addition of various drugs to dendritic cells affects the Th differentiation bias of T cells. It is the graph which showed the influence which drops.
  • FIG. 1B is a graph showing the effect of addition of various concentrations of sulpiride on dendritic cells on the Th differentiation tendency of T cells.
  • Fig. 2 is a photograph of an electrophoretic image after RT-PCR that confirmed the expression of the dopamine receptor subtype in dendritic cells.
  • Fig. 3A is a graph showing the effect of the addition of dorminamine sulpiride on changes in dendritic cell Ca 2+ concentration.
  • Fig. 3B is a graph showing the effect of the addition of dopamine sulpiride on the change in dendritic cell cAMP concentration.
  • Fig. 4A is a graph showing the effect of the addition of various drugs to dendritic cells on the production of cytodynamic in (IL-12p70) by dendritic cells.
  • FIG. 4B is a graph showing the effect of the addition of various drugs on dendritic cells on the surface antigen molecule expression of dendritic cells.
  • Fig. 5A is a photograph of a confocal microscope image showing that donomin is stored in granules in dendritic cells.
  • FIG. 5B is a photograph of a fluorescence microscopic image showing the effect of addition of various drugs on dendritic cells on the amount of dopamine stored in granules.
  • Fig. 6A is a graph showing changes in cAMP concentration in T cells due to dopamine stimulation at various concentrations.
  • FIG. 6B is a graph showing changes in cAMP concentration in T cells when SCH23390 (dopamine D1-like receptor inhibitor) is added in addition to dopamine stimulation.
  • Fig. 6C is a graph showing the effect of various concentrations of donomin stimulating cells on Th differentiation bias.
  • FIG. 7A is a photograph of a phase-contrast microscope image showing a state of dendritic cell uncondyles by co-culture (alio-MLR) of dendritic cells and T cells.
  • FIG. 7B is a graph showing the effect of colchicine treatment on the dendritic cell degranulation effect on Th differentiation bias of T cells.
  • Fig. 7C shows that ⁇ ( ⁇ - methy has the function of inhibiting the process of dopamine synthesis. This graph shows the effect of 1-p-tyrosine) on Th differentiation bias in T cells.
  • FIG. 8 is a schematic diagram showing a Th differentiation induction mechanism through donomin release from dendritic cells (DCs) suggested in Examples;! -7.
  • FIG. 9A is a graph showing the prophylactic effect of EAE by prophylactic administration of various donomin receptor inhibitors.
  • FIG. 9B is a graph showing the therapeutic effect of EAE by therapeutic administration of various dopamine receptor inhibitors.
  • FIG. 9C is a graph showing T cell Thl / Th2 / Thl 7 differentiation bias (IL-4, INF- ⁇ , IL-17 production) by prophylactic administration of various dopamine receptor inhibitors It is.
  • Fig. 9D shows Thl / Th2 / Thl 7 differentiation bias (IL-4, INF- ⁇ , IL-17 production) of sputum cells by therapeutic administration of various donomin receptor inhibitors It is a graph.
  • Fig. 10 is a graph showing the preventive effect of CIA by prophylactic administration of various donomin receptor inhibitors.
  • FIG. 11 is a graph showing the preventive effects of NOD by prophylactic administration of various donomin receptor inhibitors.
  • FIG. 12A is a photograph of a light micrograph (positive staining of hematoxylin eosin) of a positive control (PC) group showing the prevention effect of glomerulonephritis by prophylactic administration of various donomin receptor inhibitors. is there.
  • FIG. 12B is a photograph of an optical microscope image (stained with hematoxylin eosin) of the negative control (NC) group to show the prevention effect of glomerulonephritis by prophylactic administration of various dopamine receptor inhibitors. .
  • FIG. 12C is a photograph of an optical microscope image (hematoxylin eosin staining) of the SCH23390 administration group to show the effect of preventing glomerulonephritis by prophylactic administration of various donomin receptor inhibitors.
  • the medicament of the present invention is used for treatment or prevention of diseases caused by Th imbalance. It is a pharmaceutical that can be obtained and contains a compound that modifies the activity of the dopamine receptor as an active ingredient, and further contains other ingredients as necessary.
  • the disease caused by Th imbalance is preferably a disease caused by an excessive reaction of Thl 7 or Th2, and in this case, the compound that modifies the activity of the dopamine receptor is preferably a donomin D1-like receptor.
  • Antago is a second striker.
  • D1 and D5 are known as “dopamine D1-like receptors” and are coupled to Gs proteins that increase adenyl cyclase activity and increase cAMP concentration.
  • D2 to D4 are conjugated with Gi proteins that suppress adenyl cyclase activity as “dopamine D2-like receptors”. Therefore, as the “dopamine D1-like receptor antagonist”, a substance having a function of inhibiting the action of at least one of the subtypes D1 and D5 of the dopamine receptor can be used.
  • the dopamine D1-like receptor antagonist can be appropriately selected according to the purpose without any particular limitation.
  • a known dopamine D1-like receptor antagonist donomin D1-like receptor inhibitor
  • dopamine D1-like receptor antagonist examples include SCH23390, SKF83566, L-Stepholidine, LE300, and the like. Of these, SCH23390 is particularly preferable.
  • the structural formulas of the respective dopamine D1-like receptor antagonists are shown below.
  • the content of the dopamine Dl-like receptor antagonist in the medicament is not particularly limited and can be appropriately selected according to the purpose, and the medicament is the dopamine D1-like receptor antagonist itself. Moyore.
  • the other components can be appropriately selected according to the purpose within a range that does not impair the effects of the present invention without particular limitations.
  • examples thereof include pharmaceutically acceptable carriers.
  • the carrier is not particularly limited, and can be appropriately selected depending on, for example, the pharmaceutical dosage form described below. Further, the content of the other components in the medicine can be appropriately selected according to the purpose without any particular limitation.
  • the pharmaceutical dosage form is not particularly limited, and can be appropriately selected according to the desired administration method.
  • oral solid preparations tablettes, coated tablets, granules, powders, capsules, etc.
  • Oral solutions internal solutions, syrups, elixirs, etc.
  • injections solutions, suspensions, solids for erection, etc.
  • suppositories ointments, patches, gels, creams, external powders, sprays And inhalable powders.
  • Examples of the oral solid preparation include, for example, a compound that modifies the activity of the donomin receptor, an excipient, and optionally a binder, a disintegrant, a lubricant, a coloring agent, and a corrigent.
  • Examples of the excipient include lactose, sucrose, sodium chloride, glucose, starch, calcium carbonate, kaolin, microcrystalline cellulose, and silicic acid.
  • Examples of the binder include water, ethanol, propanol, simple syrup, glucose solution, starch solution, Propinorestarch, methinorescenellose, ethinoresenorelose, shellac, canolecus phosphate, polybylpyrrolidone and the like.
  • Examples of the disintegrant include dry starch, sodium alginate, agar powder, sodium hydrogen carbonate, calcium carbonate, sodium laurinole sulfate, stearic acid monoglyceride, and lactose.
  • Examples of the lubricant include purified talc, stearate, borax, and polyethylene glycol.
  • examples of the colorant include titanium oxide and iron oxide.
  • examples of the flavoring / flavoring agent include sucrose, orange peel, citrate, and tartaric acid.
  • the oral liquid preparation can be produced by a conventional method, for example, by adding additives such as a flavoring agent, a buffering agent, and a stabilizer to the compound that modifies the activity of the dopamine receptor. .
  • Examples of the flavoring / flavoring agent include sucrose, orange peel, citrate, and tartaric acid.
  • Examples of the buffer include sodium quenate.
  • Examples of the stabilizer include tragacanth, gum arabic, and gelatin.
  • a pH regulator, a buffer, a stabilizer, a tonicity agent, a local anesthetic, and the like are added to a compound that modifies the activity of the dopamine receptor, and a conventional method is used.
  • Subcutaneous, intramuscular and intravenous injections can be manufactured.
  • Examples of the pH adjusting agent and the buffering agent include sodium citrate, sodium acetate, sodium phosphate and the like.
  • Examples of the stabilizer include sodium pyrosulfite, EDTA, thioglycolic acid, and thiolactic acid.
  • Examples of the isotonic agent include sodium chloride and glucose.
  • Examples of the local anesthetic include pro-power-in hydrochloride and lidocaine hydrochloride.
  • a compound that modifies the activity of the dopamine receptor for example, a carrier for a known suppository formulation such as polyethylene glycol, lanolin, cocoa butter, fatty acid triglyceride, and a tween if necessary After adding a surfactant such as (TWEEN: registered trademark), it can be manufactured in a conventional manner.
  • a surfactant such as (TWEEN: registered trademark)
  • a compound that modifies the activity of the dopamine receptor is mixed with a known base, stabilizer, wetting agent, preservative, etc., and mixed by a conventional method. Can do.
  • Examples of the base include liquid paraffin, white petrolatum, white beeswax, octyl dodecyl alcohol, and norafine.
  • Examples of the preservative include methyl paraoxybenzoate, ethyl parabenzoate, and propyl parabenzoate.
  • the patch for example, it is possible to apply a cream, a glue, a paste or the like as the ointment to a known support by a conventional method.
  • the support include cotton, suf, woven fabrics made of chemical fibers, non-woven fabrics, soft chlorinated chloride, polyethylene, polyurethane and other films, foam sheets, and the like.
  • the target disease of the medicine is not particularly limited as long as it is a disease caused by Th imbalance, and can be appropriately selected according to the purpose, preferably a disease caused by Thl 7 or Th2 excess reaction.
  • the disease is caused by at least a partial force S of a disease that has been conventionally attributed to an excessive reaction of Thl, and actually a balance bias toward Thl 7 or Th2. Therefore, in addition to allergic diseases and many systemic autoimmune diseases that have been conventionally known as diseases caused by excessive reaction of Thl 7 or Th2, as diseases caused by Thl 7 or Th2 excessive reactions, This includes diseases that have been attributed to Thl overreaction.
  • the ability to determine whether a disease is caused by Thl 7 or Th2 hyperreactivity is assessed by, for example, inhibiting the activity of a dopamine D1-like receptor and determining whether the disease has a preventive or therapeutic effect.
  • Agents (antagonists) that suppress the activity of dopamine D1-like receptors are known as described above.
  • the target diseases in the present invention are particularly suitable for organ-specific autoimmune diseases such as rheumatoid arthritis, which is a chronic inflammatory disease, multiple sclerosis, type 1 diabetes, glomerulonephritis, and the like.
  • the administration target of the drug can be appropriately selected according to the purpose without any particular limitation, and examples thereof include humans, mice, rats, mice, pigs, monkeys and the like.
  • the administration method of the medicine is not particularly limited, depending on the dosage form of the medicine.
  • oral administration administration by injection and the like can be mentioned.
  • the dosage of the medicament can be appropriately selected according to the age, weight, sex, symptom, etc. of the patient who is not subject to any particular restriction.
  • the amount of the compound that modifies the activity of the donomin receptor is considered to be preferably about 2 to about! OOmg.
  • the frequency of administration of the medicament can be appropriately selected according to the purpose without any particular limitation. For example, the daily dose may be administered once a day, Multiple doses may be given.
  • the administration timing of the medicament can also be appropriately selected according to the purpose for which there is no particular restriction. For example, it may be administered prophylactically before the onset of the disease, or the onset of the disease It may later be administered therapeutically.
  • the screening method of the present invention is a method for screening a medicament for the treatment or prevention of a disease caused by the Th imbalance of the present invention, for example, a method using binding to a dopamine receptor as an index ( A first screening method) and a method using the modification of dopamine receptor activity as an index (second screening method).
  • the first screening method is not particularly limited as long as it is a method using the binding to the dopamine receptor as an index, and can be appropriately selected according to the purpose.
  • the disease caused by Th imbalance targeted by this method is preferably a disease caused by excessive reaction of Thl 7 or Th2, and in this case, the dopamine receptor is preferably a donomin D1-like disease. It is a receptor.
  • the test substance is not particularly limited.
  • the test substance can be appropriately selected according to the strength of the drug candidate substance and the purpose.
  • the ability of the test substance to bind to the dopamine receptor can be appropriately selected according to the purpose for which there is no particular limitation, and examples thereof include a method based on a binding assay between a cell line expressing a donomin receptor protein and the test substance.
  • the test substance is the dopamine receptor described above. It can be evaluated that it has binding ability to the body.
  • the test substance evaluated as having the ability to bind to the dopamine receptor in the step (a) is selected.
  • the second screening method is not particularly limited as long as it is a method using the activity modification of the dopamine receptor as an index, and can be appropriately selected according to the purpose.
  • the disease caused by Th imbalance to be the target of this method is preferably a disease caused by excessive reaction of TM7 or Th2, and in this case, activity modification of the donomin receptor used as a screening index Preferably, it is inhibition of dopamine D1-like receptor activity.
  • the method for evaluating the activity-modifying ability of the test substance to the dopamine receptor can be appropriately selected according to the purpose without any particular limitation.
  • Examples include methods for examining changes in intracellular cAMP concentration, intracellular dopamine (DA) synthesis, intracellular donomin (DA) storage, and the like.
  • the various changes can be examined using, for example, a conventionally known method.
  • test substance is capable of inhibiting the activity of the dopamine D1-like receptor.
  • the test substance evaluated as having an activity-modifying ability for the dopamine receptor in the step (a ′) is selected.
  • the screening method only one of the first screening and the second screening may be performed, or both may be performed, but the drug can be efficiently selected. It is preferable to carry out both in terms of possible. In this case, the medicine can be selected more efficiently by performing the first screening and the second screening in this order.
  • the drug of the present invention is a drug utilizing the new knowledge in the present invention that the action of dopamine is involved in the Thl / Th2 / Thl 7 differentiation induction mechanism mediated by dendritic cells.
  • the drug is dopamine D1-like Examples include drugs using receptor antagonists and drugs using donomin D2-like receptor antagonists.
  • a donomin D1-like receptor antagonist has a function of suppressing Thl 7 and Th2 differentiation of naive T cells or inducing Thl differentiation. It is also suggested that dopamine D1-like receptor antagonists may have a function of inhibiting dopamine synthesis or storage in dendritic cells (DC).
  • DC dendritic cells
  • the drug using the donomin D1-like receptor antagonist for example, the drug of the present invention (first drug) that inhibits the synthesis or storage of dopamine in dendritic cells, which will be described later, and And the agent of the present invention (second agent) that suppresses the differentiation of naive T cells into Thl 7 or Th2 or promotes the differentiation into Thl.
  • the first drug is a drug that inhibits the synthesis and storage of donomin in dendritic cells (DA synthesis or storage inhibitor in DC), and the second drug is directed to Thl 7 and Th2 of naive T cells. It is a drug that suppresses the differentiation of Thl or promotes the differentiation to Thl (Thl 7 or Th2 differentiation inhibitor or Thl differentiation promoter).
  • the first drug and the second drug are Each of them contains the dopamine Dl-like receptor antagonist as an active ingredient and, if necessary, other ingredients.
  • the dominine D1-like receptor antagonist in the first drug and the second drug is not particularly limited, and can be appropriately selected according to the purpose.
  • the drug of the present invention Similarly, it can be appropriately selected.
  • the content of the donomin D1-like receptor antagonist in the first drug and the second drug is not particularly limited, and can be appropriately selected according to the purpose.
  • the drug, the second drug may be the donomin D1-like receptor antagonist itself.
  • the type of the other component in the first drug and the second drug, the content of the other component, the dosage form, the production method, and the like are not particularly limited.
  • the present invention As with the above-mentioned pharmaceuticals, it can be appropriately selected.
  • donomin D2-like receptor antagonists inhibit the action of dopamine D2-like receptor in dendritic cells (DC), increase the cAMP concentration in DC, and dono in DC. It is shown to have a function of promoting the synthesis or storage of min. It is also shown that dopamine D2-like receptor antagonists have a function to induce Th2 differentiation of naive T cells.
  • examples of the drug using the donomin D2-like receptor antagonist include, for example, the drug of the present invention (third drug) for promoting dopamine synthesis or storage in dendritic cells, which will be described later, and And the agent of the present invention (fourth agent) that promotes differentiation of naive T cells into Th2.
  • the third drug is a drug that promotes the synthesis and storage of donomin in dendritic cells (DA synthesis or storage promoter in DC), and the fourth drug is the differentiation of naive T cells into Th2. It is a drug that promotes (Th2 differentiation promoting agent).
  • Each of the third drug and the fourth drug contains the dopamine D2-like receptor antagonist as an active ingredient, and other ingredients as required.
  • the donomin D2-like receptor antagonist in the third drug and the fourth drug is not particularly limited, and can be appropriately selected according to the purpose.
  • the known dopamine D2-like receptor Antagonists may be used, and by using a screening method similar to the above-described screening method of the present invention, it is evaluated that it has the ability to bind to and / or inhibit the activity of the donomin D2-like receptor. You may also use other materials.
  • Specific examples of the donomin D2-like receptor antagonist include sulpiride and nemonapride.
  • the content of the dopamine D2-like receptor antagonist in the third drug and the fourth drug is not particularly limited and can be appropriately selected according to the purpose, and the third drug The fourth drug may be the donomin D2-like receptor antagonist itself.
  • the types of the other components in the third drug and the fourth drug, the content of the other components, the dosage form, the production method, and the like are not particularly limited.
  • the present invention As with the above-mentioned pharmaceuticals, it can be appropriately selected.
  • the first to fourth agents are suitable as experimental reagents related to, for example, a Thl / Th2 / Thl7 differentiation induction mechanism via dendritic cells.
  • the first to fourth drugs may be used for treatment or prevention of various immune-related diseases for which an improvement effect is expected by administration of the various drugs.
  • the fourth drug a drug that promotes differentiation of naive T cells into Th2
  • Example 1 the effect of the addition of various drugs, including dopamine D2-like receptor inhibitors (donomin D2-like receptor antagonists), on the Th balance in the process of dendritic cells inducing T cell differentiation.
  • drugs including dopamine D2-like receptor inhibitors (donomin D2-like receptor antagonists)
  • CD14-positive cells and CD45RA-positive (na ⁇ ve) T cells were separated from human peripheral blood by MACS (magnetic cell separation method). The obtained CD14 positive cells were cultured in the presence of IL 4 and GM-CSF to induce differentiation into dendritic cells, and on the fifth day, stimulation with various drugs shown in FIGS. 1A to 1B was added, Collected on day 7.
  • FIG. 1A to FIG. 1B are graphs showing the values of IL 5 / IFN- ⁇ when various drugs are added.
  • a higher IL-5 / IFN- ⁇ value indicates a Th2 differentiation bias, and a lower IL-5 / IFN- ⁇ value indicates a Thl differentiation bias.
  • Nemonapride and sulpiride are known dopamine D2-like receptor inhibitors.
  • Forskolin is an activator of adenyl cyclase and is known to have the effect of increasing intracellular cAMP concentration.
  • LPS is a lipopolysaccharide derived from Gram-negative bacteria and is known to have Thl differentiation-inducing action. Acetic acid was used as the vehicle.
  • “none” in FIGS. 1A to 1B indicates a drug-free group (unless otherwise specified, the same applies to other figures).
  • nemonapride and sulpiride which are dopamine D2-like receptor inhibitors, and forskolin have Th2-inducing activity.
  • FIG. 1B revealed that sulpiride, a dopamine D2-like receptor inhibitor, has a concentration-dependent Th2-inducing activity.
  • Example 2 Analysis of donomin receptor subtype in dendritic cells
  • expression of dopamine receptor subtypes in dendritic cells was analyzed by RT-PCR.
  • D1 and D5 are known as dopamine D1-like receptors, coupled to Gs proteins that increase adenyl cyclase activity and increase cAMP concentration, while D2-D4 are known as dopamine D2-like receptors. It is known to couple with Gi protein which suppresses adenyl cyclase activity.
  • CD14-positive cells are cultured in the presence of IL-4 and GM-CSF for 5 days to induce differentiation into dendritic cells, RNA is recovered from the dendritic cells (DC), and RT-PCR is performed. went. For comparison, RNA was also collected from peripheral blood mononuclear cells (PMBC), naive T cells (naive T), and memory T cells (memory T), and RT-PCR was performed. RT-PCR used primers of various dopamine receptor subtypes such as Dl, D2, D3, D4, and D5. As a positive control, a primer for / 3-actin (beta-actin) was used. The result is shown in figure 2.
  • Example 3 the response of dendritic cells to dopamine stimulation (change in intracellular Ca 2+ concentration and change in intracellular cAMP concentration) was examined.
  • CD14-positive cells were cultured in the presence of IL4 and GM-CSF to induce differentiation into dendritic cells.
  • the immature dendritic cells (iDC) on day 5 were treated with sulpiride or vehicle (acetic acid), and dopamine (DA) was added at various concentrations shown in FIGS. 3A to 3B.
  • iDC immature dendritic cells
  • DA dopamine
  • FIGS. 3A to 3B For each dendritic cell after dopamine stimulation, intracellular Ca 2+ concentration (FIG. 3A) and intracellular cAMP concentration (FIG. 3B) were measured.
  • dopamine increased the Ca 2+ concentration in dendritic cells (DC).
  • dopamine is D2-like (D4) in iDC because it reduces concentration of cAMP in a concentration-dependent manner and these are suppressed by inhibition of dopamine D2-like (D4) receptors by sulpiride. It was suggested that it binds predominantly to the receptor and sends a signal into the cell.
  • Example 4 the effects of various drugs on the production of cytodynamic force and surface antigen molecule expression in dendritic cells were examined.
  • CD14-positive cells are cultured in the presence of IL4 and GM-CSF to induce differentiation into dendritic cells, and are shown in FIG. 4A to FIG. 4B on immature dendritic cells (iDC) on day 5. Stimulation with various drugs was added. After 48 hours, the amount of IL-12p70 in the culture supernatant was measured by ELISA (Fig. 4A), and the expression of surface antigen molecules of CD80, CD86, CD83, and HLA-DR was measured by FACS (Fig. 4B). did.
  • dopamine (DA) and dopamine D2-like receptor inhibitors such as sulpiride have little effect on IL 12p70 site force-in production and surface antigen molecule expression in dendritic cells. Turned out not to give.
  • Example 5 the state of dopamine storage in dendritic cells and the effect of various drugs on dopamine storage were examined.
  • CD14-positive cells were cultured in the presence of IL 4 and GM-CSF to induce differentiation into dendritic cells.
  • iDC immature dendritic cells
  • forskolin 10 M It was recovered 48 hours after stimulation. After fixation with 10% formalin, ethanol treatment was performed, and staining was performed with an anti-dopamine antibody and a FITC-labeled secondary antibody. Furthermore, double staining was performed using a Lamp-1 antibody and a Texa s-Red labeled secondary antibody! / And observed with a confocal microscope (orgin al X 60) (FIG. 5A).
  • Example 6 the response of naive T cells to dopamine stimulation (intracellular cAMP concentration change) was examined.
  • CD4-positive naive T cells were treated with IBMX (3-isobuthyl-1-methyl xanthine) lm M for 10 minutes, stimulated with each concentration of dopamine shown in Fig. 6A, and intracellular cAMP 10 minutes later When the concentration was measured, an increase in intracellular cAMP concentration dependent on dopamine concentration was observed (FIG. 6A).
  • CD4 positive naive T cells were treated with IBMXlmM for 10 minutes, and SCH23390 (dopamine D1-like receptor inhibitor) 1 ⁇ ⁇ or vehicle (acetic acid) was added. After incubation for 10 minutes, stimulation with donomin (DA) was performed, and the intracellular cAMP concentration after 10 minutes was measured. Dopamine (10_ 7 M) cAMP concentration increase by stimulation was completely inhibited by pretreatment with SCH23390 is Dono Min D1-like receptor inhibitors (Figure 6B).
  • Example 7 the presence or absence of degranulation of dendritic cells during alio-MLR and the direction of Th differentiation of T cells when the amount of dopamine released from the dendritic cells was changed were examined.
  • CD14-positive cells were cultured in the presence of IL4 and GM-CSF to induce differentiation into dendritic cells, and forskolin 10 ⁇ was added to immature dendritic cells (iDC) on day 5. It was collected 48 hours after stimulation. After washing, the cells were suspended on a 35 mm glass culture dish (Glass Base Dish), and alio human CD45RA positive cells were added. When observed with a phase-contrast microscope immediately after the start of co-culture (allo-MLR) and taken over time (time-lapse), a part of DC appears to degranulate mainly after contact with T cells. Confirmed ( Figure 7A).
  • alio-MLR was performed in the same manner as described above using iD C treated with colchicine (0.5 ng / ml) having a tubulin polymerization inhibitory effect, and anti-CD3 antibody and anti-CD28 anti-CD28 antibody were administered on the 8th day. Re-stimulated with the body. After 16 hours, the culture supernatant was collected, and IL 5 and IFN- ⁇ were measured by ELISA. DC treated with colchicine was confirmed to have decreased IL 5 / IFN- ⁇ , suggesting that inhibition of DC degranulation induces a Thl reaction (Fig. 7 ⁇ ).
  • DOPA is synthesized from tyrosine by tyrosine hydroxylase ( ⁇ ) during the dopamine synthesis process, and this ⁇ is synthesized by a-methyl-p-tyrosine ( ⁇ ). It is known to be inhibited. Therefore, alio-MLR was performed in the same manner as described above using this iDC treated with AMPT. For DC treated with AMPT, IL-5 / IFN- ⁇ is AMP It was confirmed that the concentration decreased in a T-dependent manner, suggesting that when the amount of donomin synthesized in DC was small V, a Thl reaction was induced (Fig. 7C).
  • Examples 1 to 7 suggested a mechanism for inducing Th differentiation via dendritic cells, as schematically shown in FIG.
  • the recognition of antigenic peptide 'MHC molecule by T cells involves adhesion as a secondary signal' costimulatory molecule, and SMAC (supermolecular consisting of receptor / ligand pair containing TCR / antigen peptide MHC complex) It is known that local interaction regions called activation clusters or immune synapses are formed.
  • neurotransmitters such as dopamine are released from presynaptic neurons and activate not only post-neurons but also negative feedback via self-receptors expressed in pre-neurons. Is known to have the ability to regulate dopamine synthesis!
  • dopamine is oxidized to dihydroxy xyphenylalanine (DOPA) by tyrosine hydroxylase (TH), and further decarboxylates aromatic L amino acids. It is decarboxylated by an enzyme (aromatic L-amino acid decarboxylase; AAD) and stored in vesicles.
  • DOPA dihydroxy xyphenylalanine
  • AAD aromatic L-amino acid decarboxylase
  • This dopamine production and extracellular release process is regulated mainly by cAMP and Ca 2+ by stimulation via G protein.
  • Stimulation from Gs protein leads to an increase in cAMP due to activation of adenyl cyclase (AC), which increases conversion to DOPA and increases DA storage, whereas stimulation from Gi protein causes intracellular Ca 2+ As a result of this increase, the secretion of DA storage vesicles is caused, and at the same time, the amount of DA stored in the cells is suppressed by suppressing AC activity.
  • AC adenyl cyclase
  • An immune synapse is formed between dendritic cells and T cells in the same way as the power and nerve synapses. Dendritic cells are considered to correspond to presynaptic neurons and T cells to postsynaptic receptor neurons. From the results of the above Examples;! To 7, in iDC, the adenyl cyclase (AC) activity via the Gs protein D1-like (D1, D5) receptor Gi protein, the D2-like (D4) receptor It was suggested that the amount of dopamine stored was (self) regulated by being suppressed through the body.
  • D4 receptors D2-like receptor inhibitors
  • D2-like receptor inhibitors such as sulpiride
  • D1-like receptor inhibitors such as SCH23390
  • EAE induction was started with PLP139- 151 + CFA + PTx (dayO), and as a prophylactic administration, during day3 to dayl8, L750667 (D2-like (D4) receptor inhibitor), SCH23390 (D1-like) (Dl, D5) receptor inhibitors) were orally administered every other day and evaluated by EAE clinical score.
  • Each drug was dissolved in phosphate buffered saline (PBS) and administered at an amount of 0.3 mg / kg / day.
  • PBS phosphate buffered saline
  • control group control
  • PBS phosphate buffered saline
  • mice treated with L750667 deteriorated significantly from day 32 and died on day 34.
  • the SCH23390 D1-like (Dl, D5) receptor inhibitor
  • mice improved their symptoms from day 38 compared to the two controls and reached remission on day 44 (Fig. 9B).
  • FIG. 9C is a mouse to which the drug was administered prophylactically
  • FIG. 9D was a mouse to which the drug was therapeutically administered.
  • IL-4 which is significantly higher than the control group, there was no significant difference from the control group, and because IL-17 was significantly lower than the control group, Thl differentiation was induced. On the contrary, it was confirmed that Thl 7 differentiation was suppressed.
  • L750667 D2-like (D4) receptor inhibitor
  • IL-4 was significantly higher than that in the control group, and IFN- ⁇ was significantly lower than that in the control group. Since no significant difference was observed, it was confirmed that Th2 differentiation was induced and, on the contrary, Thl differentiation was suppressed.
  • SCH23390 D1-like (Dl, D5) receptor It was confirmed that Thl differentiation was induced and Thl 7 and Th2 differentiation was suppressed in the inhibitor group.
  • immunization (+) indicates a mouse in which EAE induction is performed
  • im munizaition () indicates a mouse in which EAE induction is not performed.
  • Induction of CIA was started (dayO) in 7-week-old male mice (DB A / 1J) using sushi-derived type 2 collagen (200 Hg / animal) + CFA and boosted on day21 .
  • SCH23390 D1-like (D1, D5) receptor inhibitor
  • SCH23390 was orally administered three times a week between dayl8 and day34, and mouse spleen and serum were collected on day36.
  • L750667 D2-like (D4) receptor inhibitor
  • the CIA clinical score was evaluated for each limb according to the following criteria, and one mouse (total of 4 limbs) was evaluated with a maximum of 16 points.
  • PBS phosphate buffered saline
  • PBS phosphate buffered saline
  • Example 11 Effect of a donomin receptor inhibitor in glomerulonephritis model mice
  • 5 〜 6-week-old SJL male mice (12 mice) were used as a CFA suspension.
  • Hid IgGO. 5 mg / 20 g body weight was injected subcutaneously.
  • SCH23390 D1-like (D1, D5) receptor inhibitor
  • the drug was dissolved in phosphate buffered saline (PBS) and administered at an amount of 0.3 mg / kg / day. Only the PBS was administered to the positive control (PC) group and the negative control (NC) group. The test was conducted with 4 animals in each group.
  • PBS phosphate buffered saline
  • an anti-basement membrane antibody was administered to the SCH23390 administration group and the PC group.
  • PBS was intravenously injected into the NC group of mice. Thereafter, the patient was decapitated on the 14th day, and blood, spleen and kidney were collected.
  • the results of Examples 8 to 11 include organ-specific autoimmunity such as multiple sclerosis and glomerulonephritis, including diseases conventionally considered to be diseases caused by Thl excess reaction.
  • Rheumatoid arthritis S which is a disease and chronic inflammatory disease. Can be effectively treated or prevented by actively inducing Thl (or suppressing Thl 7 or Th2 differentiation) by administering a Dl-like (Dl, D5) receptor inhibitor It indicates that it is a disease.
  • SCH23390 D1-like (Dl, D5) receptor inhibitor
  • SCH23390 D1-like (Dl, D5) receptor inhibitor
  • the medicament of the present invention is useful as a therapeutic or prophylactic agent for diseases caused by Thl 7 or Th2 excessive reaction
  • the screening method of the present invention is useful as a method for screening the medicament.
  • the various drugs of the present invention are useful as experimental reagents related to the Thl / Th2 / Thl 7 differentiation induction mechanism mediated by dendritic cells, and an improvement effect is expected by administration of the various drugs. It is also useful as a therapeutic or prophylactic agent for various diseases

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Abstract

La présente invention concerne une nouvelle observation concernant le mécanisme d'induction de la différentiation des Th1/Th2/Th17 par les cellules dendritiques, ainsi qu'un produit pharmaceutique efficace contre une maladie liée à l'immunité fondé sur ladite observation, un procédé de criblage permettant de rechercher le produit pharmaceutique et un agent capable de réguler efficacement le mécanisme d'induction de la différentiation des Th1/Th2/Th17 par les cellules dendritiques. L'invention concerne un produit pharmaceutique destiné au traitement ou à la prévention d'une maladie causée par un déséquilibre des Th, caractérisé par le fait qu'il contient en tant que matière active un composé qui modifie l'activité du récepteur dopaminergique, ainsi qu'un procédé de criblage permettant de rechercher le produit pharmaceutique et divers agents caractérisés par le fait qu'ils contiennent en tant que matière active un antagoniste du récepteur dopaminergique de type D1 ou un antagoniste du récepteur dopaminergique de type D2.
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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112961827A (zh) * 2021-04-25 2021-06-15 河南省肿瘤医院 佛司可林在t细胞培养中的应用

Non-Patent Citations (8)

* Cited by examiner, † Cited by third party
Title
FERRARI M. ET AL.: "Dopaminergic D1-like receptor-dependent inhibition of tyrosine hydroxylase mRNA expression and catecholamine production in human lymphocytes", BIOCHEMICAL PHARMACOLOGY, vol. 67, no. 5, 2004, pages 865 - 873, XP003021041 *
FISEROVA A. ET AL.: "Effects of D2-dopamine and alpha-adrenoceptor antagonists in stress induced changes on immune responsiveness of mice", JOURNAL OF NEUROIMMUNOLOGY, vol. 130, no. 1-2, 2002, pages 55 - 65, XP003021038 *
GHOSH M.C. ET AL.: "Dopamine inhibits cytokine release and expression of tyrosine kinases, Lck and Fyn in activated T cells", INTERNATIONAL IMMUNOPHARMACOLOGY, vol. 3, no. 7, 2003, pages 1019 - 1026, XP003021039 *
LEYKIN I. ET AL.: "Short and long-term immunosuppressive effects of clozapine and haloperidol", IMMUNOPHARMACOLOGY, vol. 37, no. 1, 1997, pages 75 - 86, XP003021037 *
MCCARTY M.F. ET AL.: "Upregulation of lymphocyte apoptosis as a strategy for a role for preventing and treating autoimmune disorders: a role for whole-food vegan diets, fish oil and dopamine agonists", MEDICAL HYPOTHESES, vol. 57, no. 2, 2001, pages 258 - 275, XP003021036 *
NAKANO K. ET AL.: "Dopamine ni yoru Men'eki Chosetsu Sayo (THE IMMUNOMODULATORY EFFECT OF DOPAMINE)", JAPANESE JOURNAL OF ALLERGOLOGY, vol. 56, no. 7, July 2007 (2007-07-01), pages 679 - 684, XP003021042 *
NAKANO K. ET AL.: "Jujo Saibo wa Dopamine Hoshutsu ni yotte Th1/Th2 Bunka o Chosetsu suru", JAPANESE JOURNAL OF ALLERGOLOGY, vol. 55, no. 8/9, September 2006 (2006-09-01), pages 1107 + ABSTR. NR. MS6-5, XP003021043 *
SUZUKI H. ET AL.: "Sulpiride no Sui Naibunpitsu-kei ni Oyobosu Eikyo (The Effects of Sulpiride on the Endocrine Pancreas)", FOLIA ENDOCRINOLOGICA JAPONICA, vol. 57, 1981, pages 1707 - 1715, XP003021040 *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN112961827A (zh) * 2021-04-25 2021-06-15 河南省肿瘤医院 佛司可林在t细胞培养中的应用
CN112961827B (zh) * 2021-04-25 2024-04-26 河南省肿瘤医院 佛司可林在t细胞培养中的应用

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