EP0484512A4 - Human peripheral blood cells in an immunocompromised host - Google Patents
Human peripheral blood cells in an immunocompromised hostInfo
- Publication number
- EP0484512A4 EP0484512A4 EP19910911224 EP91911224A EP0484512A4 EP 0484512 A4 EP0484512 A4 EP 0484512A4 EP 19910911224 EP19910911224 EP 19910911224 EP 91911224 A EP91911224 A EP 91911224A EP 0484512 A4 EP0484512 A4 EP 0484512A4
- Authority
- EP
- European Patent Office
- Prior art keywords
- host
- human
- bone marrow
- cells
- murine
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Withdrawn
Links
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0271—Chimeric vertebrates, e.g. comprising exogenous cells
-
- 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
- A61K35/26—Lymph; Lymph nodes; Thymus; Spleen; Splenocytes; Thymocytes
-
- 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
- A61K35/28—Bone marrow; Haematopoietic stem cells; Mesenchymal stem cells of any origin, e.g. adipose-derived stem cells
-
- 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
- A61K35/37—Digestive system
- A61K35/407—Liver; Hepatocytes
-
- 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
- A61P37/04—Immunostimulants
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2227/00—Animals characterised by species
- A01K2227/10—Mammal
- A01K2227/105—Murine
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K2267/00—Animals characterised by purpose
- A01K2267/03—Animal model, e.g. for test or diseases
-
- A—HUMAN NECESSITIES
- A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
- A01K—ANIMAL HUSBANDRY; AVICULTURE; APICULTURE; PISCICULTURE; FISHING; REARING OR BREEDING ANIMALS, NOT OTHERWISE PROVIDED FOR; NEW BREEDS OF ANIMALS
- A01K67/00—Rearing or breeding animals, not otherwise provided for; New or modified breeds of animals
- A01K67/027—New or modified breeds of vertebrates
- A01K67/0275—Genetically modified vertebrates, e.g. transgenic
- A01K67/0276—Knock-out vertebrates
Definitions
- the field of this invention is the production of human hematopoietic cells.
- peripheral blood cells it would be desirable to have a relatively high proportion of the peripheral blood cells as human cells' and desirably have a significant proportion of the total number of hematopoietic cells being human cells. Further, it would be desirable to have circulatory myelomonocytic cells and red blood cells, besides lymphoid cells.
- Xenogeneic bone marrow is introduced into an endogenous bone marrow depleted genetically immunocompromised mammalian host, where the bone marrow may be present as bone tissue or dispersed bone marrow, particularly from a fetal source.
- the fetal bone tissue may be conveniently introduced into the peritoneal cavity or the bone marrow may be injected into the long bone of the immunocompromised host.
- Non-human mammals particularly small mammals under 25kg, are provided having human peripheral blood cells present as at least two percent (2%) of the total peripheral blood cells, preferably at least five percent (5%) of the total peripheral blood cells and more preferably at least about fifteen percent (15%) .
- the enhanced level of human cells may be achieved by depletion of endogenous bone marrow, particularly stem cells, conveniently by irradiating the host with at least a sublethal dosage of radiation, generally being at least about 200 rad and varying with the size and nature of the host.
- the blood cells are then reconstituted with human bone marrow, conveniently as human bone or bone marrow cell suspensions, particularly from a fetal source.
- the human bone marrow source may be introduced before and after ablation to enhance the survival rate of the host upon ablation, particularly by irradiation.
- Various immunocompromised hosts may be employed, where the host being immunocompromised is as a result of a natural mutation, breeding, transformation of embryonic cells to provide a transgenic mouse, or the like.
- hosts which lack a functional lymphoid lineage The lack of the immune system may be as a result of a lack of a particular organ, a genetic defect, such as an incompetent reco binase or regulatory gene regulating the expression of the recombinase, transport of slg and T cell receptors to the surface, non-functional major histocompatibility antigens, or the like.
- CB-17 scid/scid mice and mice derived therefrom which may have further enhanced immunodeficiency, e.g. lack of natural killer (NK) cells.
- the host is irradiated or treated in any convenient manner to substantially ablate the endogenous bone marrow.
- X-irradiation may be employed where the level of radiation will be selected to provide at least substantially complete ablation of the hematopoietic cell system, while maintaining a reasonable, preferably a high, proportion of viable hosts. With each type of host, the particular level of irradiation may be selected by screening for the level of remaining viable hematopoietic cells for the efficiency of the ablation.
- Other techniques for bone marrow ablation which may be employed by themselves or in combination include cytotoxic drugs, immunotoxins, antibodies to lymphokines and growth factors, antibodies to natural killer cells, etc. The selection of cytotoxic drugs would be based on their ability to clear quickly from the lymphatic and blood circulatory systems, so as to rapidly be reduced to a non-cytotoxic level, prior to or shortly after the administration of the human bone marrow.
- the human bone marrow will normally be fetal bone marrow and may be employed as bone marrow slices, fragments, chunks, or the like, coming from various parts of the fetus, such as the femur, tibia, humerus or rib.
- the longest dimensions of human bone will generally be in the size range of about 8mm to 2cm, where the bone may be fragmented along the long axis, usually in not more than about four parts.
- the total volume of fetal bone which is introduced into the host will vary with the size of the host. For mice, the volume will generally be in the range of about 40mm 3 to 1,200mm 3 .
- human fetal bone marrow cell suspensions may be injected into long bones, such as the femur or tibia.
- long bones such as the femur or tibia.
- the volume of the bone marrow suspension will be in the range of about 10ml to 50ml for a mouse.
- the age of the host will generally be at least neonatal and usually not more than about six months, more usually not more than three months.
- the particular age is not critical to this invention, but younger animals are more convenient to handle and are more economical.
- the site of introduction of the fetal bone portions may be interperitoneal, subcutaneous, mammary fat pad, or other convenient site.
- the host After introduction of the bone marrow, the host is grown in accordance with conventional ways, feeding the host as appropriate, either with or without the presence of antibiotics in the feed. Conveniently, about 0.2% to 1.2% of sulfamethoxazole/trimethoprim (Septra) may be provided in the feed. As appropriate, additional introductions of the human fetal bone marrow may be made, usually not more than about two additional explants, generally at four to twenty week intervals.
- the host may receive a variety of growth factors and cytokines, either native to the host or human. Interleukins, colony stimulating factors, hormones, or the like may be added, such as IL-1, IL-3, IL-6, and G-CSF. Generally, the amount of the additive will vary, depending upon the particular additive, the host, and the like. For example, in the case of IL-3 0.5 - 5 ⁇ g/day may be administered. In the subject host, it is found that the bone tissue shows variable cellularity from 10 to 80%.
- the human cells comprise a significant proportion of the blood cells in circulation in the peripheral blood. The cells may include members of the lymphoid, myelomonocytic and erythroid lineages.
- the cells may be detected by employing a wide variety of antibodies which are commercially available for the detection of human markers on blood cells, such as CD-3, -A , -8, -10, -13, -15, -19, -20, -33, -41, -45, -59, HLA, or the like.
- a blood sample may be taken and assayed employing a fluorescence activated cell sorter.
- the cells may be lysed and a Western blot employed.
- Other techniques which may find use for the quantitative determination of a particular cell type include the polymerase chain reaction, gel electrophoresis, HPLC, or the like.
- lymph node In addition to the bone marrow, other human organs may also be present, particularly thy us, lymph node, skin, liver, pancreas, tonsil, appendix, epithelium, kidney, etc.
- One or more mesenteric or peripheral lymph nodes may be introduced.
- the various organs may be introduced conveniently in the kidney capsule, mammary fat pad, particularly the fourth mammary fat pad for a mouse, the popliteal fossa, or other convenient site where the organ may be vascularized, lymphatic vessels connected and maintained by the host for a reasonable period of time, usually at least four weeks, preferably at least six weeks.
- the subject host may find a wide variety of uses by virtue of the significant presence of circulating human blood cells in the non-human host.
- the host may be employed for the production of human monoclonal antibodies or immortalized T lymphocytes.
- the host may be immunized in accordance with conventional ways with an appropriate immunogen, which may be injected intravascularly at an appropriate site. Of particular interest is injection at a site which is drained by a human lymph node introduced into the host.
- the immunized host may receive one or more booster shots, followed by removal of a lymphoid organ, e.g. lymph node, followed by immortalization, conveniently by fusion with an appropriate yeloid cell or transfection with Epstein-Barr virus.
- the cells may be cloned by any convenient means, at limiting dilution to provide for individual clones, and the supernatants of the individual clones may be screened for the binding affinity of the antibodies present in the host.
- the host may be used for studying T and B lymphocyte interactions, in determining the manner of stimulation of T and B lymphocytes and the mechanism for the immune reaction.
- Individual lymphocytes may be cloned to evaluate their role in disease protection against disease, identify slg or T cell receptor variable regions, isolate the DNA encoding the variable regions, or the like.
- Various immunogens may be screened for their abilities as vaccines in producing antibodies which may be effective in neutralizing pathogens and the cells or DNA provide a source of the variable regions associated with the response.
- Pathogens of interest are those particularly associated with humans, such as HIV, HTLV-I, and - II, human papilloma virus, cytomegalovirus, Epstein- Barr virus, hepatitis B virus, non-A, non-B hepatitis, chlamydia, malaria (Falciparum) etc.
- the subject system may be used in the study of cancer in attempting to develop cytotoxic cells specific for a particular cancer type.
- mice were transplanted into either untreated mice (6-10 weeks old) or mice (6-10 weeks old) pre-treated with radiation from a cesium 137 source.
- the mice are treated with either whole body irradiation or irradiation of the long bones.
- Mice treated with whole body irradiation receive 200 to 400 rads on a single dose.
- the mice are treated with 600 rads after shielding of the thorax and abdomen with a lead shield.
- the mice are anesthetized with Nembutol prior to shielded irradiation.
- the mice were CB-17.5 scid/scid mice.
- some of the mice were treated with exogenous human IL-3 in two l ⁇ g doses per day.
- the percentage of human cells in the peripheral blood is determined by employing monoclonal antibodies specific for human hematopoietic cell markers.
- a low level of human cells is observed in the peripheral blood by FACScan.
- the positive cells vary from about 0 - 1.6 percent.
- injection of IL-3 does not significantly affect the percentage of positive cells.
- the mice irradiated before marrow transplantation showed between 1.5 and 30 percent human cells in the peripheral blood. These cells appear to be of the myelomonocytic lineage. They show no staining with T or B cell markers (CD 3, 4, 8, 19), although they do stain for the myeloid cell marker (CD33) .
- the human cells have a high side scatter profile indicating that they are of the myelomonocytic lineage.
- two of the four mice which were irradiated before implantation show low but significant levels of serum immunoglobulin after six weeks.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Immunology (AREA)
- Chemical & Material Sciences (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Cell Biology (AREA)
- General Health & Medical Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Engineering & Computer Science (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Zoology (AREA)
- Developmental Biology & Embryology (AREA)
- Epidemiology (AREA)
- Organic Chemistry (AREA)
- Virology (AREA)
- Biotechnology (AREA)
- Biomedical Technology (AREA)
- Environmental Sciences (AREA)
- Molecular Biology (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nutrition Science (AREA)
- Biodiversity & Conservation Biology (AREA)
- Animal Husbandry (AREA)
- Proteomics, Peptides & Aminoacids (AREA)
- Genetics & Genomics (AREA)
- Biophysics (AREA)
- Biochemistry (AREA)
- Physiology (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Hematology (AREA)
- Medicines Containing Material From Animals Or Micro-Organisms (AREA)
- Micro-Organisms Or Cultivation Processes Thereof (AREA)
- External Artificial Organs (AREA)
Abstract
Description
Claims
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US52921790A | 1990-05-25 | 1990-05-25 | |
US529217 | 1990-05-25 |
Publications (2)
Publication Number | Publication Date |
---|---|
EP0484512A1 EP0484512A1 (en) | 1992-05-13 |
EP0484512A4 true EP0484512A4 (en) | 1993-05-05 |
Family
ID=24108994
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
EP19910911224 Withdrawn EP0484512A4 (en) | 1990-05-25 | 1991-05-13 | Human peripheral blood cells in an immunocompromised host |
Country Status (4)
Country | Link |
---|---|
EP (1) | EP0484512A4 (en) |
JP (1) | JPH05500617A (en) |
CA (1) | CA2064075A1 (en) |
WO (1) | WO1991018615A1 (en) |
Families Citing this family (17)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US5652373A (en) * | 1990-01-15 | 1997-07-29 | Yeda Research And Development Co. Ltd. | Engraftment and development of xenogeneic cells in normal mammals having reconstituted hematopoetic deficient immune systems |
US5849288A (en) * | 1990-01-15 | 1998-12-15 | Yeda Research And Development Co. Ltd. | Method for production of monoclonal antibodies in chimeric mice or rats having xenogeneic antibody-producing cells |
CA2063408A1 (en) * | 1990-05-03 | 1991-11-04 | Susan Mayo | Human lymphoid tissue in an immunocompromised host |
US5804160A (en) * | 1991-06-04 | 1998-09-08 | Yeda Research And Development Co. Ltd | Animal model for hepatitis virus infection |
US5858328A (en) * | 1991-06-04 | 1999-01-12 | Yeda Research And Development Co. Ltd. | Animal model for hepatitis virus infection |
US5849987A (en) * | 1992-06-02 | 1998-12-15 | Yeda Research And Development Co. Ltd. | Animal model for hepatitis virus infection |
EP0539970B1 (en) * | 1991-10-30 | 1999-05-26 | Idemitsu Kosan Company Limited | Methods for producing human lymphocytes and human monoclonal antibodies, and human monoclonal antibodies produced thereby |
US6353150B1 (en) * | 1991-11-22 | 2002-03-05 | Hsc Research And Development Limited Partnership | Chimeric mammals with human hematopoietic cells |
US5866757A (en) * | 1992-06-02 | 1999-02-02 | Yeda Research And Development Co. Ltd. | Engraftment and development of xenogeneic cells in normal mammals having reconstituted hematopoetic deficient immune systems |
EP0659046A1 (en) * | 1992-09-11 | 1995-06-28 | The Regents of The University of Michigan | Non-human animal with xenograft of on airway populated by human cells |
ATE221382T1 (en) * | 1993-05-24 | 2002-08-15 | Ximerex Inc | THE GENERATION OF TOLERANCE AGAINST FOREIGN TRANSPLANTS THROUGH TOLEROGENESIS WITH THE HELP OF SUBSTITUTE LIVING BEINGS |
DK2485583T3 (en) | 2009-10-06 | 2016-10-03 | Regeneron Pharma | GENETICALLY MODIFIED MICE AND inoculation |
EP4233537A3 (en) | 2011-02-15 | 2023-09-13 | Regeneron Pharmaceuticals, Inc. | Humanized m-csf mice and uses thereof |
CN108782459B (en) | 2012-09-07 | 2021-11-05 | 再生元制药公司 | Genetically modified non-human animals and methods of use thereof |
EP3556206B1 (en) | 2012-11-05 | 2021-06-02 | Regeneron Pharmaceuticals, Inc. | Genetically modified non-human animals and methods of use thereof |
MX2016014995A (en) | 2014-05-19 | 2017-03-31 | Regeneron Pharma | Genetically modified non-human animals expressing human epo. |
RU2730599C2 (en) | 2015-04-13 | 2020-08-24 | Ридженерон Фармасьютикалз, Инк. | Humanised mice with sirpa-il15 nokin and methods for using them |
Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0322240A2 (en) * | 1987-12-23 | 1989-06-28 | The Board Of Trustees Of The Leland Stanford Junior University | Chimeric immunocompromised mammals and their use |
WO1989012823A1 (en) * | 1988-06-14 | 1989-12-28 | Medical Biology Institute | Human immune system in non-human animal |
-
1991
- 1991-05-13 EP EP19910911224 patent/EP0484512A4/en not_active Withdrawn
- 1991-05-13 CA CA002064075A patent/CA2064075A1/en not_active Abandoned
- 1991-05-13 JP JP3510612A patent/JPH05500617A/en active Pending
- 1991-05-13 WO PCT/US1991/003306 patent/WO1991018615A1/en not_active Application Discontinuation
Patent Citations (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0322240A2 (en) * | 1987-12-23 | 1989-06-28 | The Board Of Trustees Of The Leland Stanford Junior University | Chimeric immunocompromised mammals and their use |
WO1989012823A1 (en) * | 1988-06-14 | 1989-12-28 | Medical Biology Institute | Human immune system in non-human animal |
Non-Patent Citations (3)
Title |
---|
BLOOD vol. 74, no. 5, October 1989, USA, pages 1537 - 1544 FULOP, G.M. & PHILIPS, R.A. 'Use of scid mice to identify and quantitate lymphoid-restricted stem cells in long-term bone marrow cultures' * |
SCIENCE vol. 241, 23 September 1988, LANCASTER, PA US pages 1581 - 1583 YANCOPOULOS, G.D. & ALT, F.W. 'Reconstruction of an immune system' * |
See also references of WO9118615A1 * |
Also Published As
Publication number | Publication date |
---|---|
JPH05500617A (en) | 1993-02-12 |
WO1991018615A1 (en) | 1991-12-12 |
EP0484512A1 (en) | 1992-05-13 |
CA2064075A1 (en) | 1991-11-26 |
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