Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
1998-11-24
2001-06-19
Saunders, David (Department: 1644)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C530S328000, C530S329000, C530S330000, C530S331000, C514S015800, C514S016700, C514S017400, C514S018700, C514S021800
Reexamination Certificate
active
06248587
ABSTRACT:
FIELD OF THE INVENTION
This present invention relates to methods for use in accelerating the proliferation and differentiation of hematopoietic and mesenchymal cells.
BACKGROUND OF THE INVENTION
Bone marrow contains pluripotent stem cells that are capable of reconstituting either the hematopoietic system or a wide range of mesenchymal tissues. The mechanisms by which hematopoietic and mesenchymal stem cells produce a range of progenitor cell types are quite dissimilar.
The hematopoietic system is composed of a multitude of cell generations ranging from the terminally differentiated to very primitive hematopoietic progenitor cells (HPC). (Traycoff, et al., Experimental Hematology 24:299-306, 1996). HPC are pluripotent progenitor cells that possess the ability to terminally differentiate into hematopoietic lineage-specific progenitor cells (HLSPC). Hematopoiesis is an ongoing process, and therefore HPC must provide a continuous source of HLSPC, which in turn can differentiate into red cells, platelets, monocytes, granulocytes and lymphocytes. (Prockop, Science 276:71-74, 1997). HPC proliferate either by “self-renewal”, to produce HPC-type progeny cells, or with accompanying differentiation, to produce HLSPC. (Traycoff, et al., supra).
HPC transplantation therapy has been successful for a variety of malignant and inherited diseases and also provides myelopoietic support for patients undergoing high-dose chemotherapy or radiotherapy. (Emerson, Blood 87:3082-3088, 1996). However, stem cell transplantation has been limited by several features. First, acquiring a sufficient quantity of stem cells to achieve benefit after transfusion requires either extensive, operative bone marrow harvests or extensive pheresis procedures. (Emerson, supra). Next, even under these circumstances, only a limited number of useful cells is obtained. Finally, mature blood cell regeneration after transfusion is slow, so that little direct therapeutic benefit is seen for periods of 1 to 3 weeks. (Emerson, supra).
The development of in vitro culture techniques for hematopoietic cells combined with technologies for isolating relatively pure populations of HPC and HLSPC has made possible their ex vivo expansion. (Alcorn and Holyoake, Blood Reviews 10:167-176, 1996, which is incorporated by reference herein). Successful ex vivo expansion of HPC, both by self-renewal and proliferation with differentiation, promises many clinical benefits, such as reduction of the number and duration of leucapheresis procedures required for autologous transplantation, thus reducing the risk of disease contamination in the apheresis products. (Alcorn and Holyoake, supra). Furthermore, ex vivo expansion may render inadequate HPC populations in peripheral blood and umbilical cord blood sufficient for autologous transplantation and adult allogeneic transplantation respectively. Finally, ex vivo expansion of HPC will greatly increase their utility as gene therapy vehicles. (Alcorn and Holyoake, supra). Similarly, ex vivo expansion of HLSPC promises substantial clinical benefits, such as re-infusion of expanded populations of myeloid precursor cells to reduce the period of obligate neutropenia following autologous transplantation, the generation of natural killer cells for use in adoptive immunotherapy protocols, generation of megakaryocyte precursors to alleviate post-transplant-associated thrombocytopenia and more efficient generation of delivery systems for gene therapy. (Alcorn and Holyoake, supra).
Human bone marrow, umbilical cord blood, and peripheral blood progenitor cells mobilized by chemotherapy and/or cytokine treatment have been shown to be effective sources of HPC for transplantation following the administration of high-dose therapy to treat malignancy. (Holyoake, et al., Blood 87:4589-4595, 1996). Whatever the source of hematopoietic cells, most studies have used cultured cell populations selected on the basis of HPC-specific surface antigens, such as CD34. These cells can be readily obtained by a number of techniques. (Alcorn and Holyoake, supra). The results of several clinical trials using ex vivo expanded hematopoietic cells suggests that a fairly small number of HPC cultured ex vivo under appropriate conditions can initiate hematologic reconstitution. (Emerson, supra).
Survival and proliferation of HPC in ex vivo culture requires a combination of synergizing growth factors; the choice of cytokine/growth factor combination and culture system used will largely determine the fate of cells used to initiate the culture. (Alcorn and Holyoake, supra). In vivo, blood cell production is thought to be regulated locally by interactions of hematopoietic stem cells with a variety of cell-bound and secreted factors produced by adjacent bone marrow stromal cells. (Alcorn and Holyoake, supra). The addition of growth factors and cytokines to the culture medium is intended to compensate for the absence of stroma-associated activities. Growth factors and cytokines that have been shown to increase production of HPC (in various combinations) include granulocyte colony-stimulating factor (G-CSF), granulocyte/macrophage colony stimulating factor (GM-CSF), stem cell factor (SCF), macrophage colony-stimulating factor (M-CSF), and interleukins 1, 3, 6, and 11 (Reviewed in Takaku, J. Cancer Res. Clin. Oncol. 121:701-709, 1995; Holyoake, et al., supra). Conversely, inclusion of macrophage inhibitory protein-1&agr; (MIP-1&agr;), tumor necrosis factor &agr; (TNF-&agr;) or transforming growth factor &bgr; (TGF&bgr;) in most expansion cultures reported to date results in decreased HPC and HLSPC yields. (Emerson, supra).
A great deal of effort has gone into defining the optimal conditions for ex vivo culture of hematopoietic cells. Methods that increase the ex vivo proliferation of HPC will greatly increase the clinical benefits of HPC transplantation. This is true both for increased “self-renewal”, which will provide a larger supply of HPC capable of reconstituting the entire hematopoietic system, and for proliferation with differentiation, which will provide a larger supply of lineage-specific progenitor cells. Similarly, methods that increase in vivo proliferation of HPC will enhance the utility of HPC transplantation therapy by rapidly increasing local concentrations of HPC (and HLSPC) in the bone marrow. Furthermore, methods that result in the differentiation of HPC and HLSPC are useful in providing populations of specific cell types for use in cell therapy.
Transfection of mammalian HPC has been accomplished. (Larochelle, et al., Nature Medicine 2:1329-1337, 1996). Thus, methods that increase the proliferation of HPC and HLSPC are also useful in rapidly providing a large population of transfected cells for use in gene therapy.
Mesenchymal stem cells (MSC) are pluripotent progenitor cells that possess the ability to differentiate into a variety of mesenchymal tissue, including bone, cartilage, tendon, muscle, marrow stroma, fat and dermis as demonstrated in a number of organisms, including humans (Bruder, et al., J. Cellul. Biochem. 56:283-294 (1994). The formation of mesenchymal tissues is known as the mesengenic process, which continues throughout life, but proceeds much more slowly in the adult than in the embryo (Caplan, Clinics in Plastic Surgery 21:429-435 (1994). The mesengenic process in the adult is a repair process but involves the same cellular events that occur during embryonic development (Reviewed in Caplan, 1994, supra). During repair processes, chemoattraction brings MSC to the site of repair where they proliferate into a mass of cells that spans the break. These cells then undergo commitment and enter into a specific lineage pathway (differentiation), where they remain capable of proliferating. Eventually, the cells in the different pathways terminally differentiate (and are no longer able to proliferate) and combine to form the appropriate skeletal tissue, in a process controlled by the local concentration of tissue-specific cytokines and growth factors (Caplan, 1994, supra).
Recently, it has been hypothesized that the limiti
DiZerega Gere
Rodgers Kathleen E.
Harper David S.
McDonnell & Boehnen Hulbert & Berghoff
Saunders David
Tung Mary Beth
University of Southern Cailfornia
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