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WO1996031233A1 - Emploi de la gelatinase b et d'enzymes apparentees pour mobiliser les cellules souches hematopoietiques en vue de transplanter des cellules souches sanguines - Google Patents

Emploi de la gelatinase b et d'enzymes apparentees pour mobiliser les cellules souches hematopoietiques en vue de transplanter des cellules souches sanguines Download PDF

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Publication number
WO1996031233A1
WO1996031233A1 PCT/NL1996/000149 NL9600149W WO9631233A1 WO 1996031233 A1 WO1996031233 A1 WO 1996031233A1 NL 9600149 W NL9600149 W NL 9600149W WO 9631233 A1 WO9631233 A1 WO 9631233A1
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gelatinase
stem cells
blood
cells
enzyme
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PCT/NL1996/000149
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English (en)
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Ghislain Marie-Mathieu Opdenakker
Willem Eduard Fibbe
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Rijksuniversiteit Leiden
Stichting Rega V.Z.W.
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Priority to AU51265/96A priority Critical patent/AU5126596A/en
Publication of WO1996031233A1 publication Critical patent/WO1996031233A1/fr

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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
    • A61K35/28—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
    • A61K35/20—Milk; Whey; Colostrum
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/43—Enzymes; Proenzymes; Derivatives thereof
    • A61K38/46—Hydrolases (3)
    • A61K38/48—Hydrolases (3) acting on peptide bonds (3.4)
    • A61K38/4886—Metalloendopeptidases (3.4.24), e.g. collagenase

Definitions

  • the invention is in the field of blood stem cell and/or progenitor cell transplantation and more in particular relates to a method to rapidly mobilize (hematopoietic) stem cells from bone marrow to blood with the purpose of harvesting these cells and using them for blood stem/progenitor cell transplantation into recipients that have received lethal chemotherapy and/or radiotherapy.
  • chemotherapeutic agents and radiotherapeutic regimens have resulted in a successful treatment of a variety of malignant disorders.
  • the most successful chemo- therapeutic regimens rely on combinations of agents that have different modes of action.
  • transfusions of platelets are given to prevent bleeding and patients are treated with non absorbable antibiotics to prevent systemic infections.
  • non absorbable antibiotics to prevent systemic infections.
  • the more intensive chemotherapeutic regimens are associated with prolonged episodes of bone marrow depression.
  • the above supportive measures are insufficient to prevent complications .
  • Very intensive chemotherapy regimens or combinations of chemotherapy and radiotherapy may result in cure of the tumor.
  • the side effects of these regimens may include permanent and complete loss of bone marrow function.
  • these patients need to be transplanted with (hemato ⁇ poietic) stem cells.
  • Transplanted stem cells are able to rapidly engraft the host, resulting in protection against the lethal complications of radiation or myeloablative chemotherapy. Another important property is their capacity of self-renewal resulting in perma ⁇ nent and complete repopulation of host hematopoietic tissues.
  • Stem cells can be harvested from the bone marrow of healthy individuals and transplanted into the recipient patient, this being called “allogeneic stem cell transplantation”. Hemato ⁇ poietic stem cells may also be harvested from the bone marrow of patients themselves, this being called “autologous bone marrow transplantation”. Although bone marrow stem cells have the desired properties of radioprotection and long-term marrow reconstitution, hematopoietic reconstitution following these intensive treatment modalities that are lethal for the bone marrow requires a period of several weeks.
  • Stem cells for transplantation into the recipient patient can also be harvested from the blood.
  • peripheral blood derived stem cells seems to achieve a more rapid restoration of marrow function in comparison with autologous bone marrow transplantation (ABMT) (Juttner et al, 1989) .
  • ABMT autologous bone marrow transplantation
  • the numbers of circulating hematopoietic stem cells are extremely low and insufficient to be used for transplantation purposes. Therefore, sufficient numbers of circulating stem cells can only be obtained when they are deliberately expanded.
  • Such a "mobilization" of stem cells can be accom ⁇ plished by administering chemotherapy, hematopoietic growth factors that are involved in regulation of blood cell production (Haas et al, 1990) or both (Gianni et al, 1989) .
  • stem cell mobilization is a property of most hematopoietic growth factors, relatively prolonged treatment is required either without or following chemotherapy. Therefore daily monitoring of peripheral blood stem cells is required to define the optimal timing for harvesting these cells.
  • the availability of hormones or other substances that specifically and rapidly induce mobilization in a reproducible fashion would therefore greatly facilitate the clinical application of blood stem cell transplantation.
  • interleukin-1 may be a useful cytokine for stem cell mobilization.
  • IL-1 is involved in host defence against infec- tious and inflammatory stimuli.
  • the hematopoietic activities of IL-1 are several-fold. It induces the production of hemato ⁇ poietic growth factors by a variety of accessory cells.
  • IL-1 may also enhance the proliferative response of hematopoietic stem cells upon in vitro stimulation with hematopoietic growth f ctors.
  • IL-1 stimulates hematopoiesis in vivo as well.
  • CSF colony-stimulating factor
  • IL-1 has the ability to enhance myelopoiesis in various conditions associated with neutropenia.
  • I -1 An increase in the number of circulating neutrophils induced by IL-1 represents one of the major hallmarks of the host defence against infections, called the acute phase response. Studies in our laboratory have indicated that I -1 also has a similar releasing effect on the number of circulating hematopoietic (progenitor and) stem cells. Injection of a single dose of IL-1 resulted in a marked dose dependent increase in the number of neutrophils, hematopoietic progenitor and stem cells. The maximal increase was observed between 4 and 8 hours after a single injection. Transplantation of these blood derived cells into lethally irradiated recipient animals resulted in long term survival of the majority of the recipient animals (Fibbe et al, 1992) .
  • the bone marrow cells of recipients were of donor origin indicating that transplanta ⁇ tion of peripheral blood cells obtained from IL-1 treated animals resulted in long term survival of irradiated recipient animals as well as long term repopulation of their hematopoietic systems by do or derived cells.
  • IL-8 a cytokine belonging to the family of chemokines.
  • Interleukin-8 belongs to the family of C-X-C chemokines that act mainly on neutrophils. IL-8 is rapidly produced by fibroblasts, endo- thelial cells, smooth muscle cells and a variety of other cells in response to other cytokines, such as IL-1 and tumor necrosis factor- ⁇ . Receptors for IL-8 are abundantly present on the surface of human neutrophils . Lower numbers of IL-8 receptors were found on various other types of leukocytes, including
  • T lymphocytes and monocytes T lymphocytes and monocytes. Expression of receptors for IL-8 on human hematopoietic progenitor cells or stem cells has not yet been studied.
  • IL-8 stimulates neutrophils to migrate towards the side of inflammation.
  • th s effect can be measured in a so-called Boyden chamber (Van Damme et al, 1989) .
  • Neutrophils contain storaged enzymes that can be released upon stimulation with cytokines.
  • IL-8 induces rapid degranulation and the release of certain enzymes, such as gelatinase B, ⁇ -glucuronidase, elastase, myeloperoxidase and lactoferrine .
  • gelatinase B help neutrophils to reach the inflammatory site by degrading the matrix molecules which constitute the microenvironment of many tissues
  • Matrix molecules in the bone marrow microenvironment may have an important role in the regulation of hematopoiesis, since hematopoietic stem cells are attached to these molecules.
  • enzymes which are involved in degrading matrix molecules might be capable of inducing the release of stem cells from the marrow to the blood.
  • MMP matrix metalloproteinases
  • gelatinases In humans, two types of gelatinases have been purified and characterized, called the 72 kDa form (gelatinase A) and a related form with a different molecular weight of 92 kDa (gelatinase ⁇ ) (Collier et al, 1988; Wilhelm et al, 1989; Huhtala et al, 1991) . Most cell types, such as fibroblasts, endothelial cells and tumor cells are capable of constitutively producing gelatinase A. The production of the other 92 kDa form of the enzyme, gelatinase B, is dependent on specific stimuli. IL-8 induces within 5-10 minutes the production of gelatinase B by human neutrophils (Masure et al; Opdenakker et al, 1991) .
  • cytokines like IL-1 also induce production of gelatinase B by monocytes and macrophages (Opdenakker et al, 1991b) .
  • Gelatinase activity in cell culture supernatants can be detected by SDS-PAGE zymography using gelatine as a substrate for the enzyme (Masure et al, 1990) .
  • the gene encoding the mouse gelatinase B protein has been identified and cloned from a murine cell line WEHI-3 (Masure et al, 1993) .
  • the human gelatinase E protein is not only active in human cells but also on mouse derived cells. Thus, human gelatinase B can be used to study activities on human and primate cells.
  • TIMP-1 and TIMP-2 tissue inhibitors of metalloproteinases
  • Human TIMP-1 and TIMP-2 inhibit all known metalloproteinases in their activated form including both types of gelatinase.
  • the TIMP-1 molecule specifically binds to the 92 kDa progelatinase, whereas TIMP-2 preferentially binds to the 72 kDa progelatinase.
  • the production of these inhibitors is also tightly regulated by cytokines, such as IL-6 and IL-1 (for review, see Opdenakker and Van Damme, 1994) .
  • cytokines such as IL-6 and IL-1 (for review, see Opdenakker and Van Damme, 1994) .
  • the mouse TIMP-1 molecule has been cloned from L929 fibroblasts (Masure et al, 1993) . Therefore, recombinant protein can be used to inhibit enzyme activity of gelatinase B.
  • Intravenous injection of IL-8 in animals leads to an immediate decrease in the number of circulating white blood cells (leukocytopenia) . After several hours, a rebound neutro- philia is observed (Van Damme et al, 1988) .
  • the IL-8 induced neutropenia may be related to adhesion molecules that are expressed on the surface of neutrophils .
  • IL-8 induces a rapid down-regulation and shedding of one of these molecules (L-selectin) that is involved in binding of neutrophils to the surface of blood vessels.
  • Monkeys treated with IL-8 exhibit rapid neutrophilia with peak responses at one hour after injection and lasting 3-4 hours (Jagels and Hugli, 1992) . This effect was accompanied by release of precursor cells suggesting the recruitment of cells from a reservoir in the bone marrow.
  • chemokine IL-8 has potent stem cell mobilizing properties.
  • a mean 20 fold increase in the number of circulating CFU-GM was observed.
  • This effect was specific for IL-8 and could be completely prevented by pretreating the animals with a neutralizing polyclonal anti- IL-8 antibody.
  • the effect was not mediated by the intraperitoneal injection itself, since saline-treated control animals exhibited no increase in the number of circulating pro ⁇ genitor cells.
  • IL-8 induces a rapid mobilization of multipotent stem cells that have radioprotective capacity and long-term marrow repopulating ability in both lymphoid and the myeloid lineages (Laterveer et al, Blood in press 1995) .
  • IL-8 Stem cell mobilization induced by interleukin-8 in primates
  • rhesus monkeys were injected with a single i.v. dose of 30-100 ⁇ g of IL-8 per kg body weight.
  • IL-8 induced a profound (0.2 x 10 9 /1) neutropenia between 1-5 min after injection.
  • a single dose of 30 or 100 ⁇ g/kg a reproducible 100-fold increase in the number of circulating progenitor cells to 2,800 CFU-GM/ml was observed.
  • Neutrophilia to 30-40 x 10 9 /1 was observed at 60-120 min after injection, lasting for 2-3 hours.
  • IL-8 has a similar potent and rapid stem cell mobilizing effect in primates as observed in mice and suggest that IL-8 may be potentially useful in the clinical setting of peripheral blood stem cell transplantation.
  • Concomitant with the increase in circulating progenitor cells a dramatic increase (1,000 fold) in the circulating levels of the metalloproteinase gelatinase B was observed.
  • Enzyme levels decreased at 2 hours after injection of IL-8, simultaneously with the decrease in the number of circulating HFC.
  • the invention provides a method to rapidly mobilize hemato ⁇ poietic progenitor cells and stem cells from the bone marrow to the blood in warm-blooded animals, in particular mammals such as mice, primates and men. It also comprises the harvesting and isolation of these cells from blood and the use of these cells for transplantation into recipients treated with lethal irradiation or chemotherapy.
  • enzymes that are involved in degradation of the extracellular matrix i.e. belonging to the group of gelatinases, stromelysins, collagenases, can be used to rapidly induce mobilization of stem cells to the blood. More specifically, the invention proposes the use of the enzyme gelatinase B to induce stem cell mobilization.
  • the invention also comprises other enzymes and other forms of these enzymes that induce rapid mobilization for a longer period of time to enable harvesting of hematopoietic progenitor cells and stem cells from the blood.
  • the subject invention provides a method for- mobilizing hematopoietic progenitor or stem cells from the bone marrow to the blood in a warm-blooded animal, comprising administering to the animal an effective amount of an extracellular matrix degrading enzyme.
  • the invention is not limited to particular animals and is widely applicable to any warm-blooded animal. Practically, however, the invention will be used primarily with mammals, especially human beings and certain valuable mammalian species, such as horses, dogs, cats, camels, etc. Usually, said warm ⁇ blooded animal will be a human individual.
  • hematopoietic progenitor or stem cells intends to cover in a broad sense all bone marrow cells which have the capability to differentiate to specialized cells, in particular to blood cells.
  • the term covers multipotent stem cells, but also specific kinds of hematopoietic progenitor cells, including CFU- G, CFU-GM, CFU-GEMM en BFU-E .
  • extracellular matrix degrading enzyme intends to cover any enzym involved in the degradation of the extracellular matrix.
  • the enzyme will usually be a matrix metalloproteinase, more particularly an enzyme selected from the group consisting of gelatinases, collagenases and stromelysins.
  • said extracellular matrix degrading enzyme preferably is a gelatinase B or a modified form thereof, most preferably a human gelatinase B or a modified form thereof.
  • modified form thereof intends to cover all substances derived from the gelatinase B by, e.g. chemical derivation which does not substantially affect the stem cell mobilizing effect of the compound. Modifications may comprise changes in the amino acid sequence (additions, substitutions and/or deletions), the length of the molecule, the composition or structure of the carbohydrate side-chains, attachment of reactive or blocking groups or other molecules, etc.
  • the method of this invention preferably further comprises harvesting the mobilized hematopoietic progenitor or stem cells from the blood, and optionally purifying or enriching them.
  • the subject invention furthermore provides an enzyme having extracellular matrix degrading activity for use in the mobilization of hematopoietic progenitor or stem cells from the bone marrow to the blood in a warm-blooded animal, and provides the use of an enzyme having extracellular matrix degrading activity in the preparation of a pharmaceutical composition for mobilizing hematopoietic progenitor or stem cells from the bone marrow to the blood in a warm-blooded animal.
  • the subject invention provides a pharmaceutical composition comprising an enzyme having extracellular matrix degrading activity and a pharmaceutically acceptable carrier.
  • Such pharmaceutical composition is useful for mobilizing hematopoietic progenitor or stem cells from the bone marrow to the blood in a warm-blooded animal.
  • This invention also provides a pharmaceutical composition comprising hematopoietic progenitor or stem cells obtained by the above method (which includes the steps of harvesting the mobilized hematopoietic progenitor or stem cells from the blood, and optionally purifying or enriching them) and a pharmaceuti- cally acceptable carrier.
  • Such pharmaceutical composition may be used for effecting hematopoietic or bone marrow reconstitution.
  • the subject invention relates to the use of hematopoietic progenitor or stem cells obtained by the above method in the preparation of a pharmaceutical composition for effecting hematopoietic or bone marrow reconstitution.
  • pharmaceutically acceptable carrier refers to any conventional or unconventional carrier, diluent, solvent, excipient or adjuvant appropriate for use in a pharmaceutical composition for obtaining the effects defined herein.
  • suitability of a carrier depends on the intended route of administration, which will usually be by injection or infusion, such as by intravenous or intraarterial injection or infusion. Suitable routes of administration and carrier materials useful with such routes of administration are well known to the Derson skilled in the art and will not be detailed herein.
  • persons skilled in the art will easily recognize that e.g. the concentration of the enzyme resp. of the stem cells may vary between broad limits and will depend on many factors, such as the age, weight, sexe, condition, etc.
  • the concentration of enzyme may, e.g. vary from about 1 ⁇ g per kg body weight up to about 100 mg per kg body weight, usually from about 10 ⁇ g per kg body weight up to about 10 mg per kg body weight .
  • the invention circumvents the use of cytokines that are now commonly used to induce stem cell mobilization in men. This comprises the use of hematopoietic growth factors, such as human rec G-CSF, human rec GM-CSF, human rec IL-3.
  • metalloproteinases such as gelatinase B, may be used to rapidly induce stem cell mobilization within a period of from 5 to 60 minutes following a single injection.
  • IL-8 could be used as well, but could result in many other effects, including undesirable effects.
  • gelatinase B secreted by human neutrophils.
  • the gelatinase B was purified to homogeneity from peripheral blood neutrophils. The purification was done by a one-step affinity chromatography on gelatin-sepharose (Masure et al . , 1991) . The purity was quality controlled by zymographic analysis of enzyme activity, by silver stain analysis of the electrophoretic purity of the protein and by aminoterminal sequence analysis.
  • This gelatinase is hereafter called human neutrophil gelatinase B: it is free of human TIMP and this natural product is glycosylated by the neutrophils .
  • gelatinase B produced by recombinant DNA technology may be used, and will be used in a preferred embodiment of the invention. More particularly, it s preferred to use a gelatinase B produced by appropriately transformed eukaryotic host cells, especially mammalian cells, such as Chinese Hamster Ovary (CHO) cells or human cell cultures useful for the production of heterologous proteins. Recombinant gelatinase B produced in microorganisms such as, for example in suitable yeast cells, may likewise be useful.
  • eukaryotic host cells especially mammalian cells, such as Chinese Hamster Ovary (CHO) cells or human cell cultures useful for the production of heterologous proteins.
  • Recombinant gelatinase B produced in microorganisms such as, for example in suitable yeast cells, may likewise be useful.
  • the invention includes the possibility to produce the enzyme by chemical synthesis, or by in vitro translation, or by whatever technique is developed for the production of proteins in general or the subject enzyme in particular.
  • human gelatinase B i.e. a protein having a composition and structure which essentially corresponds to the composition and structure of human gelatinase B, such as an essentially similar amino acid composition and sequence and an essentially similar carbohydrate (or glycosylation) composition and structure
  • modified forms of human gelatinase B may be used, or gelatinase B enzymes derived from a different species, in particular from primates, more generally from mammals such as monkeys, pigs, cows, horses, mice, rats, goats, sheep, dogs, cats, camels, etc., including modified forms thereof.
  • Zymography i.e. a protein having a composition and structure which essentially corresponds to the composition and structure of human gelatinase B, such as an essentially similar amino acid composition and sequence and an essentially similar carbohydrate (or
  • the activity of the described enzymes is measured by a sub ⁇ strate conversion assay in which gelatin is used as a substrate. Briefly, an SDS/polyacrylamide gel is copolymerised with 1 mg/ml of gelatin (warmed to 45°C) . The samples to be analysed are separated in this gel by electrophoresis . Thereafter the SDS is washed out by incubation in triton X100. The enzymes are re ⁇ activated and start to degrade the copolymerized gelatin in sit u . After overnight incubation the gelatin lysis zones can be visualized by staining of the residual substrate with Coomassie brilliant blue.
  • gelatinases are then visualized as clear lysis zones on a blue background and can be absolutely quanti ⁇ fied by image analysis provided that a standard preparation of gelatinase is run on the gel. Because most body fluids (serum, synovial fluid, peritoneal fluid, cerebrospinal fluid) contain a constitutive endogenous gelatinase, called gelatinase A, which under normal conditions will not vary, this enzyme can always be used as an internal standard. Relating the (relative) activities of gelatinase B to this endogenous activity of gelatinase A circumvents errors being introduced by the sample preparation and handling.
  • TIMP-1 This is prepared by expression of the mouse cDNA (Masure et al, 1993) in the methanotrophic yeast, Pichia pastoris . This material, hereafter called rec mouse TIMP, will be tested in vitro for its inhibitory activity and by staining analysis for its purity.
  • mice were injected with a bolus of human neutrophil gelatinase B intravenously and the resulting enzyme levels were analysed by zymography. Gelatinase B was detected in the peri ⁇ pheral circulation.
  • Gelatinase B activity was studied as in sub 2. after injec- tion of rec IL-8 in monkeys. It was observed that a rapid and transient increase of gelatinase B activity remained detectable for about 4 hours and peaked to levels over a thousand fold over base level concentrations within minutes after the IL-8 bolus .
  • Recombinant human IL-8 was administered as a single intra ⁇ venous injection at doses of 10, 30 and 100 mg/kg body weight to Rhesus monkeys (age 2-3 years, body weight 2.5-4.5 kg) .
  • Venous blood samples were obtained at time intervals ranging from 1 to 480 minutes after injection of IL-8.
  • Peripheral blood cell coun ⁇ ting and colony assays, as well as immunotyping were performed. Hematopoietic progenitor cells were assessed using a semisolid culture assay in methylcellulose.
  • Cells were cultured in 3.5 cm dishes, in 1 ml medium containing 10 ng/rhuGM-CSF, 10 ng/rhuG- CSF, 10 ng/rhuSCF, 2 U/rhEPO and 15 ng rhuIL-3, 10 _5 M ⁇ -mercap- toethanol, 500 ng transferrin, 1.1% methylcellulose and 20% V/V human plasma in IMDM. Blood cell samples were plated in triplet at a concentration of 5xl0 5 cells/mi. After 7-8 days of culture at 37°C, 5% CO2 in a fully humidified atmosphere, the numbers of colony-forming units were scored using an inverted microscope.
  • IL-8 injection resulted in a dose dependent increase in the numbers of circulating progenitor cells starting at 5 minutes after injection and reaching maximum levels at 30 minutes after injection.
  • a mean number of 1,382 ⁇ 599 colony forming units per ml blood was reached after an injection of 100 ⁇ g IL-8/kg body weight (mean ⁇ SD of 8 experiments) .
  • the mean number of colony forming units per ml blood was 9 ⁇ 7.
  • the increment in the absolute numbers of progenitor cells ranged from 10 to 100-fold at a dose of 100 ⁇ g/kg IL-8.
  • Colony assays revealed that all types of hemato ⁇ poietic progenitor cells inducing CFU-G, CFU-GM, CFU-GEMM and BFU-E were mooilized. IL-8 did not result in a shift of the type of colony forming cells.
  • Monkeys were sequentially injected with multiple doses of IL-8.
  • time intervals between tne first and second injection were varied. Irrespective of the time interval between the first and second in ection of IL-8, ne trophii a was observed. The increment in the numoer of circulating stem cells however varie ⁇ depending on the time interval.
  • Mon ⁇ eys given two injections of IL-8 with an interval of 4 hours na ⁇ d significant increase in tne number of circulating progenitors after the first injection, but no increase after the second injection.
  • Animals given a second injection of IL-8 at 24 hours after the first injection of IL-8 had an intermediate increase in progenitor cells after the second injection.
  • Human neutrophil gelatinase B was dissolved in phosphate- buffered saline (PBS) at a concentration of 1 mg/ml. This stock solution was further diluted in PBS to a total volume of 10 ml. Monkeys were then injected intravenously over a time course of 30-60 seconds with gelatinase B at a dose of 10-100 ⁇ g/kg body weight. At various time intervals after intravenous injection, blood samples were drawn to assess the numbers of progenitor cells . References
  • Gianni AM Siena A, Bregni M, Tarella C, Stern AC, Pileri A, Bonadonna G. Granulocyte-macrophage colony-stimulating factor to harvest circulating hemopoietic stem cells for auto- transplantation. Lancet 2: 580 (1989) .
  • Haas R Ho AD, Bredthauer U, Cayeux S, Egerer G, Knauf W, Hunstein W. Successful autologous transplantation of blood stem cells mobilized with recombinant human granulocyte-macrophage colony-stimulating factor. Exp Hematol 18: 94-98 (1990) .
  • Huhtala P Tuuttilla A, Chow LT, Lohi J, Keski-Oja J, Tryggvason K. Complete structure of the human gene for 92-kDa type IV collagenase. Divergent regulation of expression for the 92- and 72-kilodalton enzyme genes in HT-1080 cells. J Biol Chem 266: 16485-16490 (1991) . Jagels MA, Hugli TE. Neutrophil chemotactic factor promote leukocytosis. Jrn Immunol 148: 1119-1128 (1992) .
  • Juttner CA To LB, Ho JQK, Bardy PG, Dyson PG, Haylock DN, Kimber RJ. Early lympho-hematopoietic recovery after auto- grafting using peripheral blood stem cells in acute nonlympho- blastic leukemia. Transplant Proc 20: 40 (1988) .
  • Interleukin-8 induces rapid mobilization of hemato ⁇ poietic progenitor cells with radioprotective capacity and long- term lymphomyeloid repopulating ability. Blood, in press 1995.
  • Matrisian LM The matrix-degrading metalloproteinases. Bioassays 14: 455-463 (1992) .
  • Opdenakker G Masure S, Grillet B, Van Damme J. Cytokine- mediated regulation of human leukocyte gelatinases and role in arthritis. Lymphokine and Cytokine Research 10: 317-324 (1991) .
  • Opdenakker G Van Damme J. Cytokine-regulated proteases in autoimmune diseases. Immunology Today 15, 103-107 (1994) . Oppenheim JJ, Zachariae COC, Mukaida N, Matsushima K. Properties of the novel proinflammatory supergene intercrine cytokine family. Ann Rev Immunol 9: 617-648 (1991) .

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Abstract

Des enzymes ayant une activité extracellulaire de dégradation de matrices sont utilisées pour mobiliser des cellules souches hématopoïétiques provenant de la moëlle osseuse vers le sang d'animaux à sang chaud, en particulier des mammifères. Une enzyme de métalloprotéinase de matrice telle que la gélatinase B, en particulier quand elle est humaine, est capable de provoquer efficacement une mobilisation rapide de cellules souches moins d'une heure après une seule injection. Les cellules souches hématopoïétiques mobilisées sont récoltées, et éventuellement purifiées ou enrichies, puis transplantées dans un animal récepteur, en particulier une personne, pour la reconstitution hématopoïétique ou de la moëlle osseuse, en particulier chez les sujets qui ont subi un traitement intensif de chimio ou radiothérapie, ou les deux.
PCT/NL1996/000149 1995-04-07 1996-04-09 Emploi de la gelatinase b et d'enzymes apparentees pour mobiliser les cellules souches hematopoietiques en vue de transplanter des cellules souches sanguines WO1996031233A1 (fr)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004090120A3 (fr) * 2003-04-08 2005-05-12 Yeda Res & Dev Cellules souches presentant une sensibilite accrue a un chimioattracteur, et leurs procedes d'obtention et d'utilisation
US8765119B2 (en) * 2004-05-06 2014-07-01 University Of South Florida Treating amyotrophic lateral sclerosis (ALS)with isolated aldehyde dehydrogenase-positive umbilical cord blood cells
WO2015038058A1 (fr) * 2013-09-16 2015-03-19 Elastomics Ab Modification des propriétés mécaniques d'un tissu vivant

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DE1924715A1 (de) * 1968-05-15 1969-11-27 Worthington Biochem Corp Arzneipraeparate zur Behandlung des Bandscheibenvorfalles

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AU2004227204B2 (en) * 2003-04-08 2010-06-03 Yeda Research And Development Co. Ltd Stem cells having increased sensitivity to SDF-1 and methods of generating and using same
US8252588B2 (en) 2003-04-08 2012-08-28 Yeda Research And Development Co. Ltd. Stem cells having increased sensitivity to SDF-1 and methods of generating and using same
US8765119B2 (en) * 2004-05-06 2014-07-01 University Of South Florida Treating amyotrophic lateral sclerosis (ALS)with isolated aldehyde dehydrogenase-positive umbilical cord blood cells
WO2015038058A1 (fr) * 2013-09-16 2015-03-19 Elastomics Ab Modification des propriétés mécaniques d'un tissu vivant

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