THE ROLE OF CD4 IN MACROPHAGE DIFFERENTIATION AND FUNCTION
Scott G Kitchen, Assistant Professor
University Of California Los Angeles, Office Of Research Administration, Los Angeles, Ca 90095
Grant 1R01AI078806-01A2 from National Institute Of Allergy And Infectious Diseases
Abstract: The CD4 molecule has an important role in the human immune system and in the pathogenesis of HIV. A key factor in HIV pathogenesis is the use of the CD4 molecule as the primary receptor for cellular infection. In addition to CD4+ T helper cells, there are numerous other cells of the immune system that express CD4 that are susceptible to infection by HIV. One of the primary targets and an important and poorly understood reservoir for HIV in an infected individual are monocytes/macrophages. Other than allowing HIV infection of these cells, the role of the CD4 receptor in the function and development of monocyte/macrophages is not known. We have recently determined that ligation of CD4 on monocytes/macrophages modulates gene and cytokine protein expression as well as T cell responses. We are interested in examining this and other roles and functions of the CD4 molecule on the monocyte/ macrophage cell subset. Our central hypothesis in this proposal is that CD4 has a role in monocyte/ macrophage differentiation and function by modulating the expression of factors that control cellular development and other immune responses. This, in turn, has important implications in HIV infection and the understanding of the monocyte/ macrophage reservoir of infected cells in disease progression. This proposal will focus on addressing these issues and will focus on the following three Specific Aims 1. To determine the mechanisms regulating CD4 expression during monocyte/macrophage development. 2. To determine the function(s) and consequence(s) of CD4 expression during monocyte/macrophage lineage differentiation and development. 3. To determine the role(s) of the CD4 molecule on mature monocyte/ macrophage function. To achieve this, we will utilize a novel embryonic stem cell-based system that we can genetically manipulate and examine monocyte/ macrophage differentiation and function from a cell type that is among the earliest in human hematopoietic development. In summary, it is anticipated that these studies will shed light on the potential roles and importance of CD4 in monocyte/macrophage development and/or function. Further, it is anticipated that the proposed studies will allow a more comprehensive understanding of the consequences of HIV infection in this cell type. The experimental approach described in this proposal is designed to address the central hypothesis that the CD4 molecule has a broader function in the immune response, and by extension in HIV pathogenesis, than its capacity on CD4+ T helper cells. These studies will increase our knowledge of how the CD4 molecule influences monocyte/ macrophage development and immune function and how HIV may impact this process; thus, increasing our understanding of the mechanisms of HIV infection and pathogenesis. Further, the use of embryonic stem cells in these studies, due to their high plasticity, self-renewal ability, and ability to be genetically manipulated, may allow the development of immune replacement therapeutic strategies to be developed for HIV and other similar diseases
Keywords: AIDS; AIDS Virus; APC; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Address; Antigen-Presenting Cells; Blood monocyte; Body Tissues; CD4 Antigen (P55); CD4 Antigens; CD4 Molecule; CD4 Positive T Lymphocytes; CD4 Protein; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD8; CD8B; CD8B1; CD8B1 gene; Cancers; Canine Species; Canis familiaris; Cell Function; Cell Process; Cell physiology; Cells; Cells, CD4; Cellular Function; Cellular Physiology; Cellular Process; Cessation of life; Closure by Ligation; Coupled; Cytokine Gene; Cytotoxic cell; Death; Defect; Derivation; Derivation procedure; Development; Disease; Disease Progression; Disorder; Dogs; ES cell; Family suidae; HIV; HTLV-III; Helper Cells; Helper T-Cells; Helper-Inducer T-Lymphocyte; Hematopoietic; Hortega cell; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human, General; Immune; Immune Function, Cellular; Immune response; Immune system; Immunologic Accessory Cells; Immunologic Deficiency Syndrome, Acquired; Individual; Inducer Cells; Infection; K lymphocyte; Knowledge; LAV-HTLV-III; LYT3; Ligation; Light; Lymphadenopathy-Associated Virus; Malignant Neoplasms; Malignant Tumor; Mammals, Dogs; Mammals, Mice; Mammals, Primates; Man (Taxonomy); Man, Modern; Marrow monocyte; Mice; Microglia; Monocytes / Macrophages / APC; Murine; Mus; NK Cells; Natural Killer Cells; Nature; OKT4 antigen; Opportunistic Infections; Organ; Pathogenesis; Photoradiation; Pigs; Play; Primates; Process; Public Health; Receptor Protein; Receptors, CD4; Receptors, Surface CD4; Research; Role; Subcellular Process; Suidae; Swine; System; System, LOINC Axis 4; T-Cell Antigen T4/Leu3; T-Cell Surface Antigen T4/Leu-3; T-Cells; T-Cells, Helper-Inducer; T-Lymphocyte; T-Lymphocytes, Helper; T-Lymphocytes, Inducer; T4 Cells; T4 Lymphocytes; T4 molecule; Therapeutic; Thymus-Dependent Lymphocytes; Tissues; Viral Diseases; Virus; Virus Diseases; Virus-HIV; Viruses, General; accessory cell; base; body system, allergic/immunologic; canine; cell type; cellular development; cytokine; design; designing; disease/disorder; domestic dog; embryonic stem cell; genetic manipulation; gitter cell; hESC; helper T cell; helper T lymphocyte marker; host response; human ES cell; human ESC; human embryonic stem cell; immune function; immunoresponse; interest; macrophage; malignancy; mesoglia; microglial cell; microgliocyte; monocyte; neoplasm/cancer; novel; organ system, allergic/immunologic; pathogen; perivascular glial cell; porcine; protein expression; public health medicine (field); public health relevance; receptor; response; self-renewal; social role; stem cell of embryonic origin; suid; thymocyte; thymus derived lymphocyte; viral infection; virus infection; virus pathogenesis
Relevance: Relevance to Public Health The experimental approach described in this proposal is designed to address the central hypothesis that the CD4 molecule has a broader function in the immune response, and by extension in HIV pathogenesis, than its capacity on CD4+ T helper cells. These studies will increase our knowledge of how the CD4 molecule influences monocyte/ macrophage development and immune function and how HIV may impact this process; thus, increasing our understanding of the mechanisms of HIV infection and pathogenesis. Further, the use of embryonic stem cells in these studies, due to their high plasticity, self-renewal ability, and ability to be genetically manipulated, may allow the development of immune replacement therapeutic strategies to be developed for HIV and other similar diseases
Project start date: 2009-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2009
Budget end date: 30-JUN-2010
PFA/PA: PA-07-070
1R01AI078806-01A2 (2009): $385000
Sponsored Links Excellgen http://Excellgen.com
Grants awarded to Scott G Kitchen
The Role Of CD8 On CD4+ T Cells
Scott G Kitchen
University Of California Los Angeles Office Of Research Administration Los Angeles, Ca 90095
Grant 5R21AI057057-02 from National Institute Of Allergy And Infectious Diseases IRG: AARR
Abstract: There are many mechanisms that contribute to the decline of the immune response in HIV disease. Infection and perturbation of CD4+ T cells by HIV dramatically contributes to viral replication and a decreased ability to respond to antigenic insult. There are many different functional subsets of CD4+ T cells, and HIV appears to target the highly activated populations, particularly those cell that specifically respond to HIV infected cells. We have shown that CD4 expression by CD8+ T cells plays an important role in CD8 cell function. Recently, our laboratory has identified a highly activated population of CD4+ T cells that express the CD8 molecule. Preliminary studies indicate that this population is more abundant in HIV-infected people and may reflect the greater levels of cellular activation seen in these individuals. This high level of activation could render these cells more susceptible to infection and destruction by HIV. This proposal describes studies that examine the function of this subset and the role of the CD8 molecule on CD4+ T cells. We will examine the expression of this molecule during CD4+ T cell activation, as well as the phenotypic and function characteristics of this cell type. We will investigate the following three Specific Aims 1) Further explore the acquisition of CD8 expression by CD4+ T cells, 2) Determine the function of the CD8 molecule on CD4+ T cells, 3) To examine the functional role of CD8 expression on CD4+ T cells in vivo in response to viral infection and alloantigen. The experiments outlined in this proposal will help us understand the role of CD8 on CD4+ T cells and the effects of HIV infection on this subset. Further, it will allow us to determine the function of the CD4+CD8dim subset seen in vivo. These studies combined will allow us to determine the possible effects that the appearance or loss of this subset may have on HIV disease progression and antiviral immunity.
Keywords: CD8 molecule, HIV infection, helper T lymphocyte, leukocyte activation /transformation, virus infection mechanism, HIV envelope protein gp120, cytotoxic T lymphocyte, immunoregulation, clinical research, flow cytometry, human subject, laboratory mouse, polymerase chain reaction
Project start date: 2003-08-01
Project end date: 2006-07-31
5R21AI057057-02 (2004): $230376
1R21AI057057-01 (2003): $228876
THE ROLE OF CD4 IN MACROPHAGE DIFFERENTIATION AND FUNCTION
Scott G Kitchen, Assistant Professor
University Of California Los Angeles, Office Of Research Administration, Los Angeles, Ca 90095
Grant 5R01AI078806-02 from National Institute Of Allergy And Infectious Diseases
Abstract: The CD4 molecule has an important role in the human immune system and in the pathogenesis of HIV. A key factor in HIV pathogenesis is the use of the CD4 molecule as the primary receptor for cellular infection. In addition to CD4+ T helper cells, there are numerous other cells of the immune system that express CD4 that are susceptible to infection by HIV. One of the primary targets and an important and poorly understood reservoir for HIV in an infected individual are monocytes/macrophages. Other than allowing HIV infection of these cells, the role of the CD4 receptor in the function and development of monocyte/macrophages is not known. We have recently determined that ligation of CD4 on monocytes/macrophages modulates gene and cytokine protein expression as well as T cell responses. We are interested in examining this and other roles and functions of the CD4 molecule on the monocyte/ macrophage cell subset. Our central hypothesis in this proposal is that CD4 has a role in monocyte/ macrophage differentiation and function by modulating the expression of factors that control cellular development and other immune responses. This, in turn, has important implications in HIV infection and the understanding of the monocyte/ macrophage reservoir of infected cells in disease progression. This proposal will focus on addressing these issues and will focus on the following three Specific Aims 1. To determine the mechanisms regulating CD4 expression during monocyte/macrophage development. 2. To determine the function(s) and consequence(s) of CD4 expression during monocyte/macrophage lineage differentiation and development. 3. To determine the role(s) of the CD4 molecule on mature monocyte/ macrophage function. To achieve this, we will utilize a novel embryonic stem cell-based system that we can genetically manipulate and examine monocyte/ macrophage differentiation and function from a cell type that is among the earliest in human hematopoietic development. In summary, it is anticipated that these studies will shed light on the potential roles and importance of CD4 in monocyte/macrophage development and/or function. Further, it is anticipated that the proposed studies will allow a more comprehensive understanding of the consequences of HIV infection in this cell type. The experimental approach described in this proposal is designed to address the central hypothesis that the CD4 molecule has a broader function in the immune response, and by extension in HIV pathogenesis, than its capacity on CD4+ T helper cells. These studies will increase our knowledge of how the CD4 molecule influences monocyte/ macrophage development and immune function and how HIV may impact this process; thus, increasing our understanding of the mechanisms of HIV infection and pathogenesis. Further, the use of embryonic stem cells in these studies, due to their high plasticity, self-renewal ability, and ability to be genetically manipulated, may allow the development of immune replacement therapeutic strategies to be developed for HIV and other similar diseases
Keywords: AIDS; AIDS Virus; APC; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immune Deficiency Syndrome Virus; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Acquired Immunodeficiency Syndrome Virus; Address; Antigen-Presenting Cells; Blood monocyte; Body Tissues; CD4 Antigen (P55); CD4 Antigens; CD4 Molecule; CD4 Positive T Lymphocytes; CD4 Protein; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD8; CD8B; CD8B1; CD8B1 gene; Cancers; Canine Species; Canis familiaris; Cell Function; Cell Process; Cell physiology; Cells; Cells, CD4; Cellular Function; Cellular Physiology; Cellular Process; Cessation of life; Closure by Ligation; Coupled; Cytokine Gene; Cytotoxic cell; Death; Defect; Derivation; Derivation procedure; Development; Disease; Disease Progression; Disorder; Dogs; ES cell; Family suidae; HIV; HTLV-III; Helper Cells; Helper T-Cells; Helper-Inducer T-Lymphocyte; Hematopoietic; Hortega cell; Human; Human Immunodeficiency Viruses; Human T-Cell Leukemia Virus Type III; Human T-Cell Lymphotropic Virus Type III; Human T-Lymphotropic Virus Type III; Human, General; Immune; Immune Function, Cellular; Immune response; Immune system; Immunologic Accessory Cells; Immunologic Deficiency Syndrome, Acquired; Individual; Inducer Cells; Infection; K lymphocyte; Knowledge; LAV-HTLV-III; LYT3; Ligation; Light; Lymphadenopathy-Associated Virus; Malignant Neoplasms; Malignant Tumor; Mammals, Dogs; Mammals, Mice; Mammals, Primates; Man (Taxonomy); Man, Modern; Marrow monocyte; Mice; Microglia; Monocytes / Macrophages / APC; Murine; Mus; NK Cells; Natural Killer Cells; Nature; OKT4 antigen; Opportunistic Infections; Organ; Pathogenesis; Photoradiation; Pigs; Play; Primates; Process; Public Health; Receptor Protein; Receptors, CD4; Receptors, Surface CD4; Research; Role; Subcellular Process; Suidae; Swine; System; System, LOINC Axis 4; T cell response; T-Cell Antigen T4/Leu3; T-Cell Surface Antigen T4/Leu-3; T-Cells; T-Cells, Helper-Inducer; T-Lymphocyte; T-Lymphocytes, Helper; T-Lymphocytes, Inducer; T4 Cells; T4 Lymphocytes; T4 molecule; Therapeutic; Thymus-Dependent Lymphocytes; Tissues; Viral Diseases; Virus; Virus Diseases; Virus-HIV; Viruses, General; accessory cell; base; body system, allergic/immunologic; canine; cell type; cellular development; cytokine; design; designing; disease/disorder; domestic dog; embryonic stem cell; genetic manipulation; gitter cell; hESC; helper T cell; helper T lymphocyte marker; host response; human ES cell; human ESC; human embryonic stem cell; immune function; immunoresponse; interest; macrophage; malignancy; mesoglia; microglial cell; microgliocyte; monocyte; neoplasm/cancer; novel; organ system, allergic/immunologic; pathogen; perivascular glial cell; porcine; protein expression; public health medicine (field); public health relevance; receptor; self-renewal; social role; stem cell of embryonic origin; suid; thymocyte; thymus derived lymphocyte; viral infection; virus infection; virus pathogenesis
Relevance: Relevance to Public Health The experimental approach described in this proposal is designed to address the central hypothesis that the CD4 molecule has a broader function in the immune response, and by extension in HIV pathogenesis, than its capacity on CD4+ T helper cells. These studies will increase our knowledge of how the CD4 molecule influences monocyte/ macrophage development and immune function and how HIV may impact this process; thus, increasing our understanding of the mechanisms of HIV infection and pathogenesis. Further, the use of embryonic stem cells in these studies, due to their high plasticity, self-renewal ability, and ability to be genetically manipulated, may allow the development of immune replacement therapeutic strategies to be developed for HIV and other similar diseases
Project start date: 2009-07-01
Project end date: 2014-06-30
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
PFA/PA: PA-07-070
5R01AI078806-02 (2010): $381150
Scott G Kitchen, Assistant Professor
University Of California Los Angeles, Office Of Research Administration, Los Angeles, Ca 90095
Abstract: In vivo models are critical to the understanding of viral diseases. The lack of animal models that display pathology following infection with human immunodeficiency virus type 1 (HIV-1) has hindered our knowledge of the viral mechanisms associated with pathogenesis. The development of human/immunodeficient mouse chimeras has provided novel model systems with which to study the human immune system and the effect of HIV infection on human cells and tissues. These models involve transplantation of various types of human tissues into mice who possess one of several types of immune defects. These defects prevent the rejection of the transplanted tissue by the host, thereby providing an in vivo environment for culturing human tissue. The CFAR-supported Mouse/Human Chimera Core is designed to assist AIDS investigators at UCLA with their research by providing state-of-the-art human/mouse chimera technologies and appropriate animal housing facilities. This facility will supply and house several types of immunodeficient mice for AIDS-related research under both Biosafety Level 2 and Biosafety Level 2+ conditions. This facility will also provide consultation on the use of chimeric models, as well as construct various mouse/human chimeric animals for distribution to Core users
Keywords: AIDS; AIDS Virus; Acquired Immune Deficiency; Acquired Immune Deficiency Syndrome; Acquired Immuno-Deficiency Syndrome; Acquired Immunodeficiency Syndrome; Animal Housing; Animal Model; Animal Models and Related Studies; Animals; Animals, Laboratory; Arts; Biological Models; Blood; Blood Precursor Cell; Body Tissues; Cells; Chimera; Chimera organism; Consultations; Defect; Disease; Disorder; Environment; Epidemic; Expertise, Technical; Gene Transfer Clinical; Gene Transfer Procedure; Gene-Tx; Genetic Intervention; Goals; Graft Material; HIV Infections; HIV-1; HIV-I; HIV1; HTLV-III Infections; HTLV-III-LAV Infections; Hematopoietic stem cells; Housing; Housing, Animal; Human; Human Development; Human immunodeficiency virus 1; Human, General; Immune; Immune system; Immunodeficiency Virus Type 1, Human; Immunodeficient Mouse; Immunologic Deficiency Syndrome, Acquired; Infection; Intervention, Genetic; Investigators; Knowledge; Laboratory Animals; Mammals, Mice; Man (Taxonomy); Man, Modern; Mice; Model System; Modeling; Models, Biologic; Molecular Biology, Gene Therapy; Murine; Mus; Pathogenesis; Pathology; Progenitor Cells, Hematopoietic; Research; Research Personnel; Researchers; Reticuloendothelial System, Blood; T-Lymphotropic Virus Type III Infections, Human; Technical Expertise; Technology; Therapy, DNA; Tissues; Transplantation; Transplanted tissue; Viral; Viral Diseases; Virus; Virus Diseases; Viruses, General; body system, allergic/immunologic; cost; design; designing; disease/disorder; gene therapy; genetic therapy; human T cell leukemia virus III; human T lymphotropic virus III; human tissue; in vivo; in vivo Model; model organism; mouse development; novel; organ system, allergic/immunologic; prevent; preventing; transplant; viral infection; virus infection
Budget start date: 1-MAR-2010
Budget end date: 28-FEB-2011
5P30AI028697-21_9022 (2010): $77958