Andrew D Wells
Childrens Hospital Of Philadelphia
Project start date: 2008-01-15
Project end date: 2012-12-31
Sponsored Links Excellgen http://Excellgen.com
Andrew D Wells, Assistant Professor
Children´s Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Grant 5R01AI070807-03 from National Institute Of Allergy And Infectious Diseases
Keywords: Aldesleukin Gene; Animal Welfare; Autoimmune Diseases; B-Cell Stimulatory Factor 1 Gene; BSF-1 Gene; BSF1 Gene; Bibliography; Binding; Binding (Molecular Function); CD25; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD8; CD8B; CD8B1; CD8B1 gene; CSIF; CSIF-10; Carcinoma; Cell Function; Cell Process; Cell physiology; Cells; Cells, CD4; Cellular Function; Cellular Physiology; Cellular Process; Clinical, Transplantation, Organ; Co-Stimulator; Costimulator; Country; Cytokine Gene; Cytokine Synthesis Inhibitory Factor; Cytokine formation-inhibiting factor (mouse clone F115 protein moiety reduced); DNA Binding; DNA Binding Interaction; DNA-Binding Proteins; Diabetes Mellitus; Ecological impact; Environment; Environmental Impact; Epidermal Thymocyte Activating Factor; Epithelial Neoplasms, Malignant; Epithelial Tumors, Malignant; Equipment; Ethics Committees, Research; Experimental Models; Experimental Models, Other; Family; Figs; Figs - dietary; Gene Expression; Gene Targeting; Gene Transcription; Genetic Algorithm; Genetic Alteration; Genetic Change; Genetic Programming; Genetic Transcription; Genetic defect; Graft Rejection; Grafting Procedure; Human; Human Resources; Human, General; IACUC; IL-10; IL-2; IL-2 Gene; IL-4 Gene; IL10; IL10A; IL2; IL2 Protein; IL2 gene; IL2R; IL2RA; IL2RA gene; IL4; IL4 gene; IRBs; Immune; Immune Tolerance; Immunologic Tolerance; Impact, Environmental; Inflammatory; Institutional Animal Care and Use Committee; Institutional Review Boards; Interleukin 10 Precursor; Interleukin 2; Interleukin 2 Precursor; Interleukin 2 Precursor Gene; Interleukin II; Interleukin-10; Interleukin-2; Interleukin-2 Gene; Interleukin-4 Gene; Interleukin-4 Precursor Gene; Interleukine 2; Interleukine 2 Precursor; Interleukine II; International; Investigators; Jurkat Cells; LYT3; Laboratories; Literature; Lymphocyte Mitogenic Factor; Mammals, Mice; Man (Taxonomy); Man, Modern; Manpower; Methods and Techniques; Methods, Other; Mice; Mitogenic Factor; Modeling; Models, Experimental; Molecular; Molecular Interaction; Murine; Mus; Mutation; Names; Organ Transplantation; Organ Transplants; Organ Transplants, Including Bone Marrow for DCT; Participant; Pathology; Principal Investigator; Programs (PT); Programs [Publication Type]; Promoter; Promoters (Genetics); Promotor; Promotor (Genetics); Publishing; RNA Expression; Regulation; Regulatory T-Lymphocyte; Reporter; Repression; Research; Research Ethics Committees; Research Personnel; Research Resources; Researchers; Resources; Reticuloendothelial System, Thymus; Retroviral Vector; Retrovirus Vector; Structure; Subcellular Process; T cell growth factor; T-Cell Growth Factor; T-Cell Growth Factor Gene; T-Cell Stimulating Factor; T-Cells; T-Lymphocyte; T-Lymphocyte, Regulatory; T4 Cells; T4 Lymphocytes; TCGF Gene; TCGFR; Targetings, Gene; Techniques; Thymocyte Stimulating Factor; Thymus; Thymus Gland; Thymus Proper; Thymus-Dependent Lymphocytes; Transcription; Transcription, Genetic; Transplant Rejection; Transplantation Rejection; Transplantation Surgery; Vertebrate Animals; Vertebrates; ing; allograft rejection; autoimmune disorder; design; designing; diabetes; epithelial carcinoma; experience; experiment; experimental research; experimental study; expiration; gene induction; genome mutation; helper T cell; human subject; immune system tolerance; immune unresponsiveness; immunological paralysis; improved; member; mutant; new therapeutics; next generation therapeutics; novel therapeutics; organ allograft; organ graft; organ xenograft; personnel; programs; research study; thymus derived lymphocyte; vertebrata
Project start date: 2008-01-15
Project end date: 2012-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2010
PFA/PA: PA-07-070
5R01AI070807-03 (2010): $333113
Grants awarded to Andrew D Wells
T CELL DIVISION, SURVIVAL AND MEMORY IN TRANSPLANTATION
Andrew D Wells
Pathology And Lab Medicineuniversity Of Pennsylvania
3451 Walnut Street
philadelphia, Pa 19104
Grant 5K01DK002771-02 from National Institute Of Diabetes And Digestive And Kidney Diseases IRG: DDK
Abstract: The immune responses that cause transplant rejection and many autoimmune disorders such as diabetes mellitus are T cell-dependent. T cells responding to alloantigens or autoantigens produce cytokines and proliferate, leading to the differentiation of immune effector cells including T cells themselves, macrophages, and B cells. While a tremendous degree of proliferation occurs during this process, it is clear that a great deal of cell death occurs as well. The balance between survival and death is an important factor in determining the strength and longevity of the response. In the case of organ transplants, this initial response is manifest as acute rejection. An equally important immunologic event is the emergence of memory T cells, the small population of previously activated cells which do not die early in the response. In the case of organ transplantation, these memory cells mediate chronic rejection (the most common cause of late allograft loss, and a major clinical dilemma), and are important in providing help to B cells that produce alloantibody (the sine qua non of "sensitized" patients, and a major contributor to extended times on transplant waiting lists). Recently, using dye-labeling techniques to both monitor and physically sort individual T cells as a function of proliferative status, we and others have shown that T cells responding to antigen exhibit surprising heterogeneity with respect to proliferation, and that this strongly correlates with cytokine production. We have also used mice transgenic for the cell survival gene bcl-xL to develop a model in which the effector function and the survival of a responding T cell can be uncoupled, allowing us to independently assess the contribution of these two immune parameters to the induction of memory or tolerance. These data suggest that cell survival is sufficient for the development of memory, even when effector function of T cells has been significantly compromised. In this application, we propose to use T cell receptor transgenic mice specific for alloantigen and nominal antigen to study immune responses during transplantation and immunization at the single-cell level. In aim number l, we will determine if cell division plays an independent role in determining the functional outcome (tolerance vs. memory) of a T cell response. In aim number 2, we will determine if cell death plays an active role in determining the functional outcome (tolerance vs. memory) of a T cell response. Together, these studies should greatly enhance our understanding as to how these phenomena interact to shape immune responses, facilitating the design of novel strategies to induce tolerance in transplantation and autoimmunity
Keywords: T lymphocyte, cell death, immunologic memory, lymphocyte proliferation, transplantation immunology T cell receptor, immune tolerance /unresponsiveness, passive immunization laboratory mouse, transgenic animal
Project start date: 2000-03-15
Project end date: 2003-01-31
5K01DK002771-02 (2001): $92340
1K01DK002771-01 (2000): $92340
Growth Factor Signaling, Cell Division And T Cell Anergy
Andrew D Wells
Children s Hospital Of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318
Grant 5R01AI054643-05 from National Institute Of Allergy And Infectious Diseases IRG: SAT
Abstract: T cell anergy is an important mechanism of peripheral tolerance that controls the development of immunopathology in experimental models of autoimmunity and transplantation, and is most likely operative in the context of clinical organ transplantation in humans. The immunologically important costimulatory receptors CD28 and CTLA-4 regulate in the induction of anergy, primarily through their effects on the production of T cell growth factors. T cell growth factors such as IL-2 are potent inhibitors of T cell anergy, and likewise exert a powerful influence on the outcome of allograft responses. Despite the wealth of information concerning the means by which growth factors promote the proliferation and survival of T cells, surprisingly little is known about how T cell growth factors oppose the induction of anergy, and precisely how such growth factors as IL-2 and IL-15 promote graft rejection during an alloimmune response is unclear. The goal of this proposal is to further dissect how signals from CD28, CTLA-4 and IL-2 control the decision between anergy and effector differentiation, and to what extent these signals operate through the regulation of cell division. The experiments described here should allow us to determine whether cell cycle progression is necessary or sufficient for IL-2-mediated anergy avoidance, and to identify which IL-2 receptor-coupled signaling pathways specifically contribute to anergy avoidance and effector T cell differentiation. The specific questions we will address are 1) Do toleragenic stimuli induce anergy in primary T cells by inhibiting cell cycle progression?, 2) Which aspects of IL-2 receptor-coupled signal transduction are important for anergy avoidance and development of effector function in primary T cells?, and 3) How do growth factor-coupled signaling pathways and/or growth factor-driven cell division contribute to T cell effector function in vivo during an alloimmune response? A more thorough understanding of how CD28, CTLA-4 and IL-2 contribute to the induction of T cell anergy and the development of tolerance in a clinical transplantation setting may lead to therapeutic approaches with greater specificity and success.
Keywords: T lymphocyte, anergy, biological signal transduction, cell cycle, growth factor, CD28 molecule, T cell receptor, autoimmunity, cell differentiation, cell growth regulation, cytokine receptor, delayed hypersensitivity, differentiation antigen, extracellular matrix protein, gene expression, immunoregulation, interferon gamma, interleukin 2, isoantigen, mitogen activated protein kinase, phosphatidylinositol 3 kinase, transcription factor, gene targeting, genetically modified animal, laboratory mouse
Project start date: 2002-07-15
Project end date: 2007-04-30
5R01AI054643-05 (2006): $332010
5R01AI054643-04 (2005): $340000
5R01AI054643-03 (2004): $340000
1R01AI054643-01 (2002): $306000
CYCLIN-DEPENDENT KINASES: NOVEL SWITCHES IN ANERGY AND TARGETS FOR TOLERANCE
Andrew D Wells, Assistant Professor
Children´s Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Grant 5R01AI054643-08 from National Institute Of Allergy And Infectious Diseases
Abstract: T cell anergy is an important mechanism of peripheral tolerance that controls the development of immunopathology in experimental models of autoimmunity and transplantation, and is most likely operative during clinical organ transplantation in humans. Anergy involves the functional inactivation of inappropriate T cell responses, and is thought to be the result of active silencing of effector genes such as interleukin-2 (IL-2). Our progress during the first funding period of this grant established that cell cycle progression is necessary for activated T cells to escape anergy during a productive immune response, and defined a previously unappreciated role for cyclin-dependent kinases (CDK) and their genetically-encoded inhibitory proteins in the decision between T cell immunity and tolerance. The activity of these kinases opposed the induction of T cell clonal anergy in vitro, and genetic dysregulation of CDK activity during organ transplantation interfered with tolerance induced by costimulatory blockade. PUBLIC HEALTH RELEVANCE The goal of this proposal is to explore the molecular mechanisms by which cyclin-dependent kinases regulate T lymphocyte function, and to evaluate the potential of these molecules as therapeutic targets in pre-clinical models of organ transplantation. A deeper understanding of the molecular events underlying T cell tolerance could lead to new approaches to induce tolerance in the setting of autoimmunity and transplantation, and therefore the research proposed in the is application is consistent with and highly relevant to the NIH/HHS goal of improving human health
Keywords: ATGN; Aldesleukin Gene; Antigens; Apoptosis; Apoptosis Pathway; Autoimmune Status; Autoimmunity; Binding; Binding (Molecular Function); Body Tissues; CCND1 Protein; CD28; CD28 gene; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CDC2 Protein Kinase; CDC2-Related Protein Kinase Gene; CDK; CDK1; CDK2; CDK2 gene; CDK4; CDK4 gene; CMM3; Cell Communication and Signaling; Cell Cycle Controller cdc2; Cell Cycle Progression; Cell Death, Programmed; Cell Division Control Protein 2 Homolog; Cell Division Cycle 2; Cell Division Cycle 2 Protein; Cell Division Kinase 2 Gene; Cell Division Protein Kinase 2 Gene; Cell Function; Cell Process; Cell Signaling; Cell physiology; Cells, CD4; Cellular Function; Cellular Physiology; Cellular Process; Clinical, Transplantation, Organ; Clonal Anergy; Co-Stimulator; Complex; Costimulator; Couples; Cyclin D1; Cyclin-Dependent Kinase 1; Cyclin-Dependent Kinase 2 Isoform 1 Gene; Cyclin-Dependent Kinase 2 Isoform 2 Gene; Cyclin-Dependent Kinases; Cyclin-Dependent Protein Kinases; Cyclins; Development; Drugs; Dysfunction; EC 2.7; Effector Cell; Enzymes; Epidermal Thymocyte Activating Factor; Event; Experimental Models; Experimental Models, Other; Family; Functional disorder; Funding; G1/S-Specific Cyclin D1; GVHD; Gene Expression; Genes; Genes, p53; Genetic; Goals; Graft-Versus-Host Disease; Graft-vs-Host Disease; Grafting Procedure; Grafting, Heart; Grant; Health; Heart Transplantation; Homologous Wasting Disease; Human; Human, General; IL-2; IL-2 Gene; IL2; IL2 Protein; IL2 gene; Immune response; Immunity; Immunosuppressants; Immunosuppressive Agents; In Vitro; Interleukin 2; Interleukin 2 Precursor; Interleukin 2 Precursor Gene; Interleukin II; Interleukin-2; Interleukin-2 Gene; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Intracellular Communication and Signaling; Kinases; Lead; Lymphocyte Function; Lymphocyte Mitogenic Factor; MGC14458; Mammals, Mice; Man (Taxonomy); Man, Modern; Medication; Mice; Mitogenic Factor; Modeling; Models, Experimental; Molecular; Molecular Interaction; Murine; Mus; Organ Transplantation; Organ Transplants; Organ Transplants, Including Bone Marrow for DCT; P53; PRAD1 Protein; PSK-J3; Pathway interactions; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Phase; Phosphotransferases; Physiopathology; Population; Pre-Clinical Model; Preclinical Models; Predisposition; Process; Proteins; Proto-Oncogene Proteins c-bcl-1; Regulation; Regulatory Protein; Research; Resistance; Role; Runt Disease; Signal Transduction; Signal Transduction Systems; Signaling; Subcellular Process; Susceptibility; T cell anergy; T cell differentiation; T cell growth factor; T cell regulation; T cell response; T-Cell Growth Factor; T-Cell Growth Factor Gene; T-Cell Proliferation; T-Cell Stimulating Factor; T-Cells; T-Lymphocyte; T4 Cells; T4 Lymphocytes; T44; TCGF Gene; TP53; TP53 gene; TRP53; Testing; Thymocyte Stimulating Factor; Thymus-Dependent Lymphocytes; Tissues; Transphosphorylases; Transplantation; Transplantation Surgery; Transplantation, Cardiac; Tumor Protein p53 Gene; Work; anergy; base; bcl-1 Proto-Oncogene Products; bcl-1 Proto-Oncogene Proteins; bcl1 Proto-Oncogene Proteins; biological signal transduction; c-bcl-1 Proteins; cardiac allograft; cardiac graft; cdc2 gene product; cdc2+ Protein; cdk Proteins; cdk1 Kinase; cyclin D; drug/agent; gain of function; gene product; genetic regulatory protein; heart allograft; heart transplant; heavy metal Pb; heavy metal lead; helper T cell; host response; immunogen; immunopathology; immunoresponse; immunosuppressive; improved; in vivo; inhibitor; inhibitor/antagonist; loss of function; mutant; new approaches; novel; novel approaches; novel strategies; novel strategy; organ allograft; organ graft; organ xenograft; p33 Protein Kinase Gene; p33(CDK2) Gene; p34 (cdc2); p34 Protein Kinase; p34CDC2; pathophysiology; pathway; peripheral tolerance; public health relevance; reconstitute; reconstitution; regulatory gene product; resistant; response; self recognition (immune); small molecule; social role; therapeutic target; thymus derived lymphocyte; transplant
Project start date: 2002-07-15
Project end date: 2013-05-31
Budget start date: 1-JUN-2010
Budget end date: 31-MAY-2011
PFA/PA: PA-07-070
5R01AI054643-08 (2010): $407138
5R01AI054643-07 (2009): $411250
Role Of Ikaros In IL-2 Gene Expression And T Cell Anergy
Andrew D Wells
Children s Hospital Of Philadelphia Joseph Stokes, Jr. Research Institute Philadelphia, Pa 191044318
Grant 5R21AI059881-02 from National Institute Of Allergy And Infectious Diseases IRG: ZAI1
Abstract: T cell anergy is an important mechanism of peripheral tolerance that controls the development of immunopathology in experimental models of autoimmunity and alloimmunity. Anergy involves the functional inactivation of inappropriate T cell responses and is thought to be largely the result of active silencing of effector gene transcription. Perhaps the most relevant gene affected by this phenomenon encodes the T cell growth factor IL-2, but the means by which this and other genes are silenced during this mode of tolerance induction is poorly understood. We find that the IL-2 promoter contains two putative binding motifs for Ikaros, a lymphoid-specific zinc-finger DNA binding protein required for normal T lymphocyte development. Interestingly, Ikaros acts primarily as a transcriptional repressor by recruiting histone deacetylases and chromatin remodeling complexes to gene promoters and enhancers. Our preliminary data suggest that Ikaros associates with the endogenous IL-2 promoter in primary T cells, and therefore could potentially contribute to active silencing of the IL-2 gene. The specific goal of the proposed studies outlined in this grant application is to determine whether Ikaros regulates IL-2 gene expression in naive T cells in response to signals from antigen and costimulatory receptors, and whether chromatin remodeling mediated by this factor contributes to silencing of the IL-2 gene during the induction of T cell anergy. Our hypothesis that Ikaros and/or chromatin remodeling may the influence IL-2 gene expression, and the induction of immune tolerance is novel, and represents an innovative approach to studying the molecular basis of immune tolerance. Therefore, the studies proposed are consistent with the exploratory nature of the R21 mechanism.
Keywords: T lymphocyte, anergy, gene expression, immunogenetics, interleukin 2, protein structure function, transcription factor, chromatin, gene induction /repression, immune tolerance /unresponsiveness, nuclear factor kappa beta, chromatin immunoprecipitation, enzyme linked immunosorbent assay, gel mobility shift assay, genetically modified animal, laboratory mouse
Project start date: 2004-04-01
Project end date: 2006-03-31
5R21AI059881-02 (2005): $255000
1R21AI059881-01 (2004): $255000
Sponsored Links Excellgen http://Excellgen.com
Andrew D Wells, Assistant Professor
Children´s Hospital Of Philadelphia, Research Institute, Philadelphia, Pa 19104-4318
Grant 3R01AI070807-02S1 from National Institute Of Allergy And Infectious Diseases
Abstract: Regulatory T cells are crucial for the control of immune-mediated pathology during organ transplant rejection and autoimmune disease, therefore understanding the underlying mechanisms by which these cells function will be critical for promoting immune tolerance in humans. Recent studies in experimental models have established that Foxp3, which is a member of the forkhead family of DNA binding proteins, is necessary and sufficient for specification of regulatory T lymphocyte lineage choice and function. and therefore is crucial for acquired immune tolerance. Expression of Foxp3 initiates a unique transcriptional program which includes the induction of genes such as GITR, CD25, CTLA-4, IL-10 and TGF2, and repression of pro-inflammatory cytokine genes such as IL-2 and IFN?. The mechanisms by which Foxp3 enforces this genetic program are unclear. The studies proposed in this application are centered around basic questions of how Foxp3 binds to target genes, and how Foxp3 represses or induces transcription at these loci. The proposed studies will add significantly to our understanding of how Foxp3 regulates gene expression, and the information gained from these studies will have relevance for the design of novel therapeutic strategies by which tolerance can be promoted in humans
Keywords: Address; Allergy; Antimorphic mutation; Autoimmune Diseases; Binding; Binding (Molecular Function); Biology; CD25; CHIP assay; CSIF; CSIF-10; Cell Communication and Signaling; Cell Function; Cell Process; Cell Signaling; Cell physiology; Cellular Function; Cellular Physiology; Cellular Process; ChIP (chromatin immunoprecipitation); Chemicals; Chromatin; Chromatin Structure; Clinical Treatment; Clinical, Transplantation, Organ; Co-Stimulator; Consensus; Consensus Sequence; ConsensusSequence; Costimulator; Cytokine Gene; Cytokine Synthesis Inhibitory Factor; Cytokine formation-inhibiting factor (mouse clone F115 protein moiety reduced); DNA; DNA Binding; DNA Binding Interaction; DNA Sequence; DNA-Binding Proteins; DNase; Data; Deacetylase; Deoxyribonucleases; Deoxyribonucleic Acid; Dominant Negative; Dominant-Negative Mutant; Dominant-Negative Mutation; EMSA; Elements; Enhancers; Enzymes; Epidermal Thymocyte Activating Factor; Experimental Models; Experimental Models, Other; Family; Gene Down-Regulation; Gene Expression; Gene Targeting; Gene Transcription; Genes; Genetic Algorithm; Genetic Alteration; Genetic Change; Genetic Programming; Genetic Transcription; Genetic defect; Genome; Goals; Graft Rejection; Grafting Procedure; Histone Acetylase; Histones; Human; Human, General; Hypersensitivity; IFN; IL-10; IL-2; IL10; IL10A; IL2; IL2 Protein; IL2R; IL2RA; IL2RA gene; Immune; Immune Tolerance; Immunologic Tolerance; In Vitro; Inflammatory; Interferons; Interleukin 10 Precursor; Interleukin 2; Interleukin 2 Precursor; Interleukin II; Interleukin-10; Interleukin-2; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Intracellular Communication and Signaling; Lymphocyte; Lymphocyte Mitogenic Factor; Lymphocytic; MHC Receptor; Major Histocompatibility Complex Receptor; Man (Taxonomy); Man, Modern; Measures; Mediating; Mitogenic Factor; Models, Experimental; Modification; Molecular Configuration; Molecular Conformation; Molecular Interaction; Molecular Stereochemistry; Monitor; Mutate; Mutation; Nucleases, DNA; Organ Transplantation; Organ Transplants; Organ Transplants, Including Bone Marrow for DCT; Pathology; Programs (PT); Programs [Publication Type]; Promoter; Promoter Regions; Promoter Regions (Genetics); Promoters (Genetics); Promotor; Promotor (Genetics); Promotor Regions; Promotor Regions (Genetics); RNA Expression; Receptors, Antigen, T-Cell; Recruitment Activity; Regulation; Regulatory T-Lymphocyte; Reporter; Repression; Signal Transduction; Signal Transduction Systems; Signaling; Subcellular Process; T cell growth factor; T-Cell Growth Factor; T-Cell Receptor; T-Cell Stimulating Factor; T-Cell Subsets; T-Cells; T-Lymphocyte; T-Lymphocyte Subsets; T-Lymphocyte, Regulatory; TCGFR; Targetings, Gene; Thymocyte Stimulating Factor; Thymus-Dependent Lymphocytes; Transcription; Transcription Activator; Transcription Coactivator; Transcription Corepressor; Transcription Factor Coactivator; Transcription Regulation; Transcription Repression; Transcription Repressor; Transcription Repressor/Corepressor; Transcription, Genetic; Transcriptional Activator; Transcriptional Activator/Coactivator; Transcriptional Coactivator; Transcriptional Control; Transcriptional Corepressor; Transcriptional Regulation; Transcriptional Repression; Transcriptional Repressor; Transcriptional Repressor/Corepressor; Transgenic Organisms; Transplant Rejection; Transplantation Rejection; Transplantation Surgery; Tumor Immunity; autoimmune disorder; base; biological signal transduction; chromatin immunoprecipitation; conformation; conformational state; design; designing; gene induction; gene repression; genetic promoter element; genome mutation; histone acetyltransferase; histone modification; immune system tolerance; immune unresponsiveness; immunological paralysis; in vivo; inhibitor; inhibitor/antagonist; insight; lymph cell; member; new therapeutics; next generation therapeutics; novel therapeutics; organ allograft; organ graft; organ xenograft; overexpression; programs; recruit; thymus derived lymphocyte; transcription factor; transgenic; trial regimen; trial treatment
Project start date: 2009-07-18
Project end date: 2010-06-30
Budget start date: 18-JUL-2009
Budget end date: 30-JUN-2010
PFA/PA: PA-07-070
3R01AI070807-02S1 (2009): $155780
EFFECT OF IPEX MUTATIONS ON FOXP3 DNA BINDING AND CHROMATIN REMODELING
Andrew D Wells, Assistant Professor
University Of Pennsylvania, 3451 Walnut Street, Philadelphia, Pa 19104
Abstract: Humans with mutations in the foxpS gene suffer from a complex of autoimmune disorders (IPEX) that results from the lack of regulatory T lymphocytes, and leads to the eventual death of these patients in childhood. Recent studies in experimental models have established that FoxpS, which is a member of the forkhead family of DMA binding proteins, is necessary and sufficient for specification of regulatory T lymphocyte lineage choice and function, and therefore is crucial for acquired immune tolerance. Expression of FoxpS by T lymphocytes leads to the induction of genes associated with tolerance, and to the repression of genes that cause inflammation and immune pathology. The mechanisms by which FoxpS induces this genetic program, however, are not known. Regulatory T cells are also thought to be crucial for the inhibition of alloimmune responses during organ transplantation, and have been implicated in the control of autoimmune disease. An important goal in the treatment of patients with autoimmune disorders or organ transplants is to induce immunologic tolerance, and a basic understanding of the mechanisms that underly this process will likely be a prerequisite for the successful clinical treatment of these diseases. The studies proposed in this application are centered around basic questions of FoxpS transcriptional biology, and will add significantly to our understanding of how FoxpS regulates gene expression and promotes tolerance. A central tenet of these studies is that the regions of FoxpS mutated in IPEX patients are required for basic aspects of FoxpS function, and the studies herein are designed to determine these functions. The information gained from these studies will likewise lead to novel therapeutic strategies by which tolerance can be promoted in patients with autoimmune disease and organ transplants
Keywords: Address; Affect; Allergy; Antigen-Antibody Complex; Autoimmune Diseases; Binding; Binding (Molecular Function); Binding Proteins; Biology; CD25; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CHIP assay; Cell Fractionation; Cell Function; Cell Process; Cell physiology; Cells, CD4; Cellular Function; Cellular Physiology; Cellular Process; Cessation of life; ChIP (chromatin immunoprecipitation); Childhood; Chromatin; Chromatin Remodeling Complex; Chromatin Remodeling Factor; Chromatin Structure; Clinical Treatment; Clinical, Transplantation, Organ; Co-Stimulator; Complex; Costimulator; DNA; DNA Binding; DNA Binding Interaction; DNase; Death; Deoxyribonucleases; Deoxyribonucleic Acid; Disease; Disorder; Drugs; ELISA; EMSA; Elements; Enzyme-Linked Immunosorbent Assay; Enzymes; Epidermal Thymocyte Activating Factor; Experimental Models; Experimental Models, Other; Family; Gene Down-Regulation; Gene Expression; Gene Transcription; Genes; Genes, Regulator; Genetic Algorithm; Genetic Alteration; Genetic Change; Genetic Programming; Genetic Transcription; Genetic defect; Goals; Graft Rejection; Grafting Procedure; HDAC; HDAC Proteins; Histone Acetylation; Histone Deacetylase; Histones; Human; Human, General; Hypersensitivity; IL-2; IL2; IL2 Protein; IL2R; IL2RA; IL2RA gene; INFLM; Immune; Immune Complex; Immune Tolerance; Immunoblotting; Immunologic Tolerance; In Situ; In Vitro; Inflammation; Interleukin 2; Interleukin 2 Precursor; Interleukin II; Interleukin-2; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Lead; Ligand Binding Protein; Link; Lymphocyte Mitogenic Factor; Mammals, Mice; Man (Taxonomy); Man, Modern; Mediating; Medication; Methylation; Mice; Mitogenic Factor; Models, Experimental; Modification; Molecular Configuration; Molecular Conformation; Molecular Interaction; Molecular Stereochemistry; Murine; Mus; Mutate; Mutation; Nucleases, DNA; Nucleic Acid Regulatory Sequences; Organ Transplantation; Organ Transplants; Organ Transplants, Including Bone Marrow for DCT; Pathology; Patients; Pb element; Pharmaceutic Preparations; Pharmaceutical Preparations; Process; Promoter; Promoter Regions; Promoter Regions (Genetics); Promoters (Genetics); Promotor; Promotor (Genetics); Promotor Regions; Promotor Regions (Genetics); Protein Methylation; RNA Expression; Recruitment Activity; Regulation; Regulator Genes; Regulator Regions, Nucleic Acid; Regulatory Regions; Regulatory Regions, Nucleic Acid (Genetics); Regulatory Sequences, Nucleic Acid; Regulatory T-Lymphocyte; Repression; Site; Specific qualifier value; Specified; Subcellular Process; Syndrome; System; System, LOINC Axis 4; T cell growth factor; T-Cell Growth Factor; T-Cell Stimulating Factor; T-Cell Subsets; T-Cells; T-Lymphocyte; T-Lymphocyte Subsets; T4 Cells; T4 Lymphocytes; TCGFR; Testing; Thymocyte Stimulating Factor; Thymus-Dependent Lymphocytes; Transcription; Transcription Activator; Transcription Coactivator; Transcription Factor Coactivator; Transcription Regulatory Protein; Transcription Repression; Transcription, Genetic; Transcriptional Activator; Transcriptional Activator/Coactivator; Transcriptional Coactivator; Transcriptional Regulatory Elements; Transcriptional Regulatory Protein; Transcriptional Repression; Transplant Rejection; Transplantation Rejection; Transplantation Surgery; autoimmune disorder; chromatin immunoprecipitation; chromatin modification; chromatin remodeling; conformation; conformational state; design; designing; disease/disorder; drug/agent; gene induction; gene repression; genetic promoter element; genetic regulatory element; genome mutation; heavy metal Pb; heavy metal lead; helper T cell; immune system tolerance; immune unresponsiveness; immunocytochemistry; immunological paralysis; in vivo; insight; member; mutant; new therapeutics; next generation therapeutics; novel therapeutics; organ allograft; organ graft; organ xenograft; pediatric; recruit; regulatory gene; response; subcellular fractionation; thymus derived lymphocyte; trans acting element; transcription factor; trial regimen; trial treatment
Budget start date: 1-JUL-2010
Budget end date: 30-JUN-2011
5P01AI073489-03_0002 (2010): $373494
5P01AI073489-02_0002 (2009): $378572