WO2014038864A1 - Composition pour la prévention et le traitement de maladies immunitaires à l'aide de cellules dérivées du cartilage foetal humain - Google Patents

Composition pour la prévention et le traitement de maladies immunitaires à l'aide de cellules dérivées du cartilage foetal humain Download PDF

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WO2014038864A1
WO2014038864A1 PCT/KR2013/008016 KR2013008016W WO2014038864A1 WO 2014038864 A1 WO2014038864 A1 WO 2014038864A1 KR 2013008016 W KR2013008016 W KR 2013008016W WO 2014038864 A1 WO2014038864 A1 WO 2014038864A1
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cells
immune
derived
fetal
derived cells
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PCT/KR2013/008016
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English (en)
Korean (ko)
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민병현
박소라
이수정
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아주대학교산학협력단
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Priority claimed from KR1020130106091A external-priority patent/KR101536815B1/ko
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    • 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
    • A61K35/32—Bones; Osteocytes; Osteoblasts; Tendons; Tenocytes; Teeth; Odontoblasts; Cartilage; Chondrocytes; Synovial membrane
    • 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

Definitions

  • the present invention relates to a novel immunomodulatory composition for regenerating damaged tissues, and to a composition for the prevention and treatment of immune diseases using fetal cartilage-derived cells with superior proliferative power or cell phenotype maintenance than known adult stem cells.
  • Adult stem cells are stem cells capable of differentiation into ground, cartilage, bone, muscle cells, etc., and are highly proliferated and have high clinical value for tissue regeneration.
  • certain adult stem cells such as mesenchymal stem cells, have immunosuppressive ability without causing an immune response. (Placenta-Derived Multipotent Cells Exhibit Immunosuppressive Properties That Are Enhanced in the Presence of Interferon- ⁇ , STEM CELLS, 2006), but there are no reports on stem cells with immunomodulatory capacity.
  • Immunomodulators known as drugs that enhance the immune function of living organisms, enhance the immune function of cancer patients by using immunostimulators in the treatment based on the immunological background of cancer patients who have proven to be impaired in immune response at various stages. So-called nonspecific immunotherapy, which also induces immunity against, has been widely practiced. In the case of using live bacteria, cell wall skeleton (CWS) is frequently used as a purified cell component because of its stability and side effects. Immunomodulators are mainly used for cancer treatment.
  • CWS cell wall skeleton
  • An object of the present invention is to provide a composition for the prevention or treatment of immune diseases using fetal cartilage-derived cells that can suppress the proliferation of activated lymphocytes without causing an immune response.
  • the present inventors have found that cells isolated from fetal chondrocytes can overcome the limitations of existing stem cells by regulating the immune response that may occur during transplantation with regeneration of damaged tissue. It has led to the development of immunomodulatory compositions that can be used as an alternative.
  • the present invention provides a composition for the prevention or treatment of immune diseases containing fetal cartilage-derived cells as an active ingredient.
  • the fetal chondrocyte-derived cells may express the surface antigen proteins of stem cells, and in one embodiment, the fetal chondrocyte-derived cells express CD29, CD44, CD90 and CD105, which are specific surface antigens of adult bone marrow-derived mesenchymal stem cells. In addition, embryonic stem cell-specific surface antigens can express SSEA4 and Oct-4.
  • the fetal cartilage-derived cells can control the expression of immune cytokines produced in activated lymphocytes.
  • the fetal cartilage-derived cells can inhibit the expression of TNF- ⁇ , IL-13, IFN- ⁇ related to immune or inflammatory responses.
  • the fetal cartilage-derived cells can modulate immune activity by not affecting or increasing the expression of anti-inflammatory cytokine IL-10.
  • the immunomodulatory composition may include fetal cartilage-derived cell extracts or secreted molecules.
  • the fetal cartilage-derived cells are (a) separating and culturing chondrocytes from fetal cartilage tissue; (b) separating the cells expressing the surface antigen proteins of the stem cells from the cells cultured in step (a); And (c) it can be obtained through the step of verifying the proliferation capacity and multi-differentiation capacity of the cells isolated in step (b) through fetal cartilage derived stem cells.
  • the immunomodulation of fetal cartilage-derived cells is (a) a method for analyzing the proliferation of lymphocytes for cells when cultured together with cells isolated from fetal cartilage tissue and lymphocytes isolated from allogeneic whole blood, and (b) interferon known as immunointerferon. Analysis of the characteristics of cells isolated from fetal chondrocytes reacted with gamma, or (c) to determine the immunoregulatory cytokines secreted during the culturing in step (a) or one or more of the methods. Can be.
  • Fetal cartilage-derived cells according to the present invention do not cause an immune response, but rather have the property of inhibiting the proliferation of activated lymphocytes and controlling the expression of immune cytokines produced in the activated lymphocytes, and proliferating ability and various cell tissues.
  • the differentiation ability of is superior to that of adult stem cells, and can be usefully used as an immunomodulator to control the immune response that may occur during transplantation with regeneration of damaged tissues.
  • fetal cartilage-derived cells do not induce an immune response as a result of analyzing the proliferation of lymphocytes after mixed culture of lymphocytes isolated from fetal cartilage-derived cells and allogeneic blood that inhibited proliferation.
  • Figure 2 shows that fetal chondrocyte-derived cells and adult chondrocytes that inhibited proliferation were treated with mixed lymphocyte reactions using ConA, respectively, and the proliferation of lymphocytes was analyzed. Is to show.
  • Figure 3 shows the immunogenicity of fetal cartilage-derived cells with or without interferon stimulation by flow cytometry shows that the fetal cartilage-derived cells are not activated by interferon gamma (IFN- ⁇ ).
  • IFN- ⁇ interferon gamma
  • Figure 5 shows the mitigating effect of fetal cartilage-derived cells using an animal model.
  • the present invention provides a composition for the prevention or treatment of immune diseases using fetal cartilage tissue-derived cells as an active ingredient that can overcome the limitations of the existing stem cells by regulating the immune response that may occur during transplantation with damaged tissue regeneration. do.
  • the composition for the prevention or treatment of clinically available immune diseases was confirmed by confirming that the immune control ability was not caused. to provide.
  • the fetal cartilage-derived cells are (a) confirming the proliferation of lymphocytes to cells when cultured together with cells isolated from fetal chondrocytes and lymphocytes isolated from allogeneic whole blood, or (b) reacted with interferon gamma known as immunointerferon.
  • the immunomodulatory function can be confirmed by analyzing the characteristics of the cells isolated from fetal cartilage tissue, or (c) identifying the immunoregulatory cytokines secreted during the culturing in step (a). Analysis of whether the immunomodulatory function of can be analyzed by conventional methods known to those skilled in the art, so is not limited thereto.
  • the fetal cartilage-derived cells can express the bone marrow-derived mesenchymal stem cell-specific surface antigens CD29, CD44, CD90, and CD105 in adults, while expressing the embryonic stem cell-specific surface antigens SSEA4 and Oct-4.
  • the fetal cartilage-derived cells are (a) separating and culturing chondrocytes from fetal cartilage tissue; (b) separating the cells expressing the surface antigen proteins of the stem cells from the cells cultured in step (a); And (c) it can be obtained through the step of verifying the proliferation capacity and multi-differentiation capacity of the cells isolated in step (b) through fetal cartilage derived stem cells.
  • Chondrocytes isolated from fetal chondrocytes can be obtained from 12-15 weeks of aborted fetus using collagenase (Collagenase) or obtained through trituration.
  • the fetal chondrocyte-derived cells may express the surface antigen proteins of stem cells, and in one embodiment, the fetal chondrocyte-derived cells express CD29, CD44, CD90 and CD105, which are specific surface antigens of adult bone marrow-derived mesenchymal stem cells. In addition, embryonic stem cell-specific surface antigens can express SSEA4 and Oct-4.
  • the fetal cartilage-derived cells can control the expression of immune cytokines produced in activated lymphocytes. More specifically, the fetal cartilage-derived cells can inhibit the expression of TNF- ⁇ , IL-13, IFN- ⁇ related to immune or inflammatory responses. In addition, the fetal cartilage-derived cells can modulate immune activity by not affecting or increasing the expression of anti-inflammatory cytokine IL-10.
  • the simultaneous expression of the surface antigens of mesenchymal stem cells and the surface antigens of embryonic stem cells in the fetal chondrocyte-derived cells are characterized by Fluorescent-Assisted Cell Sorting (FACS) and Magnetic-Activated Cells. It can be analyzed by immunochemical separation methods including Cell Sorting (MACS) method.
  • FACS Fluorescent-Assisted Cell Sorting
  • MCS Cell Sorting
  • the fetal cartilage-derived cells include musculoskeletal tissue cells, including cartilage, bone, muscle, skin and fat cells; Nerve cell; Hepatocytes; Pancreatic cell; Cardiomyocytes; And it may have a multipotent ability to differentiate into any one of the vascular cells.
  • fetal cartilage-derived cells of the present invention do not stimulate allogeneic lymphocytes, and when lymphocyte activation is induced, the proliferation of lymphocytes is reduced, in particular TNF- ⁇ and IL-13 associated with immune responses.
  • IL-10 which is known as an anti-inflammatory cytokine, inhibits the expression of IFN- [gamma] but does not affect or increase the immune activity.
  • the immunomodulatory composition according to the present invention includes a cell therapeutic agent, but is not limited thereto and may be utilized in various therapeutic forms. Specifically, it may include fetal cartilage-derived cell extracts or secreted molecules. Fetal cartilage-derived cell extracts or secreted molecules may mean any form that can be obtained from fetal cartilage-derived cells, as well as the cells themselves, suspensions or cultures thereof, or concentrates or pastes thereof. It may mean a product, a dry product, a dilution or any product made through metabolism of the cells.
  • the immune disease may be an autoimmune disease, an inflammatory disease and a transplant rejection disease of cells, tissues or organs, and specifically, arthritis, autoimmune hepatitis, rheumatoid arthritis, osteoarthritis, insulin dependent diabetes mellitus, ulcerative colitis, Crohn's disease, Multiple sclerosis, autoimmune myocarditis, scleroderma, myasthenia gravis, multiple myositis / skin myositis, Hashimoto's disease, autoimmune cytopenia, Sjogren's syndrome, vasculitis syndrome, and systemic lupus erythematosus.
  • arthritis autoimmune hepatitis, rheumatoid arthritis, osteoarthritis, insulin dependent diabetes mellitus, ulcerative colitis, Crohn's disease, Multiple sclerosis, autoimmune myocarditis, scleroderma, myasthenia gravis, multiple myositis / skin myositis, Hashimoto's disease
  • composition for preventing or treating immunological diseases of one embodiment of the present invention may be prepared in various mixtures with a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier for example, binders, lubricants, disintegrants, excipients, solubilizers, dispersants, stabilizers, suspending agents, pigments, flavorings and the like can be used in combination as pharmaceutically acceptable carriers.
  • buffers, preservatives, analgesics, solubilizers, isotonic agents, stabilizers and the like can be used in combination.
  • injectables may be prepared in unit dosage ampoules or in multiple dosage forms.
  • bases, excipients, lubricants, preservatives and the like can be used during topical administration.
  • the present invention is not limited thereto, and those skilled in the art may form a composition for preventing or treating the immune disease in various forms, and may include various carriers or additives. I will understand.
  • composition of the present invention can be administered by a variety of routes to mammals, such as rats, mice, livestock, humans. All modes of administration can be expected, for example by oral, rectal or intravenous, intramuscular, subcutaneous, intrauterine dural or intracerebroventricular injection.
  • dosage of the active ingredient in the composition may vary depending on the route of administration, the degree of disease, the age, sex, and weight of the patient, and may be administered once to several times daily.
  • stem cells are cells that have the ability to differentiate into various kinds of body tissues, that is, undifferentiated cells.
  • the stem cells include adult stem cells (multipotent stem cells) such as embryonic stem cells (pluripotent stem cells) that can be made using human embryos, and bone marrow cells that constantly make blood cells. .
  • Embryonic Stem Cell is an embryonic cell less than 14 days old, and can be differentiated into all cells and tissues constituting the human body in the future, 'almighty cell' or 'pluripotent cell' It is called Fertilized eggs form blastocysts through cell division, inside which there is a mass of cells called inner cell masses, which form embryos. When the cells of this inner cell mass are isolated from the blastocyst and cultured, they become embryonic stem cells that do not differentiate but still have differentiation capacity.
  • “Adult Stem Cell” is extracted from umbilical cord blood (umbilical cord blood) or mature adult bone marrow and blood, and the raw material immediately before differentiation into cells of specific organs such as bone, liver, and blood. It's a cell. These include hematopoietic stem cells, mesenchymal stem cells, and neural stem cells, which are in the spotlight of regenerative medicine. In addition, there are stem cells in the liver, epidermis, and pancreas. The adult stem cells are difficult to proliferate and tend to be easily differentiated. Instead, the adult stem cells can be regenerated according to the characteristics of each organ after transplantation by using various types of adult stem cells as well as the regeneration of organs required by actual medicine. It has characteristics that can be.
  • MSC meenchymal stem cells
  • bone bone
  • cartilage cartilage
  • fat fat
  • tendon tendon
  • nerve tissue nerve tissue
  • fibroblast fibroblast
  • multipotent progenitors before they are differentiated into cells of specific organs such as muscle cells.
  • the "cell therapeutic agent” is a medicine (US FDA regulation) used for the purpose of treatment, diagnosis, and prevention of cells and tissues prepared through isolation, culture, and special chewing from humans. It refers to a medicine used for the purpose of treatment, diagnosis, and prevention through a series of actions such as proliferating, selecting, or otherwise changing the biological characteristics of a living autologous, allogeneic, or heterologous cell in vitro.
  • Cell therapy agents are largely classified into somatic cell therapy and stem cell therapy according to the degree of differentiation of cells, and the present invention relates in particular to stem cell therapy.
  • fetal cartilage-derived cells were carried out as described in detail in patent application 2013-0090233 [Fetal Cartilage Tissue-Derived Stem Cell Sources and Cell Therapeutic Agents Comprising the Same]. That is, the collected cartilage tissue is washed several times with phosphate buffered saline (PBS) and finely chopped and cultured with 0.1% collagenase and 1% bovine serum (FBS). After treatment, the cells were left for 12 hours in an incubator at 37 ° C. and 5% CO 2 . Cells isolated by collagenase were washed with a culture medium containing 10% FBS and the method was as follows.
  • PBS phosphate buffered saline
  • FBS bovine serum
  • the cells suspended in the culture medium was centrifuged at 1700 rpm for 10 minutes, the supernatant was removed, the collected cells were obtained, and then suspended again in the culture medium. At this time, after staining some cells with trypan blue (trypan Blue) the cell number was measured using a hemocytometer under an optical microscope.
  • the cells suspended in the culture medium were dispensed into a culture vessel at a concentration of 8 ⁇ 10 4 / cm 2 and then cultured in an incubator at 37 ° C. and 5% CO 2 . Subculture was done when the cells filled 80-90% of the culture vessel.
  • the obtained fetal chondrocyte-derived cells were analyzed by flow cytometry (FACScantoII), and CD29 (Integrin ⁇ 1 chain), CD44, which is widely known as a cell surface factor of bone marrow-derived mesenchymal stem cells.
  • FACScantoII flow cytometry
  • CD29 Integrin ⁇ 1 chain
  • CD44 which is widely known as a cell surface factor of bone marrow-derived mesenchymal stem cells.
  • HA receptor HA receptor
  • CD 90 Thy-1
  • CD105 Endoglin
  • peripheral blood-derived lymphocytes generally used a method of separating lymphocytes from whole blood using Ficoll.
  • lymphocytes isolated from allogeneic blood were divided into 10 5 cells on the same plate and cultured together for 4 days.
  • the ratio of cell division between fetal cartilage-derived cells and lymphocytes was 1: 1000, 1: 100 and 1:10.
  • concanavalin A T cell mitogen
  • 10 ⁇ g / ml was added together with 10 ⁇ g / ml and cultured for 4 days in order to induce activity in the lymphocyte-only group.
  • the suspended lymphocytes and supernatants were collected together and subjected to BrdU assay (Cell proliferation ELISA, BrdU, Roche Diagnostice, Germany).
  • Lymphocytes treated with concanavalin A showed increased proliferation than lymphocytes not treated. It was found that the isolated lymphocytes are normally activated. And it was confirmed that lymphocytes do not proliferate in the group treated with fetal cartilage-derived cells (see FIG. 1). It was determined that fetal cartilage-derived cells do not activate lymphocytes.
  • Isolation and culturing of fetal cartilage-derived cells were performed in the same manner as in the previous example, and the separation of peripheral blood-derived lymphocytes was generally performed using Ficoll to separate lymphocytes from whole blood.
  • lymphocyte proliferation was performed to confirm the inhibition of lymphocyte proliferation of fetal chondrocytes.
  • fetal cartilage-derived cells were treated with gamma rays (3000rad, 5 minutes) to inhibit proliferation, and the cells were divided into 10 3 and 10 4 cells in 96 well plates.
  • lymphocytes isolated from allogeneic blood were dispensed in 10 5 aliquots on the same plate and cultured together for 4 days.
  • the ratio of cell division between fetal cartilage-derived cells and lymphocytes was 1: 100 and 1:10.
  • conkanavalin A T cell mitogen
  • 10 ⁇ g / ml a cell mitogen
  • the suspended lymphocytes and supernatants were collected together and subjected to BrdU assay (Cell proliferation ELISA, BrdU, Roche Diagnostice, Germany).
  • BrdU assay Cell proliferation ELISA, BrdU, Roche Diagnostice, Germany.
  • the adult chondrocytes used as a comparison group were also experimented using the same method.
  • Lymphocytes treated with concanavalin A showed increased proliferation than lymphocytes not treated.
  • the proliferation of lymphocytes decreased as the number of fetal cartilage-derived cells increased (see FIG. 2).
  • Fetal cartilage-derived cells were determined to have properties that could inhibit the proliferation of lymphocytes activated with Concanavalin A.
  • lymphocytes were activated and proliferated in adult chondrocytes. It can be seen that adult chondrocytes do not have the ability to inhibit lymphocyte proliferation.
  • Interferon gamma IFN- ⁇
  • IFN- ⁇ Interferon gamma
  • HLA human leukocyte antigens
  • CD80 CD86 (B7.1, B7.2), which are activated co-stimulatory molecules when inducing signaling to T cells of antigen-presenting cells in the immune response, it was confirmed that there was no change in CD80. (See FIG. 3).
  • fetal cartilage-derived cells do not have antigens that can trigger immune responses and inhibit the proliferation of allogeneic lymphocytes.
  • mixed lymphocyte reaction was performed to confirm the cytokine production of fetal cartilage-derived cells.
  • fetal cartilage-derived cells were treated with gamma rays (3000rad, 5 minutes) to inhibit proliferation, and then divided into 12 well plates with 10 5 and 10 6 cells. After 16 hours, isolated lymphocytes were dispensed for 10 6 minutes. At this time, the ratio of cell division between fetal cartilage-derived cells and lymphocytes was 1:10 and 1: 1.
  • concanavalin A T cell mitogen
  • allogeneic lymphocytes, lymphocytes treated with concanavalin A, and fetal cartilage-derived cells were cultured. After 4 days of culture, the supernatant was collected and centrifuged at 2000 rpm for 5 minutes to remove suspended lymphocytes, and then the supernatant was collected and subjected to cytokine-ELISA analysis (eBioscience, Ready-SET-Go ELISA set).
  • Tumor necrosis factor-alpha (TNF- ⁇ ), a cytokine in acute immune and inflammatory reactions, was produced in the group of lymphocytes activated by concanavalin A, but incubated with fetal cartilage-derived cells. It was confirmed that no generation was made in the group (see FIG. 4 (A)).
  • interleukin-13 IL-13
  • IL-13 interleukin-13
  • IFN- ⁇ immunostimulation gamma
  • Interleukin-10 produced by regulatory T cells or dendritic cells is a cytokine that is used as an anti-inflammatory agent by inducing immune tolerance by inhibiting immune cells that attack autologous tissues.
  • IL-10 Interleukin-10
  • lymphocytes When fetal cartilage-derived cells and lymphocytes were reacted, it was confirmed that the production of interleukin-10 increased as the ratio of fetal cartilage-derived cells increased (see FIG. 4 (D)).
  • Rats of the fetal cartilage-derived cells injected with immunomodulatory capacity were confirmed to have reduced edema by decreasing knee circumference from day 7 (see FIG. 5).
  • the known immunomodulatory agent has a limitation that can not play a role in the treatment of tissue transplantation or tissue regeneration, fetal cartilage-derived cells of the present invention is more proliferative and differentiating ability than adult stem cells, which are widely studied as cell therapy, homogeneous
  • the immunomodulatory composition according to the present invention can be utilized in various therapeutic forms, including cell therapy.

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Abstract

La présente invention concerne une composition pour prévenir ou traiter une maladie immunitaire à l'aide de cellules dérivées du cartilage fœtal humain, capable de bloquer/contrôler la réponse immunitaire à une greffe de tissu. De manière plus spécifique, les cellules dérivées du cartilage fœtal humain ne provoquent pas de réponse immunitaire, mais empêchent la prolifération de lymphocytes activés, régulent l'expression de la cytokine immunitaire générée dans les lymphocytes activés, et présentent une capacité améliorée de prolifération et de différenciation en différents tissus cellulaires par comparaison à des cellules souches adultes, et peuvent ainsi être utiles pour la régénération d'un tissu endommagé et comme agent immunomodulateur pour contrôler la réponse immunitaire à une greffe.
PCT/KR2013/008016 2012-09-05 2013-09-05 Composition pour la prévention et le traitement de maladies immunitaires à l'aide de cellules dérivées du cartilage foetal humain WO2014038864A1 (fr)

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KR10-2012-0097974 2012-09-05
KR20120097974 2012-09-05
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KR1020130106091A KR101536815B1 (ko) 2012-09-05 2013-09-04 태아연골유래 세포를 이용한 면역질환의 예방 및 치료용 조성물

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043401A2 (fr) * 2002-11-13 2004-05-27 Wackvom Limited Technique de preparation de medicaments antiangiogeniques a partir de cartilage et de chondrocytes et methodes d'utilisation
KR20080063406A (ko) * 2005-10-13 2008-07-03 안트로제네시스 코포레이션 태반 줄기세포를 이용한 면역 조절
KR20100084142A (ko) * 2009-01-15 2010-07-23 코아스템(주) 연골줄기세포를 유효성분으로 포함하는 골질환 치료용 또는 항염증용 약제학적 조성물
WO2011064669A2 (fr) * 2009-11-30 2011-06-03 Pluristem Ltd. Cellules adhérentes du placenta et leur utilisation dans le traitement de pathologies

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004043401A2 (fr) * 2002-11-13 2004-05-27 Wackvom Limited Technique de preparation de medicaments antiangiogeniques a partir de cartilage et de chondrocytes et methodes d'utilisation
KR20080063406A (ko) * 2005-10-13 2008-07-03 안트로제네시스 코포레이션 태반 줄기세포를 이용한 면역 조절
KR20100084142A (ko) * 2009-01-15 2010-07-23 코아스템(주) 연골줄기세포를 유효성분으로 포함하는 골질환 치료용 또는 항염증용 약제학적 조성물
WO2011064669A2 (fr) * 2009-11-30 2011-06-03 Pluristem Ltd. Cellules adhérentes du placenta et leur utilisation dans le traitement de pathologies

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
CHANG, C. -J. ET AL.: "Placenta-derived multipotent cells exhibit immunosuppressive properties that are enhanced in the presence of interferon-gamma", STEM CELLS, vol. 24, 2006, pages 2466 - 2477 *

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