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WO2024108691A1 - Lymphocyte t régulateur et son procédé de préparation - Google Patents

Lymphocyte t régulateur et son procédé de préparation Download PDF

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Publication number
WO2024108691A1
WO2024108691A1 PCT/CN2022/139120 CN2022139120W WO2024108691A1 WO 2024108691 A1 WO2024108691 A1 WO 2024108691A1 CN 2022139120 W CN2022139120 W CN 2022139120W WO 2024108691 A1 WO2024108691 A1 WO 2024108691A1
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Prior art keywords
cells
regulatory
preparation
ampk
cell
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PCT/CN2022/139120
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English (en)
Chinese (zh)
Inventor
王爱婷
潘璠
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Shenzhen Institute of Advanced Technology of CAS
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Shenzhen Institute of Advanced Technology of CAS
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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
    • C12N5/0636—T lymphocytes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K35/00—Medicinal preparations containing materials or reaction products thereof with undetermined constitution
    • A61K35/12—Materials from mammals; Compositions comprising non-specified tissues or cells; Compositions comprising non-embryonic stem cells; Genetically modified cells
    • A61K35/14—Blood; Artificial blood
    • A61K35/17—Lymphocytes; B-cells; T-cells; Natural killer cells; Interferon-activated or cytokine-activated lymphocytes
    • 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
    • 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]
    • 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
    • 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
    • C12N2501/00—Active agents used in cell culture processes, e.g. differentation
    • C12N2501/70—Enzymes
    • C12N2501/72—Transferases [EC 2.]
    • C12N2501/727—Kinases (EC 2.7.)

Definitions

  • the present invention relates to the field of molecular immunology, and in particular to a regulatory T cell and a preparation method and application thereof.
  • IBD Inflammatory bowel disease
  • UC ulcerative colitis
  • CD Crohn's disease
  • Colitis is a relatively broad term, referring to inflammatory lesions of the colon caused by various reasons such as bacterial infection or IBD, which is often a sign of UC or CD.
  • IBD ulcerative colitis
  • CD Crohn's disease
  • AMPK adenosine 5’-monophosphate
  • AMPK adenosine 5’-monophosphate
  • AMPK adenosine 5’-monophosphate
  • AMPK AMP-Activated Protein Kinase
  • AMPK is a highly conserved energy sensor in eukaryotic cells. When the energy level in the cell is low, AMPK is activated and participates in the regulation of a series of physiological processes, ultimately increasing energy products and reducing ATP usage.
  • AMPK is a heterotrimer composed of an ⁇ catalytic subunit and ⁇ and ⁇ regulatory subunits. Phosphorylation modification at Thr172 on the ⁇ catalytic subunit has an important effect on the AMPK kinase activity.
  • the main upstream kinases that can phosphorylate the ⁇ subunit of AMPK at Thr172 include liver kinase B1 (LKB1), while Ca2+/Calmodulin-dependent Protein Kinase Kinase ⁇ (CaMKK ⁇ ) and TGF- ⁇ activated kinase 1 (Tak1) are also upstream kinases of AMPK.
  • AMPK is activated, promoting the catabolic pathway that produces ATP and inhibiting the anabolic pathway that consumes ATP, thereby maintaining energy homeostasis.
  • the catabolic pathways activated by AMPK include: glucose uptake, glycolysis, fatty acid uptake, fatty acid oxidation, mitochondrial biogenesis and autophagy.
  • the anabolic pathways inhibited by AMPK include: fatty acid synthesis, triglyceride synthesis, cholesterol synthesis, transcription of enzymes in gluconeogenesis, glycogen synthesis, protein synthesis and ribosomal RNA synthesis.
  • DSS dextran sulfate sodium salt
  • metformin is administered orally or intraperitoneally for treatment.
  • Specific schemes include: Scheme 1: mice are fed with an aqueous solution containing 2.5% DSS from day 0 to day 7 to induce acute colitis, and normal water is used from day 7 to day 11. Then, 125, 250 or 500 mg/kg of metformin is administered orally every day from day 0 to day 11, and PBS is administered orally as a control group.
  • mice are fed with an aqueous solution containing 3% DSS from day 0 to day 7 to induce acute colitis, and normal water is used from day 7 to day 11. Then, 150 mg/kg of metformin is administered intraperitoneally every day from day 0 to day 7, and PBS is administered intraperitoneally as a control group.
  • metformin is not a small molecule drug that selectively targets AMPK, which means that the drug has other targets and may affect the functioning of other normal cells in the body.
  • Dorsomorphin also known as Compound C
  • the drug has no effect on other kinases with similar structures, which improves the drug's selectivity for AMPK. Its chemical structure is shown in Figure 1.
  • the use of the above two AMPK-targeted drugs may interfere with the metabolism of intestinal cells and intestinal flora, affecting the body's normal physiological functions.
  • the purpose of the present invention is to overcome the deficiencies of the prior art and solve the problem mentioned in the above background technology that the administration of AMPK targeted drugs has an adverse effect on the metabolism of intestinal cells and intestinal flora and the normal physiological functions of the body.
  • the first aspect of the present invention provides a method for preparing regulatory T cells, comprising sorting the regulatory T cells; co-incubating the regulatory T cells with an AMP-activated protein kinase selective inhibitor in vitro; and adoptively transferring the regulatory T cells.
  • the regulatory T cells obtained from the sorted regulatory T cells are CD4+CD25+ Treg cells.
  • the co-incubation time is 12 h.
  • the adoptive transfer is by intravenous injection.
  • the selective inhibitor of AMP-activated protein kinase is Dorsomorphin.
  • the second aspect of the present invention provides a regulatory T cell, wherein the regulatory T cell is prepared by a preparation method.
  • the third aspect of the present invention provides a drug for treating inflammatory bowel disease, wherein the drug comprises the regulatory T cells.
  • the fourth aspect of the present invention provides a drug for use in enhancing the immunosuppressive effect of regulatory T cells in vitro, inhibiting interleukin-17 secretion in the regulatory T cells and/or promoting the expression of forkhead box protein P3 in the regulatory T cells.
  • the promoting the expression of forkhead box protein P3 in regulatory T cells is promoting the expression of forkhead box protein P3 in HEK293T cells and/or iTreg cells.
  • the method for enhancing the immunosuppressive effect of regulatory T cells in vitro can produce cells for inflammatory bowel disease, and the cells can be adopted and transferred without adversely affecting the metabolism of intestinal cells and intestinal flora.
  • the present invention clarifies the intrinsic mechanism of the selective inhibitor of AMPK, Compound C, on the AMPK target, providing an important reference for the prevention and treatment of inflammatory bowel disease.
  • FIG. 1 shows the chemical structure of Compound C
  • Fig. 2 is a graph showing the weight of mice
  • Fig. 3 is a graph showing the measurement of mouse colon length
  • Figure 4 is a HE staining analysis of mouse colon tissue sections, wherein Figure A is a HE staining analysis of colon tissue sections of control mice (Prkaa1+/+Prkaa2+/+Foxp3-Cre); Figure B is a HE staining analysis of colon tissue sections of Treg cell conditional AMPK knockout mice (Prkaa1fl/flPrkaa2fl/flFoxp3-Cre);
  • Figure 5 shows the effect of Compound C on IL-17A and Foxp3 expression
  • FIG6 is a diagram showing the interaction between AMPK and Foxp3 in HEK293T cells
  • FIG. 7 is a diagram showing the interaction between AMPK and Foxp3 in iTreg cells.
  • Treg Regulatory T cells
  • Treg cells refer to CD4+CD25+ Treg cells
  • CD4 and CD25 are surface markers of Treg cells.
  • Foxp3 Foxp3 protein is a characteristic transcription factor of Treg cells and plays an important role in the immunosuppressive function of Treg cells.
  • Overexpression of Foxp3 protein in mouse CD25lowCD4+ T cells can enable cells to acquire immunosuppressive activity, inhibit IL-2 and promote the transcription of downstream genes such as Cd25 and Ctla4.
  • Foxp3 gene deficiency can lead to immunosuppressive dysfunction in mice, thereby developing severe autoimmune diseases.
  • mutations in the human Foxp3 encoding gene can also lead to X-linked immune disorder syndrome.
  • the destruction of the stability and inhibitory function of Treg cells can lead to autoimmune diseases in the body, while the excessive inhibitory function of Treg cells can promote the occurrence and development of cancer. Therefore, maintaining the stability and function of Treg cells is particularly important for maintaining the body's immune balance.
  • Treg cells show a high activation state of AMPK and are dependent on fatty acid oxidation.
  • Rapamycin and fatty acid treatment can both increase the proportion of Treg cells, and in the presence of transforming growth factor- ⁇ (TGF- ⁇ ), both have a stronger ability to promote the generation of Treg cells.
  • TGF- ⁇ transforming growth factor- ⁇
  • inhibitors of fatty acid oxidation prevented the generation of Treg cells induced by Rapamycin and TGF- ⁇ , indicating that the development of Treg cells caused by inhibition of mammalian rapamycin target protein (mTOR) requires the participation of fatty acid oxidation.
  • mTOR mammalian rapamycin target protein
  • AMPK has two catalytic subunits, ⁇ 1 and ⁇ 2, encoded by genes Prkaa1 and Prkaa2, respectively.
  • DSS Dextran sulfate sodium salt
  • the present invention provides a method for preparing regulatory T cells, including sorting regulatory T cells; co-incubating a selective inhibitor of adenylate-activated protein kinase with regulatory T cells in vitro; and adoptively transferring regulatory T cells.
  • the preparation method can produce a regulatory T cell, which can be used as a therapeutic drug for diseases such as inflammatory bowel disease, inhibit drug-induced and T cell-induced colitis inflammatory reactions, and intervene in the progression of inflammatory bowel disease.
  • the above-mentioned drug can enhance the immunosuppressive effect of regulatory T cells in vitro, inhibit interleukin-17 secretion in regulatory T cells, and/or promote the expression of forkhead box protein P3 of regulatory T cells.
  • this scheme uses the immunosuppressive activity of adoptively transferred Treg cells to slow down the inflammatory response of colitis, without affecting intestinal cells and intestinal flora.
  • Example 1 Experiment on knocking out AMPK gene in Treg cells to slow down the progression of inflammatory bowel disease
  • mice were tested for body weight, colon length, and HE staining analysis of colon tissue sections.
  • the scale bar in the HE staining analysis was 500 ⁇ m, P ⁇ 0.05, which was significantly different.
  • Foxp3 is a characteristic transcription factor of Treg cells, and Foxp3-Cre is used to specifically knock out a gene in Treg cells.
  • Prkaa1+/+Prkaa2+/+Foxp3-Cre is a control mouse, equivalent to wild-type mice; Prkaa1fl/flPrkaa2fl/flFoxp3-Cre specifically knocks out the two catalytic subunits of AMPK, ⁇ 1 and ⁇ 2, in Treg cells.
  • mice with conditional knockout of AMPK by Treg cells had reduced colitis symptoms. Specifically, compared with control mice, conditional knockout mice lost weight more slowly, had longer colons, and had less inflammatory cell infiltration in colon tissues.
  • Wild-type mouse CD4+CD25+ Treg cells were sorted by flow cytometry, and two groups of experiments were set up. One group treated Treg cells with phosphate buffered saline (PBS) overnight in vitro, and the other group pretreated Treg cells with AMPK inhibitor Compound C overnight in vitro.
  • PBS phosphate buffered saline
  • the sorting process specifically includes: enriching mouse CD4+ T cells from the cell suspension obtained from the spleen and lymph nodes of mice, using mouse CD4 (L3T4) MicroBeads (Miltenyi Biotec, 130-049-201).
  • the enriched mouse-derived CD4+ T cells were resuspended in 1mL MACS buffer for every 10 ⁇ 106 cells, and 1 ⁇ L of flow cytometry antibodies anti-CD4-PercP-Cy5.5 and anti-CD25-APC were added and mixed, and stained at 4°C for 30 minutes in the dark. Then 3mL MACS buffer was added to wash the cells, and the supernatant was discarded after centrifugation at 350 ⁇ g for 5 minutes.
  • the precipitate was resuspended in an appropriate volume of MACS buffer, and then sorted using a BD FACS AriaII flow cytometer to obtain CD4+CD25high Treg cells.
  • the overnight treatment specifically includes: treating Treg cells with 0.5-1 ⁇ M Dorsomorphin for 12 hours, the culture medium is PRMI 1640 complete culture medium, containing 10% fetal bovine serum, sodium pyruvate, non-essential amino acids, penicillin and streptomycin, and the culture conditions are 37°C 5% CO2 cell culture incubator.
  • the two groups of Treg cells pretreated overnight in Example 2 were used for adoptive transfer experiments as drug interventions for the progression of drug-induced colitis. There were three groups in the experiment, all of which used DSS to induce colitis in wild-type mice. One group injected PBS into mice, one group adopted Treg cells into mice, and one group adopted Treg cells treated with Compound C into mice, wherein the adoptively transferred cells were all injected into the tail vein. In addition, solution or cell injection was performed simultaneously in the above three groups of experiments, and it was recorded as day 0.
  • mice in each group were fed with an aqueous solution containing 2.5% DSS, and then replaced with normal water on day 7.
  • the weight changes and clinical scores of the mice were monitored every day.
  • the mice were killed, and the colons of the mice were isolated, sectioned, stained, and analyzed by flow cytometry to detect inflammation.
  • the two groups of Treg cells pretreated overnight in Example 2 were used for adoptive transfer experiments to intervene in the progression of T cell-induced colitis as drugs. There were three groups in the experiment, all of which induced colitis by adoptively transferring CD45RBhi na ⁇ ve CD4+ T cells to Rag-2 knockout mice.
  • One group adopted CD45RBhi na ⁇ ve CD4+ T cells (CD45.1+) to mice, one group adopted PBS pretreated Treg cells (CD45.2+) and CD45RBhi na ⁇ ve CD4+ T cells (CD45.1+) to mice, and one group adopted Compound C pretreated Treg cells (CD45.2+) and CD45RBhi na ⁇ ve CD4+ T cells (CD45.1+) to mice.
  • adoptive transfer cells were all injected by tail vein, na ⁇ ve CD4+ T cells were initial/na ⁇ ve CD4+ T cells, and CD45.1 and CD45.2 were used to distinguish the different sources of Treg cells and na ⁇ ve CD4+ T cells in the adoptive transfer model, so as to facilitate flow cytometry detection after adoptive transfer.
  • mice The body weight of mice was monitored weekly, and the mice were sacrificed 8 weeks after adoptive transfer to analyze the levels of inflammatory cytokines produced by T cells using flow cytometry.
  • Na ⁇ ve CD4+ T cells from wild-type mice were sorted and cultured in vitro under Th17 polarization conditions.
  • the Th17 polarization conditions used IMDM complete medium, with a mass concentration of 2 ⁇ g/mL for anti-CD3, 2 ⁇ g/mL for anti-CD28, 1 ng/mL for TGF- ⁇ , 30 ng/mL for IL-6, 10 ng/mL for IL-23, 10 ng/mL for IL-1 ⁇ , 10 ⁇ g/mL for anti-IFN- ⁇ , and 10 ⁇ g/mL for anti-IL-4.
  • the cells were treated with 0.5 or 1 ⁇ M Compound C or solvent, and after 72 hours of in vitro differentiation, the expression of IL-17A and Foxp3 in CD4+ T cells was analyzed by flow cytometry.
  • the ⁇ subunit is the catalytic subunit of AMPK and it mainly expresses ⁇ 1 in T cells. Therefore, HA-AMPK- ⁇ 1 and Flag-FOXP3 were overexpressed in HEK293T cells alone or simultaneously. The cells were lysed and the total cell protein was extracted. Then, two-way immunoprecipitation experiments were performed using anti-HA or anti-Flag antibodies, and immunoblotting experiments were performed using the corresponding antibodies.
  • IgG Primary Treg cells were induced and differentiated in vitro to obtain iTreg cells. IgG of the same species was used as an isotype control, and endogenous immunoprecipitation experiments were performed using anti-AMPK- ⁇ 1 antibody.
  • this application starts from the treatment of inflammatory bowel disease, considers the feasibility of selectively targeting AMPK, designs a regulatory T cell and its preparation method, and clarifies the relevant intrinsic mechanism of action.
  • the preparation method can enhance the immunosuppressive effect of regulatory T cells in vitro, inhibit interleukin-17 secretion in regulatory T cells, and promote the expression of forkhead box protein P3 of regulatory T cells.
  • the prepared regulatory T cells can be used as drugs to intervene in the progression of inflammatory bowel disease, and will not adversely affect the metabolism of intestinal cells and intestinal flora, providing an important reference for the prevention and treatment of inflammatory bowel disease.

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Abstract

La présente invention concerne spécifiquement un lymphocyte T régulateur, son procédé de préparation et son application, qui relèvent du domaine de l'immunologie moléculaire. En traitant les lymphocytes Treg in vitro au moyen d'un inhibiteur sélectif de la protéine kinase activée par l'adénosine 5'-monophosphate (composé C), l'effet immunosuppresseur des lymphocytes Treg est renforcé de manière sélective. De plus, grâce au transfert adoptif des lymphocytes Treg, la sécrétion d'interleukine-17 est inhibée, et l'expression d'une protéine forkhead box P3 est favorisée, ce qui constitue une référence pour le traitement des maladies inflammatoires intestinales.
PCT/CN2022/139120 2022-11-25 2022-12-14 Lymphocyte t régulateur et son procédé de préparation Ceased WO2024108691A1 (fr)

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CN202211491903.5A CN118086202A (zh) 2022-11-25 2022-11-25 一种调节性t细胞及其制备方法
CN202211491903.5 2022-11-25

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2013067300A1 (fr) * 2011-11-04 2013-05-10 Glaxosmithkline Intellectual Property (No. 2) Limited Méthode de traitement
AU2015255182A1 (en) * 2010-08-16 2015-11-26 Allergan, Inc Method of activating regulatory t cells with alpha-2b adrenergic receptor agonists
CN113825832A (zh) * 2020-07-28 2021-12-21 浙江大学 一种体外诱导CD4+Foxp3+CD69+Treg的扩增方法及其用途
US20220259561A1 (en) * 2019-05-14 2022-08-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Regulatory t cells targeted by lymphotoxin alpha blocking agent and uses thereof

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2015255182A1 (en) * 2010-08-16 2015-11-26 Allergan, Inc Method of activating regulatory t cells with alpha-2b adrenergic receptor agonists
WO2013067300A1 (fr) * 2011-11-04 2013-05-10 Glaxosmithkline Intellectual Property (No. 2) Limited Méthode de traitement
US20220259561A1 (en) * 2019-05-14 2022-08-18 INSERM (Institut National de la Santé et de la Recherche Médicale) Regulatory t cells targeted by lymphotoxin alpha blocking agent and uses thereof
CN113825832A (zh) * 2020-07-28 2021-12-21 浙江大学 一种体外诱导CD4+Foxp3+CD69+Treg的扩增方法及其用途

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
RAO ENYU, ZHANG YUWEN; LI QIANG; HAO JIAQING; EGILMEZ NEJAT K; SUTTLES JILL; LI BING: "AMPK-dependent and independent effects of AICAR and compound C on T-cell responses", ONCOTARGET, vol. 7, no. 23, 10 May 2016 (2016-05-10), pages 33783 - 33795, XP093173216 *
YOSHIOKA, Y. ET AL.: "Differential effects of inhibition of bone morphogenic protein (BMP) signalling on T-cell activation and differentiation", EUR. J. IMMUNOL., vol. 42, 20 December 2011 (2011-12-20), pages 749 - 759, XP071226192, DOI: 10.1002/eji.201141702 *

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