Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of detaching cells – digesting tissue or establishing...
Patent
1996-01-16
1999-07-20
Stanton, Brian R.
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of detaching cells, digesting tissue or establishing...
530350, C12N 500, C07K 100
Patent
active
059255684
DESCRIPTION:
BRIEF SUMMARY
This invention relates to te use of stem cell inhibitors (SCIs), including wild-type molecules and variants (both naturally occurring and engineered), as agents to promote the release and mobilisation of haematopoietic cells from the marrow. Such agents are useful in enhancing immune responses and in cell harvesting.
The various mature blood cell types are all ultimately derived from a single class of progenitor cell known as haematopoietic stem cells. True stem cells are both pluripotent--that is they can give rise to all cell types--and capable of self-renewal. This is defined by their ability to repopulate am whose haematopoietic system has been destroyed by radiation. Stem cells represent a very small percentage of bone marrow cells, and are normally quiescent. When stimulated to divide, they give rise to more committed, differentiated daughter cells with greater proliferative potential. The term stem cell is often also applied to these so-called "early progenitors " cells. Sequential rounds of division and differentiation give rise to an enormous amplification of cell numbers, necessary for the production of mature blood cells. This process of division and differentiation is subject to regulation at many levels to control cell production. Thus positive factors such as the Colony Stimulating Factors (CSFs) act to promote division of early progenitors and differentiation down particular lineages, for example G-CSF drives neutrophil production whilst erythropoietin promotes formation of erythrocytes. More recently, it has been recognised that negative factors may also play an important role in regulating haematopoiesis.
Leukocytic, haematopoietic cells are important in maintaining the body's defence against disease. For example, macrophages and lymphocytes are involved in potentiating the body's response to infection and tumours; granulocytes (neutrophils, eosinophils and basophils) are involved in overcoming infection, parasites and tumours.
Other cell types derived from haematopoietic stem cells include platelets and erythrocytes. Platelets form an important element in the haemostatic mechanism through initiating thrombus formation by their adhesion to each other and to damaged surfaces, and by the release of factors which assist in the formation of the fibrin clot. Eryrocytes are mainly involved in the transport of oxygen.
Purified populations of cells are increasingly being used therapeutically and it would therefore be advantageous to be able to increase the number of circulating blood cells. It is also useful to be able to harvest haematopoietic cells prior to chemotherapy or radiotherapy, thus protecting them from the effects of this therapy; after therapy, the cells can be returned to the patient. It would therefore be highly beneficial to provide an agent which promoted the release and mobilisation of a number of haematopoietic cells. Such an agent would be useful for enhancing the responses to infection.
A number of cytokines have been implicated in causing chemokinesis of haematopoietic cells; for example IL-8 (a member of the C-X-C family of chemokines) is chemotactic for neutrophils but not for monocytes, whereas LD78 (a member of the C-C family of chemokines) is chemotactic for monocytes but not for neutrophils. Chemokinesis is an in vitro phenomenon, reflecting the ability of cells to move towards a stimulus. It is, however, distinct from the release and mobilisation of cells, which is an in vivo phenomenon in which cells leave one tissue compartment and enter the bloodstream. If there is a relationship between chemokinesis and release/mobilisation, it is unclear what its nature is.
Neutrophils, along with other granulocytes, are an essential component of the body's cellular defences against infection. This is illustrated by the fact that individuals with a leukocyte dysfunction such as LAD (leukocyte adhesion deficiency) are very prone to infection. Neutrophils are continuously produced in large numbers from myeloid precursors in the bone marrow. Neutrophils are released into the circulat
REFERENCES:
Pragnell et al. From clone to clinic--a stem cell inhibitory cytokine with clinical potential. Leukemia, vol. 7, No. 5, pp. 777-778, May 1993.
Dunlop et al. Demonstration of stem cell inhibition and myeloprotective effects of SCI/rhMIP1-alpha in vivo. Blood, vol. 79, No. 9, pp. 2221-2225, May 1, 1992.
Lord et al. MIP-1-alpha protects CFU-S from the cytotoxic effects of hydroxyurea in vivo. 18th Meeting of the European study group for Cell proliferation, May 6-9, 1992. Cell Proliferation, vol. 25, No. 5, p. 503, May 1992.
Zwierzina, H. Practical aspects of cytokine therapy. Stem Cells, vol. 11, No. 3, pp. 143-153, May 1993.
Comer Michael Berisford
Edwards Richard Mark
Hunter Michael George
McCourt Matthew John
Wood Lars Michael
British Biotech Pharmaceuticals Limited
Clark Deborah J. R.
Stanton Brian R.
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