PREVENTION OF UV-CARCINOGENESIS THROUGH DNA REPAIR-DEPENDENT IMMUNOMODULATION
Xu Hui
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 5R01CA140197-03 from National Cancer Institute
Keywords: Accounting; Address; Adverse effects; Affect; Age; Animal Model; Antigens; Artichoke; base; Bone Marrow Transplantation; carcinogenesis; Caucasians; Caucasoid Race; Cells; Chemopreventive Agent; Chronic; Contact hypersensitivity; Cosmetics; Cutaneous Melanoma; cytokine; Data; Defect; Dendritic Cells; Development; Devices; DNA Damage; DNA Repair; Effector Cell; Environment; Equilibrium; Excision; Expenditure; Exposure to; Family; Flavonoids; Generations; Genetic; Goals; Haptens; Healthcare; Human; Immune response; Immune system; immunoregulation; Immunosuppressive Agents; improved; In Vitro; in vivo; Incidence; Inflammation Mediators; insight; Interferons; Interleukin-10; Interleukin-12; Interleukin-4; Interleukin-5; Knowledge; Langerhans cell; Lead; Link; Malignant Neoplasms; Mediating; member; Milk Thistle; Molecular; mouse model; Mus; Natural immunosuppression; novel; Nucleotide Excision Repair; Ozone; Phytochemical; Plants; Population; prevent; Prevention; Preventive; Production; public health medicine (field); public health relevance; Pyrimidine Dimers; Regulatory T-Lymphocyte; repaired; research study; response; restoration; Risk; Silymarin; Skin; Skin Cancer; skin cancer prevention; Skin Carcinoma; Skin Neoplasms; Skin tanning; Skin Tissue; Squamous cell carcinoma; Suppressor-Effector T-Lymphocytes; Surface; T-Cell Activation; T-Lymphocyte; Testing; Th2 Cells; The Sun; tumor; ultraviolet; ultraviolet irradiation; Ultraviolet Rays; United States; UV induced; UV Radiation Exposure; UVB induced
Relevance: Chronic exposure of the skin to solar ultraviolet (UV) radiation induces multiple adverse effects including the risk of skin cancer development. In vitro and in vivo studies have indicated that silymarin, a plant flavonoid obtained from milk thistle, possesses potent anti-photocarcinogenic activity. In the current application, we will determine the molecular mechanism of prevention of photocarcinogenesis by silymarin. This study will also highlight that rapid repair of UVB-induced DNA damage by silymarin will result in the enhancement or restoration of immune system and that will lead to the prevention of UV-carcinogenesis. The generation of new knowledge will provide novel insights into the mechanisms by which silymarin can either correct, or compensate for, the UV-induced damage that triggers or promotes photocarcinogenesis
Project start date: 2010-07-01
Project end date: 2014-12-31
Budget start date: 1-JAN-2012
Budget end date: 31-DEC-2012
5R01CA140197-03 (2012): $298556
Sponsored Links Excellgen http://Excellgen.com
PREVENTION OF UV-CARCINOGENESIS THROUGH DNA REPAIR-DEPENDENT IMMUNOMODULATION
Xu Hui, Associate Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 5R01CA140197-02 from National Cancer Institute
Abstract: The goals of the proposed studies are to (1) Identify the mechanisms by which silymarin, a phytochemical obtained from milk thistle (Silybum marianum L.), ameliorates ultraviolet (UV) radiation-induced immunosuppression and DNA damage; and (2) Determine the contribution of these mechanisms to silymarin-mediated prevention of skin cancer. Both UV-induced DNA damage, in the form of cyclobutane pyrimidine dimers (CPDs), and immune suppression have been shown to be associated with an increased risk of skin cancer. We have demonstrated that topical treatment with silymarin provides significant protection against both UV-induced immunosuppression and carcinogenesis in an in vivo mouse model. UV irradiation is known to impair the function of dendritic cells and effector T cells but induce suppressor T cells. Furthermore, UV-induced DNA damage, predominantly the formation of CPDs, is an important molecular trigger for UV-mediated immunosuppression. We have demonstrated that silymarin has the ability to enhance the removal or repair of CPD+ cells in UV-exposed skin, and inhibits UVB-induced suppression of the contact hypersensitivity response in mice. Our preliminary data further indicate that silymarin can enhance the removal of CPDs in UV-exposed dendritic cells and restore dendritic cell-mediated activities including stimulation of T cells. However, silymarin mediated inhibition of UV-induced immunosuppression is abolished in mice that have defect in DNA repair. Collectively, these data implicate key links between the ability of silymarin to inhibit UV-induced immunosuppression and its ability to prevent photocarcinogenesis. Our hypothesis is that the repair of UVB-induced DNA damage by silymarin is critical for its chemopreventive effects on UV-induced immunosuppression and photocarcinogenesis. We propose four inter-related Specific Aims in which we will use genetically modified mouse model, including nucleotide excision repair-deficient mice (1) Determine whether silymarin inhibits the development of UV-induced tolerogenic dendritic cells through restoration of dendritic cell activity; (2) Determine whether silymarin- induced inhibition of UV-induced immunosuppression occurs through enhancement of T-cell activation, (3) Determine whether silymarin inhibits the development of UV-induced regulatory T cells; and (4) Determine whether silymarin inhibition of photocarcinogenesis is mediated through DNA repair. The proposed studies should identify the mechanisms by which silymarin acts to correct UV-induced immunosuppression in photocarcinogenesis. We address a major public health concern as overexposure of the human skin to solar UV radiation is the major etiologic factor for the development of melanoma and non-melanoma skin cancers in the United States. The development of new strategies using silymarin may help to reduce the risk of skin cancer in humans. Chronic exposure of the skin to solar ultraviolet (UV) radiation induces multiple adverse effects including the risk of skin cancer development. In vitro and in vivo studies have indicated that silymarin, a plant flavonoid obtained from milk thistle, possesses potent anti-photocarcinogenic activity. In the current application, we will determine the molecular mechanism of prevention of photocarcinogenesis by silymarin. This study will also highlight that rapid repair of UVB-induced DNA damage by silymarin will result in the enhancement or restoration of immune system and that will lead to the prevention of UV-carcinogenesis. The generation of new knowledge will provide novel insights into the mechanisms by which silymarin can either correct, or compensate for, the UV-induced damage that triggers or promotes photocarcinogenesis
Keywords: 2-Phenyl-Benzopyrans; 2-Phenyl-Chromenes; Abscission; Accounting; Actinic Rays; Address; Adverse effects; Affect; Age; Animal Model; Animal Models and Related Studies; anticarcinogenic; Antigens; Artichoke; ATGN; B cell activating factor; B Cell Differentiation Factor I; B cell growth factor; B cell growth factor 2; B-Cell Differentiation Factor-1; B-Cell Growth Factor-1; B-Cell Growth Factor-I; B-Cell Growth Factor-II; B-Cell Proliferating Factor; B-Cell Stimulating Factor; B-Cell Stimulating Factor-1; B-Cell Stimulation Factor-1; B-Cell Stimulatory Factor-1; BAF; balance; balance function; base; BCDF-1; BCGF; BCGF-1; BCGF-II; BCGF2; BCGF2 (B cell growth factor 2); BCSF 1; Binetrakin; body system, allergic/immunologic; Bone Marrow Transplant; Bone Marrow Transplantation; BSF-1; BSF1; BSF1 (B cell stimulating factor 1); Cancer Induction; Cancers; carcinogenesis; Carcinoma, Epidermoid; Carcinoma, Planocellular; Carcinoma, Squamous; Carduus marianus; Care, Health; Caucasian; Caucasian Race; Caucasians; Caucasoid; Caucasoid Race; Cells; Chemopreventive; Chemopreventive Agent; Chronic; Contact hypersensitivity; cosmetic product; Cosmetics; CSIF; CSIF-10; Cutaneous Melanoma; Cyclobutane-Pyrimidine Dimers; cytokine; Cytokine formation-inhibiting factor (mouse clone F115 protein moiety reduced); Cytokine Synthesis Inhibitory Factor; Data; Defect; Dendritic Cells; Development; Devices; DNA Damage; DNA Damage Repair; DNA Injury; DNA Repair; EDF; Edodekin Alfa; Effector Cell; Environment; Eo-CSF; Eosinophil Differentiation Factor; Equilibrium; Excision; Expenditure; experiment; experimental research; experimental study; Exposure to; Exposure to ultraviolet radiation; Extirpation; Family; Flavonoids; Generations; Genetic; Goals; Grafting, Bone Marrow; Haptens; Healthcare; heavy metal lead; heavy metal Pb; host response; Human; Human, General; IFN; IgA enhancing factor; IL-10; IL-12; IL-4; IL-5; IL10; IL10A; IL12; IL4; IL4 Protein; IL5; immune modulation; Immune response; Immune system; immunogen; immunologic reactivity control; Immunomodulation; immunoregulation; immunoresponse; Immunosuppressants; immunosuppression; Immunosuppression Effect; Immunosuppressions (Physiology); immunosuppressive; Immunosuppressive Agents; Immunosuppressive Effect; improved; In Vitro; in vivo; Incidence; Inflammation Mediators; insight; Interferons; Interleukin 10 Precursor; Interleukin 5 (Colony-Stimulating Factor, Eosinophil); Interleukin 5 Precursor; Interleukin-10; Interleukin-12; Interleukin-4; Interleukin-4 Precursor; Interleukin-5; Knowledge; Langerhans cell; Lead; Link; Lymphocyte Stimulatory Factor 1; malignancy; Malignant Cutaneous Melanoma; Malignant Melanoma of Skin; Malignant Melanoma of Skin Stage Unspecified; Malignant Neoplasms; Malignant Skin Neoplasm; Malignant Tumor; Malignant Tumor of the Skin; Mammals, Mice; Man (Taxonomy); Man, Modern; Marrow Transplantation; Mast Cell Growth Factor-2; MCGF-2; Mediating; Melanoma and Non-Melanoma Skin Cancer; member; Mice; Milk Thistle; model organism; Molecular; mouse model; Murine; Mus; Natural immunosuppression; Natural Killer Cell Stimulatory Factor; neoplasm/cancer; NKSF; nonmelanoma skin cancer; novel; Nucleotide Excision Repair; Occidental; organ system, allergic/immunologic; Ozone; Pb element; Phytochemical; Plants; Plants, General; Population; prevent; Prevent skin cancer; preventing; Prevention; Prevention of Skin Cancer; Preventive; Production; Public Health; public health medicine (field); public health relevance; Pyrimidine Dimers; Regulatory T-Lymphocyte; Removal; repair; repaired; research study; resection; response; restoration; Risk; side effect; Silimarin; Silybum marianum; Silymarin; Skin; Skin Cancer; skin cancer prevention; Skin Cancer, Including Melanoma; Skin Cancer, Non-Melanoma; Skin Carcinoma; Skin Neoplasms; Skin tanning; Skin Tissue; Skin, Melanoma; Squamous cell carcinoma; Squamous Cell Epithelioma; Sun/Ultra-Violet Rays; Suppressor Cells; suppressor T lymphocyte; Suppressor-Effector T-Lymphocytes; Surface; Surgical Removal; T cell replacing factor; T Suppressor Cell; T-Cell Activation; T-Cell Growth Factor 2; T-Cell Replacing Factor; T-Cells; T-Cells, Suppressor-Effector; T-Lymphocyte; T-Lymphocytes, Suppressor-Effector; Tanning; Tannings; Testing; Th-2 Cell; Th2 Cells; The Sun; therapy adverse effect; thymus derived lymphocyte; Thymus-Dependent Lymphocytes; treatment adverse effect; Treatment Side Effects; tumor; Tumor of the Skin; Type 2 Helper Cell; ultra violet irradiation; ultraviolet; ultraviolet irradiation; ultraviolet light; ultraviolet radiation; Ultraviolet Radiation Related Exposure; Ultraviolet Rays; United States; Unscheduled DNA Synthesis; UV exposure; UV induced; UV irradiated; UV irradiation; UV irridated; UV radiation; UV Radiation Exposure; UVB induced; Veiled Cells; white race
Relevance: Chronic exposure of the skin to solar ultraviolet (UV) radiation induces multiple adverse effects including the risk of skin cancer development. In vitro and in vivo studies have indicated that silymarin, a plant flavonoid obtained from milk thistle, possesses potent anti-photocarcinogenic activity. In the current application, we will determine the molecular mechanism of prevention of photocarcinogenesis by silymarin. This study will also highlight that rapid repair of UVB-induced DNA damage by silymarin will result in the enhancement or restoration of immune system and that will lead to the prevention of UV-carcinogenesis. The generation of new knowledge will provide novel insights into the mechanisms by which silymarin can either correct, or compensate for, the UV-induced damage that triggers or promotes photocarcinogenesis
Project start date: 2010-07-01
Project end date: 2014-12-31
Budget start date: 1-JAN-2011
Budget end date: 31-DEC-2011
PFA/PA: PA-07-070
5R01CA140197-02 (2011): $307788
Grants awarded to Xu Hui
THE ROLE OF CD5 IN DENDRITIC CELL MEDIATED IMMUNE SUPPRESSION
Xu Hui, Associate Professor
University Of Alabama At Birminghamcity: Birmingham country: United States (us)
Grant 5R21AR057163-02 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: The immune system is not supposed to react to self-antigens (tolerance) but does recognize and eliminate non-self antigens (immunity). However, over reaction of the immune system to non-self antigens can cause diseases termed hypersensitivity. Contact hypersensitivity (CHS) is a T cell mediated delayed type hypersensitivity response to haptens in the skin. Dendritic cells (DC) are prominent antigen presenting cells for the induction of CHS responses. However, less is known about DC mediated suppressive mechanisms in the immune response. CD5 is a surface molecule which is expressed by T cells and DC. It is well known that CD5 mediates inhibitory signals for T cells and plays important roles in immune tolerance. However, it is unexplored whether CD5 expressed on DC has a role in DC mediated immune regulations. Our preliminary studies have showed that CD5 is expressed by CD11c+ myeloid and lymphoid DC from spleen, lymph node and thymus whereas it is not detectable in plasmacytoid DC. Transfer of hapten labeled CD11c+ DC from CD5 gene knockout (CD5-/-) mice induces a significant higher level of CHS responses than wild type DC. Correspondingly, hapten primed T cells from CD5-/- DC sensitized mice produce higher levels of inflammatory cytokines than those from wild type DC sensitized animals. Further experiments show that CD5-/- DC are more potent than wild type DC to activate CD4+ and CD8+ T cells and induce anti-tumor immunity. These data have for the first time demonstrated that CD5 molecules expressed on DC have an inhibitory effect on DC functions in the activation of T cells and induction of immune responses. The hypothesis of the current application is that the CD5-CD5 interaction between DC and T cells inhibits T cell activation and is an important mechanism for DC induced immune suppression. Three specific aims are proposed to examine the hypothesis. Aim 1 is to determine whether CD5 is an inhibitory molecule for DC mediated activation of T cells and induction of immune responses. We will examine whether restoration or over-expression of CD5 by CD5-/- DC inhibits their functions and renders DC tolerogenic. We will also examine whether an effect of CD5 on the development of T cell subpopulations is a mechanism for DC CD5 mediated effects on immune responses. Aim 2 will determine whether CD5 molecules expressed on DC have an inhibitory effect on effector T cells and regulate the elicitation of immune responses. We will examine mechanism by which CD5 expressed on DC regulates effector T cells and whether application of DC with a high level of CD5 expression can desensitize hapten sensitized animals to hapten challenge. Aim 3 will examine mechanisms by which CD5 expressed on DC inhibits T cell activation and DC function. We will determine whether CD5 is a homotypic ligand for CD5 mediated suppression of T cell activation or CD5 mediated signals in DC are responsible for the suppression of DC functions. The outcome of the proposal will yield new insights into a novel role of CD5 in DC mediated immune regulations, advance our understandings of immune pathogenesis for hypersensitivity diseases, and provide important information for development of new therapeutic strategies. CD5 is a membrane protein that mediates inhibitory signals for T lymphocyte activation and plays important roles in inflammatory immune diseases. Antigen presenting dendritic cells are required for the activation of T lymphocytes and induction of immune responses. It is unknown whether CD5-CD5 interactions between antigen presenting dendritic cells and T lymphocytes regulate immune responses. The current proposal will determine whether the expression level of CD5 by antigen presenting dendritic cells is related to their ability to inhibit the function of lymphocytes in immune responses. The outcome will elucidate a novel mechanism for CD5 mediated immune suppression in inflammatory diseases and may be exploited to new therapeutic strategies
Keywords: Animals; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Diseases; B-Lymphocyte Subsets; B-Lymphocytes; base; CD5 Antigens; CD8B1 gene; Cell physiology; Cellular biology; Contact hypersensitivity; cytokine; Data; Delayed Hypersensitivity; Dendritic Cells; Development; Disease; Exposure to; functional status; Funding; Grant; Haptens; Hypersensitivity; Immune; Immune response; Immune system; Immune System Diseases; Immune Tolerance; Immunity; Inflammatory; insight; ITGAX gene; knockout gene; Label; Ligands; lymph nodes; Lymphocyte Activation; Lymphocyte Function; Lymphoid; Mature T-Lymphocyte; Mediating; Membrane Proteins; Mus; Myelogenous; Natural immunosuppression; novel; novel therapeutics; Outcome; Pathogenesis; Play; public health relevance; Reaction; Regulation; research study; response; restoration; Role; Signal Transduction; Skin; Spleen; Surface; T-Cell Activation; T-Cell Development; T-Lymphocyte; thymocyte; Thymus Gland; Time; tumor; Tumor Immunity
Relevance: CD5 is a membrane protein that mediates inhibitory signals for T lymphocyte activation and plays important roles in inflammatory immune diseases. Antigen presenting dendritic cells are required for the activation of T lymphocytes and induction of immune responses. It is unknown whether CD5-CD5 interactions between antigen presenting dendritic cells and T lymphocytes regulate immune responses. The current proposal will determine whether the expression level of CD5 by antigen presenting dendritic cells is related to their ability to inhibit the function of lymphocytes in immune responses. The outcome will elucidate a novel mechanism for CD5 mediated immune suppression in inflammatory diseases and may be exploited to new therapeutic strategies
Project start date: 2010-07-01
Project end date: 2012-04-30
Budget start date: 1-MAY-2011
Budget end date: 30-APR-2012
PFA/PA: PA-09-164
5R21AR057163-02 (2011): $158220