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Methods for cell mobilization using in vivo treatment with hyaluronan (ha)

Methods for cell mobilization using in vivo treatment with hyaluronan (ha) description/claims

The invention relates generally to methods using exogenous forms of hyaluronan (HA) for mobilizing hematopoietic cells to the circulation enabling various methods of treatment of humans, including mammals, including methods for obtaining hematopoietic cell transplantation, methods for treating immunosuppression, anemia, osteoporosis, methods for treating cancer, methods for treating allergy and asthma, methods for performing organ transplantation, methods for performing hematopoietic cell transplantation, methods for treating organ/tissue rejection, methods for treating autoimmunity and autoimmune-like conditions, and methods for in vitro fertilization, and in vivo fertility treatments.

Hyaluronan (HA) is a ubiquitous glucosaminoglycan in the extracellular matrix, shown to play a central role in embyrogenesis, inflammation, wound healing, and tumour metastasis. (Toole, B. P. (1990) Hyaluronan and its binding proteins, the hyaladherins. Curr. Opin. Cell. Biol. 2: 839-844. Toole, B. P. (1982). Development role of hyaluronate. Conn. Tiss. Res 10: 93-100.)

Interaction between HA and RHAMM, a receptor for HA-mediated motility are required for motile behaviour of a wide variety of cells including sperm, fibroblasts, astrocytes, microglia and white blood cells. (Entwistle, J. Zhang, S., Yang, B., Wong, C. Hall, C. L., Curpen, G., Mowat M., Greenberg, A. H., and Turley, E. A. (1995). Cloning and characterization of the gene encoding the hyaluronan receptor RHAMM; the role of a secreted isoform in the regulation of focal adhesion formation. Gene 163: 233-238 Yang, B., Yang, X. Zhang, S., Turley, M., Samuel, S., Savani, R. C., Greenberg, A. H., and Turley, E. A. (1995). Overexpression of the hyaluronan receptor RHAMM is transforming, and is required for H-ras transformation. Cell 82: 19-28. Masellis-Smith, A., Belch, A. R., Mant, M. J., Turley, E. A., and Pilarski., L. M. (1996). Hyaluronan-dependent motility of B cells and leukemic plasma cells in multiple myeloma: Alternate usage of RHAMM and CD44. Blood 87: 1891-1899. Turley, E. A., Belch, A. R., Poppema, S., and Pilarski, L. M. (1993). Expression and function of a receptor for hyaluronan-mediated motility (RHAMM) on normal and malignant B lymphocytes. Blood 81: 446-453. Pilarski, L. M. Miszta, H., and Turley, E. A. (1993). Regulation expression of receptor for hyaluronan-mediated motility RHAMM) on human thymocytes and T cells. J. Immunol. 150: 4292-4302 S., K. B., McCoshen, J., Kredentser, J., and Turley, E. (1994). The Regulation of Sperm Motility by a Novel Hyaluronan Receptor. Fertility and Sterility 61: 935-940. Turley, E. A., Sossain, M. Z., Sorokan, T., Jordan, L. M., and Nagy, J. I. (1994) Astrocyte and microglial motility in vitro is functionally dependent on the hyaluronan receptor RHAMM. Glia 12: 68-80)

The cells that populate the blood are all derived from multipotential (or pluripotential) stem cells present in bone marrow. Multipotential stem cells continually proliferate and renew themselves, but also give rise to common progenitor cells. Once committed, progenitor cells differentiate into immature precursor cells of the various blood cell lineages which, following further differentiation stages, eventually give rise to mature functional blood cells, such as erythrocytes, monocytes, lymphocytes, and polymorphonuclear cells. (Golub, E. S., Green, D. R. (1991) Immunology A Synthesis, 2:205; Kuby, J. (1997) Immunology, 3:50; Roitt, I., Brostoff, J., Male, D. (______) Immunology, 4:2.1). Terminally differentiated blood cells generally lose their ability to proliferate—indeed mammalian erythrocytes and platelets contain no nuclei—and thus have finite lifetimes. Granulocytes may exist only for a matter of hours, whereas human erythrocytes remain in circulation for over 100 days. Although some lymphocytes have life-spans measured in years, most are short lived (for example, 3 days-3 weeks). Therefore, to maintain steady-state numbers of particular blood cell types, there must be a continual production of these from the bone marrow. This process is known as haemopoiesis (haematopoiesis) or the haemopoietic process. While much remains to be learned, it is clear that many steps in the haemopoietic process (haemopoiesis) are controlled by certain cytokines (for example, GM-CSF and G-SCF and erythropoietin (EPO)), also known as haemopoietic growth factors, and by microenvironmental factors including stromal cells and extra-cellular matrix components (for example, hyaluronan).

Clinically, the term “mobilization” usually refers to the process whereby cells leave the bone marrow and enter the blood. The mechanism whereby this occurs is not known by those skilled in the art. However, I believe mobilization can be viewed as the stimulation of de-adhesive behaviour by hematopoietic cells.

I believe that under normal circumstances, hematopoietic cells are anchored in their environment by receptors known as adhesion molecules. These adhesion molecules bind to components of the extracellular and cellular matrix within tissues to anchor the cell, or alternatively, to permit its migratory behaviour. Among the receptors thought to be important are those binding HA.

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