Chemistry: molecular biology and microbiology – Animal cell – per se ; composition thereof; process of... – Method of regulating cell metabolism or physiology
Reexamination Certificate
1998-01-30
2001-02-27
Saunders, David (Department: 1644)
Chemistry: molecular biology and microbiology
Animal cell, per se ; composition thereof; process of...
Method of regulating cell metabolism or physiology
C435S002000, C424S093710
Reexamination Certificate
active
06194207
ABSTRACT:
BACKGROUND OF THE INVENTION
1. Field of the Invention
The invention relates to methods for the selective production of cells of the lymphohematopoietic system by culturing a mixed population of cells with a conditioned medium. The invention also relates to cells selectively produced by these methods and to methods for utilizing these cells.
2. Description of the Background
The human immune system uses several methods to prevent infection by foreign organisms. Skin, for example, provides a physical barrier to penetration while blood contains specialized white blood cells which function to recognize and destroy foreign pathogens. Neutrophils and macrophages are white blood cells attracted to sites of infection where they engulf and digest (phagocytose) foreign organisms, and initiate a typical inflammatory response. Blood also contains lymphocytes which provide specific and long-lasting immunity against a variety of infectious agents. B cells are lymphocytes which secrete antibodies that bind to and inactivate foreign agents within the bloodstream while T cells are lymphocytes that recognize and kill host cells that are infected by such foreign agents. T cells also recognize alterations in normal cellular proteins that are often associated with transformation to a cancerous state. Other lymphocytes called natural killer cells are specialized for the destruction of virally-infected and tumor cells. Thus, lymphocytes mediate a specific immune response and may play an important role in the prevention of cancer. Collectively, all cells of the immune system work in a coordinated manner to provide the body with a powerful and diversified repertoire of both nonspecific and highly specific weapons to combat foreign agents. For example, macrophages secrete factors that activate T cells, direct T cell responses toward specific foreign targets and phagocytose bacteria coated with antibody produced by B cells. Specialized T cells also secrete factors that determine whether the immune response will be dominated primarily by the production of antibodies or the generation of killer T cells. The concerted action of all cells of the immune system provides a rapid response to the entry of infectious agents as well as long-lasting immunity against re-exposure to the same agents.
Lymphocytes are short-lived cells produced from bone marrow stem cells that give rise to B cells, T cells and natural killer (NK) cells, in addition to all other blood cells. A key feature of stem cells is their ability to provide a constant source of progenitor cells that possess a high proliferative capacity, but are committed to produce cells of one or more blood cell lineage. Cells of the immune system are collectively referred to as lymphoid cells and are believed to be descended from a common lymphoid progenitor cell. Lymphoid progenitors are eventually restricted to the production of a single type of lymphoid cell during the process of differentiation or maturation. The high proliferative capacity of lymphoid progenitor cells allows for the production of large numbers of mature lymphoid cells which under resting conditions do not divide. B cells mature in the bone marrow where they are continuously released into the blood to maintain a constant number of functional B cells. Immature T cells migrate from the marrow to the thymus where they mature and are released to maintain the peripheral T cell pool. In fact most T cells die within the thymus where immature T cells undergo a process of positive and negative selection in the process of being educated to recognize only foreign, but not self-derived antigens. Mature NK cells formed in the bone marrow and are released into the bloodstream. Upon stimulation, virgin (naive) B and T lymphocytes undergo rapid proliferation and differentiation into both effector cells which mediate a rapid immune response and memory cells which may survive for many years before being called upon to mediate an immune response. Although NK cells can be activated by exposure to certain growth factors, they also provide an innate and spontaneous immunity against virally-infected and malignant cells.
B cells secrete antibodies which are capable of recognizing a vast number of chemical determinants found in proteins, carbohydrates, lipids, or other macromolecules, all of which are collectively referred to as antigens. Antibodies may reside on virgin or memory B cell membranes as antigen receptors which, when bound by the matching antigen, stimulate the proliferation and differentiation of B cells into short-lived plasma cells that secrete large amounts of soluble antibodies specific for the inducing antigen. Antibody binding can have a variety of effects including the sequestration and inactivation of toxic agents, the prevention of viral entry into host cells or the promotion of phagocytosis of infectious agents by macrophages. The release of antibody into the blood and other body fluids by B cells is the principal source of the humoral immune response. B cells also function, like macrophages, to present foreign antigens in a manner that can be recognized by T cells. B cells also release important growth factors that influence the function and activation of other immunologically important cells.
T cells recognize antigenic determinants through a surface receptor called the T cell receptor (TcR). Although similar in function to surface bound immunoglobin, T cell receptors are not secreted. T cells mediate their prime immunological function through direct contact with infected host cells. These infected cells cooperate by displaying (presenting) antigenic fragments of foreign proteins on their surface as a means of signaling to T cells that they are infected. While T cells recognize antigens presented on all host cells, T cells are first activated to recognize these antigens by specialized antigen-presenting cells such as dendritic cells, B cells and macrophages. Antigen-presenting cells also express co-stimulatory molecules on their surfaces which are required for full T cell activation. Together with macrophages, T cells are the main component of the cell-mediated immune response and, through the release of soluble factors, are required for virtually all aspects of the immune response. In addition to the T cell receptor, T cells are characterized by two major T cell-specific surface markers, CD4 and CD8, which define functionally distinct T cell populations. CD4 T cells, called T helper cells, are activated through interaction with antigen-presenting cells and function primarily to activate CD8 T cells, also known as cytotoxic or killer T cells (CTL). CTLs are the main effector T cell mediating the destruction of infected host cells and only recognize foreign antigens that are bound to specialized molecules found on virtually all cells. Thus, most infected cells of the body may serve as CTL targets. Target cells are killed by factors released from CTLs that cause rapid target cell lysis or through the induction of a highly ordered program of events leading to cell death. In addition to activating CTLs, CD4 helper cells also regulate B cell activation through the release of soluble factors. Like B cells, most resting virgin T cells are short-lived unless activated to proliferate and generate both effector and memory T cells.
T helper cells are grouped according to the type of soluble growth factors secreted after activation by specific antigens. T helper
1
(T
H
1) cells secrete the main T cell growth factor, interleukin 2 (IL-2) plus interferon gamma (IFN&ggr;) and interleukin 12. This combination of growth factors selectively activates cytotoxic T cells leading to a predominately cell-mediated immune response. T helper 2 (T
H
2) cells secrete mainly IL-4 and IL-5 which stimulate B cells and promote a predominately humoral (antibody-based) immune response. T
H
1 growth factors such as IFN&ggr; block the T
H
2 immune response while T
H
2 factors such as IL-4 block the T
H
1 response. Although the method of T
H
1/T
H
2 selection is not known, the type of immune response to a foreign agent is lar
Bell David N.
Wong Truman
Bereskin & Parr
Gravelle Micheline
Hemosol Inc.
Saunders David
Tung Mary Beth
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