WO2002046401A1 - Verwendung von aus embryonalen stammzellen hergeleiteten zellen zur erhöhung der transplantationstoleranz und zur wiederherstellung zerstörten gewebes - Google Patents
Verwendung von aus embryonalen stammzellen hergeleiteten zellen zur erhöhung der transplantationstoleranz und zur wiederherstellung zerstörten gewebes Download PDFInfo
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- WO2002046401A1 WO2002046401A1 PCT/DE2001/004512 DE0104512W WO0246401A1 WO 2002046401 A1 WO2002046401 A1 WO 2002046401A1 DE 0104512 W DE0104512 W DE 0104512W WO 0246401 A1 WO0246401 A1 WO 0246401A1
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- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
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Definitions
- the invention relates to the use of cells from cell lines, which are derived from early embryonic stages, for the donor-specific increase of the transplant tolerance and for the restoration of destroyed tissue. Areas of application of the invention are medicine and the pharmaceutical industry.
- tolerance immune tolerance
- AG specific antigen
- tolerance can be defined as persistent tissue persistence in the absence of a deleterious immune response that can be achieved without ongoing therapeutic intervention.
- tolerance is not an innate characteristic of an individual, but is acquired (Owen, Science 102: 400-401, 1945; Billingham et al., Nature 172: 603-606, 1953). It is also known that the tolerant state that exists at birth changes constantly, especially when the body is confronted with new antigens in the course of life.
- the immune system must be able to tolerate certain "foreign" antigens, such as physiological hormones released during puberty and pregnancy (Fowlkes and Ramsdell, Curr. Opin. Immunol. 5: 873-879, 1993).
- fetal life can develop and survive in a host that is not adapted to major histocompatibility complex (MHC) is another example of nature's ability to distinguish not only between foreign and non-foreign, but also between dangerous and harmless can (Vacchio and Jiang, Grit. Rev. Immunol. 19: 461-480, 1999).
- the invention is based on the object of generating a donor-specific immune tolerance in order to prevent rejection of the transplanted tissue by an immune reaction and thus to be able to restrict the administration of immunosuppressive agents.
- ECL embryonic stem cell-like cell lines
- the use of the cells from the ECLs as "tolerance vectors" is opened by a lack of MHC antigen expression and the associated immunogenic inactivity of the ECL.
- Research has shown that cells from ECLs can be transplanted and survive in the long term, producing hematopoietic cells of different origins.
- these hematopoietic cells derived from ECL have generated a constant mixed chimerism (donor and recipient hematopoietic cells coexist in the same host) and thus create the basis for long-term allograft acceptance. As a result, they can either be used as an ideal means of creating tolerance, or alternatively they can be used in a situation in which the parenchymal injury of a particular organ has to be remedied.
- WKY Wistar Kyoto
- SD Sprague Dawley
- ACI ACI
- WKY blastocysts grew very rapidly, showed strong primary growth, and more than 10% of the embryos achieved permanent cell lines (Table 1).
- SD blastocysts grew with some delay, achieved a moderate number of primary clumps, and the effectiveness of cell line generation was poor.
- ACI blastocysts took the longest time to grow, produced a very small number of primary clumps, and no cell line could be generated by this breed.
- the use of the cells from the cell lines, which were generated from the embryonic stem cells, as "tolerance vectors" to bring about donor-specific immune tolerance also requires the expression of the donor-specific MHC antigens.
- This property is achieved according to the invention in that cells of the ECLs are transfected with the genes of the donor which code for the MHC antigens.
- the administration of the transfected cells e.g. via the portal vein, by intraperitoneal, subcutaneous or intravenous injection.
- Mouse embryo fibroblasts (MEF) or rat embryo fibroblasts (REF) are prepared from 13-14 day pregnant animals that have been mitotically inactivated by 3-5 treatments with mitomycin C (10 ⁇ g / ml) for 2 or 1 hours, washed with phosphate buffered saline ( PBS) and planted in Nunc 4-wells.
- mitomycin C 10 ⁇ g / ml
- PBS phosphate buffered saline
- the blastocysts are flushed with PBS / 20% FCS (fetal calf serum) or a culture medium from the uterus of rats 4.5 days pregnant, planted on inactivated embryo fibroblasts and 3-4 days in DMEM / 15% FCS / 2,500 ⁇ / ml LIF ( "Leukemia inhibiting factor", ESGRO, Life Technologies) with additives (Iannaccone et al, Dev. Biol. 1994; 163: 288-292) left untreated in a medium of 6% CO 2 / air.
- the blastocysts develop and tie themselves to the supplier, and the ICM begins to grow, with the Efficiency depends on the genetic background.
- Outgrowths with an ES-cell-like appearance are picked up and broken up into several lumps by suction in drawn glass capillaries with a somewhat smaller diameter than the outgrowths and applied to fresh supply plates. Picking up and breaking up occurs either daily or every other day. Crumbled colonies are reset in rows until a small number of clean, steadily growing ES-like clumps are obtained. The clump population is then expanded to several dozen, stored in 35 mm dishes and slightly trypsinized into a mixture of individual cells and small aggregates. The rat ES cells produced were passaged every or every other day by trypsinization (0.05% trypsin, 0.02% EDTA-4Na, 1% chicken serum, in Ca / Mg-free PBS). The species identity of the resulting cell lines is checked by PCR using Renin gene primers (Brenin et al., Transplant. Proc. 1997; 29: 1761-1765) in order to rule out contamination by mouse ES cells.
- a first series of experiments examined the fate of a single intraportal injection of WKY-derived 1.0 x 10 6 ECL into allogeneic DA (RTl. Avl ) host rats that had received no immunosuppressive or myeloablative treatment.
- the investigations show that these cells can survive long-term (> 150 days) in DA host rats. It was found that the ECL and its descendants can produce a state of constantly mixed chimerism (hematopoietic cells of the donor and the recipient coexist in the same host). It was also found that these cells differentiate into hematopoietic cells that express class II MHC antigens (Ox-3) and B cell lineage markers (Ox-45).
- the monoclonal antibody (mAb) Ox-3 is a specific antibody of a (WKY) MHC class II donor that binds to class II MHC epitopes that are expressed on WKY but not to DA MHC positive cells class II.
- WB double-stained leukocytes
- Ox-3 + cells were detected histomorphologically (10-15%) in the interstitial space of the recipient (DA) hearts, which were selectively destroyed 100 days after a single intraportal injection of 1.0 x 10 6 ECL derived from WKY (see Fig.l).
- the stable chimeric state of these animals provides the basis for examining the fate of the WKY cardiac allograft transplanted in DA rats seven days after the intraportal ECL injection.
- Kaplan Meier diagrams show that pretreatment of DA rats with 1.0 x 10 6 ECL intraportally and heart transplantation (HTx) seven days later led to long-term (> 150 days) non-rejection allograft acceptance, whereas untreated DA rats caused WKY Reject allografts acutely (see Fig. 2).
- CAP rat heart transplants were rejected from DA rats injected with WKY-ECL within 12.4 ⁇ 1.4 days, demonstrating the immune competence of these rats.
- ECL cells described above assume differentiation into astrocytes or cardiomyocytes and hepatocytes by co-cultivation with somatic cells of neuronal or entodermal origin.
- the embryonic cell lines described are therefore also suitable for the treatment of organ-specific diseases of the central nervous system (e.g. as dopaminergic cells for the treatment of Parkinson's disease, as hepatocytes for the treatment of cirrhosis of the liver or as cardiomyocytes for the treatment of fresh heart attacks).
- organ-specific diseases of the central nervous system e.g. as dopaminergic cells for the treatment of Parkinson's disease, as hepatocytes for the treatment of cirrhosis of the liver or as cardiomyocytes for the treatment of fresh heart attacks.
- the forthcoming isolation of the signal proteins necessary for these specific forms of differentiation is of great clinical importance, since it could enable problem-free programming of the ECLs for the desired cell population.
- the goal is therefore the exact sequencing of these functional proteins in order to enable their recombinant production.
- the large sequence homology between rat and human protein would also provide information on the analog production of human functional proteins.
- the associated therapeutic application possibilities include both the use of the ECL-derived somatic cell lines described above and the functional proteins derived therefrom for future clinical use on all indication levels of tissue engineering for organ replacement, for gene therapy and for the treatment of metabolic diseases in the area of the CNS, the liver and the heart.
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Priority Applications (3)
Application Number | Priority Date | Filing Date | Title |
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US10/433,557 US20040208857A1 (en) | 2000-12-04 | 2001-12-04 | Use of cells derived from embryonic stem cells for increasing transplantation tolerance and for repairing damaged tissue |
JP2002548118A JP2004519437A (ja) | 2000-12-04 | 2001-12-04 | 移植寛容を増進させ、損傷組織を治療する為の胚性幹細胞由来細胞の利用 |
EP01995556A EP1341915A1 (de) | 2000-12-04 | 2001-12-04 | Verwendung von aus embryonalen stammzellen hergeleiteten zellen zur erhöhung der transplantationstoleranz und zur wiederherstellung zerstörten gewebes |
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DE10061334.9 | 2000-12-04 | ||
DE10061334A DE10061334A1 (de) | 2000-12-04 | 2000-12-04 | Verwendung von aus embryonalen Stammzellen hergeleiteten Zellen zur Erhöhung der Transplantationstoleranz und zur Wiederherstellung zerstörten Gewebes |
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WO2002046401A1 true WO2002046401A1 (de) | 2002-06-13 |
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PCT/DE2001/004512 WO2002046401A1 (de) | 2000-12-04 | 2001-12-04 | Verwendung von aus embryonalen stammzellen hergeleiteten zellen zur erhöhung der transplantationstoleranz und zur wiederherstellung zerstörten gewebes |
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US (1) | US20040208857A1 (de) |
EP (1) | EP1341915A1 (de) |
JP (1) | JP2004519437A (de) |
DE (1) | DE10061334A1 (de) |
WO (1) | WO2002046401A1 (de) |
Cited By (4)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002044343A2 (en) * | 2000-11-22 | 2002-06-06 | Geron Corporation | Tolerizing allografts of pluripotent stem cells |
EP1576957A1 (de) * | 2004-03-18 | 2005-09-21 | Universiteit Twente | Wiederherstellung zerstörten Gewebes mit Hilfe von pluripotenten Zellen |
GB2412379A (en) * | 2001-12-07 | 2005-09-28 | Geron Corp | Embryonic stem cells to induce immune tolerance and improve allograft acceptance |
US7799324B2 (en) | 2001-12-07 | 2010-09-21 | Geron Corporation | Using undifferentiated embryonic stem cells to control the immune system |
Families Citing this family (3)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US20040224403A1 (en) * | 2001-12-07 | 2004-11-11 | Robarts Research Institute | Reconstituting hematopoietic cell function using human embryonic stem cells |
DE10362002B4 (de) | 2003-06-23 | 2006-10-12 | Fraunhofer-Gesellschaft zur Förderung der angewandten Forschung e.V. | Adulte pluripotente Stammzellen |
WO2018139502A1 (ja) | 2017-01-25 | 2018-08-02 | 国立大学法人 東京大学 | キメラ動物における出生後の炎症の発見とその治療 |
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WO1997006241A1 (en) * | 1995-08-04 | 1997-02-20 | The General Hospital Corporation | Transgenic swine and swine cells having human hla genes |
WO1998037098A1 (fr) * | 1997-02-21 | 1998-08-27 | Commissariat A L'energie Atomique | Cellules eucaryotes exprimant a leur surface au moins une isoforme d'hla-g et leurs applications |
WO1998042838A1 (en) * | 1997-03-25 | 1998-10-01 | Morphogenesis, Inc. | Universal stem cells |
WO2000012682A1 (en) * | 1998-09-01 | 2000-03-09 | Wisconsin Alumni Research Foundation | Primate embryonic stem cells with compatible histocompatibility genes |
Family Cites Families (1)
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US7544355B2 (en) * | 2002-03-13 | 2009-06-09 | Universita Degli Studi Di Perugia | Methods and compositions for allogeneic transplantation |
-
2000
- 2000-12-04 DE DE10061334A patent/DE10061334A1/de not_active Withdrawn
-
2001
- 2001-12-04 EP EP01995556A patent/EP1341915A1/de not_active Withdrawn
- 2001-12-04 WO PCT/DE2001/004512 patent/WO2002046401A1/de active Application Filing
- 2001-12-04 JP JP2002548118A patent/JP2004519437A/ja active Pending
- 2001-12-04 US US10/433,557 patent/US20040208857A1/en not_active Abandoned
Patent Citations (4)
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WO1997006241A1 (en) * | 1995-08-04 | 1997-02-20 | The General Hospital Corporation | Transgenic swine and swine cells having human hla genes |
WO1998037098A1 (fr) * | 1997-02-21 | 1998-08-27 | Commissariat A L'energie Atomique | Cellules eucaryotes exprimant a leur surface au moins une isoforme d'hla-g et leurs applications |
WO1998042838A1 (en) * | 1997-03-25 | 1998-10-01 | Morphogenesis, Inc. | Universal stem cells |
WO2000012682A1 (en) * | 1998-09-01 | 2000-03-09 | Wisconsin Alumni Research Foundation | Primate embryonic stem cells with compatible histocompatibility genes |
Non-Patent Citations (4)
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C.A. HEATH: "Cells for tissue engineering", TRENDS IN BIOTECHNOLOGY, vol. 18, no. 1, January 2000 (2000-01-01), pages 17 - 19, XP002197365 * |
J. GEARHART: "New potential for human embryonic stem cells", SCIENCE, vol. 282, no. 5391, 6 November 1998 (1998-11-06), pages 1061 - 1062, XP000941387 * |
R.B. MANNON ET AL.,: "Gene targeting : Applications in transplantation research", KIDNEY INTERNATIONAL, vol. 56, no. 1, July 1999 (1999-07-01), pages 18 - 27, XP002197366 * |
W. WONG ET AL.,: "Haematopoietic stem cells transduced with a single donor class I histocompatibility complex gene can induce operational tolerance to fully allogeneic cardiac allografts", TRANSPLANTATION PROCEEDINGS, vol. 31, no. 1-2, February 1999 (1999-02-01) - March 1999 (1999-03-01), pages 886, XP001063290 * |
Cited By (13)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO2002044343A2 (en) * | 2000-11-22 | 2002-06-06 | Geron Corporation | Tolerizing allografts of pluripotent stem cells |
WO2002044343A3 (en) * | 2000-11-22 | 2003-01-16 | Geron Corp | Tolerizing allografts of pluripotent stem cells |
GB2386125A (en) * | 2000-11-22 | 2003-09-10 | Geron Corp | Tolerizing allografts of pluripotent stem cells |
GB2386125B (en) * | 2000-11-22 | 2005-02-23 | Geron Corp | Tolerizing allografts of pluripotent stem cells |
EP1757681A1 (de) * | 2000-11-22 | 2007-02-28 | Geron Corporation | Toleranz-induzierende Allotransplantate aus pluripotenten Stammzellen |
GB2412379A (en) * | 2001-12-07 | 2005-09-28 | Geron Corp | Embryonic stem cells to induce immune tolerance and improve allograft acceptance |
GB2412379B (en) * | 2001-12-07 | 2006-03-29 | Geron Corp | Hematopoietic cells from human embryonic stem cells |
US7799324B2 (en) | 2001-12-07 | 2010-09-21 | Geron Corporation | Using undifferentiated embryonic stem cells to control the immune system |
WO2005087239A1 (en) * | 2004-03-18 | 2005-09-22 | Cellcotec B.V | Tissue repair with multipotent cells |
EP1576957A1 (de) * | 2004-03-18 | 2005-09-21 | Universiteit Twente | Wiederherstellung zerstörten Gewebes mit Hilfe von pluripotenten Zellen |
EP1970068A1 (de) * | 2004-03-18 | 2008-09-17 | CellCoTec B.V. | Wiederherstellung zerstörten Gewebes mit Hilfe von multipotenten Zellen |
US8048671B2 (en) | 2004-03-18 | 2011-11-01 | Cellcotec B.V. | Tissue repair with multipotent cells |
US8796019B2 (en) | 2004-03-18 | 2014-08-05 | Cellcotec B.V. | Tissue repair with multipotent cells |
Also Published As
Publication number | Publication date |
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JP2004519437A (ja) | 2004-07-02 |
US20040208857A1 (en) | 2004-10-21 |
DE10061334A1 (de) | 2002-06-13 |
EP1341915A1 (de) | 2003-09-10 |
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