Arlene H Sharpe
Harvard University (medical School)
Project start date: 1995-07-15
Project end date: 2015-12-31
Sponsored Links Excellgen http://Excellgen.com
In Vivo Function Of The B7 Family Of Costimulators
Arlene H Sharpe, Professor
Harvard University (medical School) Medical School Campus Boston, Ma 02115
Grant 5R37AI038310-13 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: The overall goal of this application is to dissect the functional roles of the recently identified B7/CD28 family members ICOS and PD-L1 in regulating mucosal tolerance. This focus is driven by our recent studies that have identified essential, non-redundant roles for ICOS and PD-L1 in mucosal tolerance. We have found that ICOS and PD-L1 have similar roles in controlling the ability of orally-induced regulatory T cells to exert their protective effects. Each of these roles must be unique, since orally induced WT CD4+ Treg cannot function following transfer into ICOS-/- or PD-L1-/- mice. In contrast, PD-L1, but not ICOS, is required for the generation of functional orally induced CD4+ Treg. To investigate the relationships between ICOS and PD- L1 in regulating mucosal tolerance, we will analyze the 1) role of ICOS in the generation and/or function of pathogenic effector T cells (IL-12 driven IFN-g producing Th1 cells and IL-23 driven ThlL-17 cells), since the impaired function of orally induced WT CD4+ T reg could be a primary defect or secondary to enhanced pathogenicity of ICOS-/- effector cells 2) role of ICOS in controlling function of orally induced CD4+ Treg; and 3) relationships between ICOS and PD-L1 in controlling functions of self reactive effector and orally induced CD4+ T reg. These studies should reveal the relative roles of ICOS and PD-L1 in controlling the balance between regulatory and encephalitogenic Th1 cells in vivo. We have assembled a number of novel tools that will enable us to address these issues. To dissect the role of ICOS in mucosal tolerance, we have developed ICOS-/- mice. Our PD-L1-/- mice will serve as a definitive tool to examine how PD-L1 regulates the generation and function of orally-induced CD4+ Treg. We will use MOG35-55 specific TCR transgenic mice to visualize the effects of ICOS and PD-L1 dysregulation on activation, migration and expansion of naive and effector T cells in vivo, and development and behavior of orally induced Treg. These studies should lead to insights into how ICOS and PD-L1 regulate the responses of self-reactive T cells.
Keywords: cell, family, autoimmunity, balance, behavior, cytokine, emotion, encephalomyelitis, environment, fasting, genetically modified animal, glycoprotein, immune response, insight, laboratory mouse, lead, ligand, motivation, myelin, nose, oligodendroglia, optic neuritis, organ, peptide, role, tissue
Project start date: 1995-07-15
Project end date: 2010-12-31
5R37AI038310-13 (2007): $411461
5R37AI038310-16 (2010): $363279
Grants awarded to Arlene H Sharpe
T CELL COSTIMULATORY PATHWAYS: FUNCTIONS AND INTERACTIONS
Arlene H Sharpe
Harvard University (medical School), Medical School Campus, Boston, Ma 02115
Grant 5P01AI056299-07 from National Institute Of Allergy And Infectious Diseases
Abstract: This revised PPG competing renewal application is driven by the fundamental and therapeutic importance of costimulatory pathways for regulating T cell activation and tolerance, and builds upon our significant progress since initial awarding of this PPG in 2003. The synergy in our PPG is highlighted by 111 publications, 49 of which have been co-authored by multiple PPG investigators, and include 33 new publications since the first (May 2007) submission. Our PPG also has had a significant role in mentoring fellows who work on joint projects, and fostering development of junior faculty. Our PPG has not only provided novel insights to the field, but allowed sharing of novel mAbs and fusion proteins, and mouse strains with the broader scientific community that resulted in better understanding of the functions of costimulatory pathways above and beyond our PPG aims. The overall objective of our PPG is to achieve a mechanistic understanding of the roles of pathways in the B7CD28 family in regulating T cell activation and tolerance. Building upon our published and preliminary data, these goals include 1) investigate roles of these pathways in regulating T cell responses in target tissues versus lymphoid organs, 2) dissect functional hierarchy, dominance and redundancy among these pathways, and 3) study how these pathways regulate the balance between protective and pathogenic T cell responses, ultimately determining the fate of the immune response, using experimental models of transplantation, autoimmunity, and infection. The proposed PPG renewal application will provide a means by which PPG investigators can continue to work together to address these important issues and develop a comprehensive understanding of the functions of B7CD28 family members, ultimately leading to development of novel immunotherapeutic strategies. This PPG will facilitate communication among PPG investigators and sharing of a rich collection of tools, transgenic/knockout mice and mAbs and Ig fusion proteins, to address these issues. The use of the same standardized reagents and experimental animals makes it possible to compare and contrast results in different microenvironments and disease models. There will be 3 Projects (Transplantation, Autoimmunity, Infection) and 3 Cores (Administrative, Antibody/lg fusion protein, Transgenic/Knockout). The "Administrative Core" will be responsible for providing scientific direction and coordination, fiscal oversight and administrative support for the PPG. Overall, this PPG should provide fundamental knowledge for therapeutic manipulation of these important regulatory pathways
Relevance: RELEVANCE (See instructions}: These studies will provide the basis for understanding how, where and when costimulatory molecules regulate allograft rejection, organ-specific autoimmune diseases, and chronic viral infection These studies have implications for developing novel immunotherapies based on targeting costimulatory pathways for human chronic viral infections, cancer, autoimmune diseases and transplantation
Project start date: 2003-09-30
Project end date: 2014-08-31
Budget start date: 1-SEP-2010
Budget end date: 31-AUG-2011
5P01AI056299-07 (2010): $2160908
2P01AI056299-06A1 (2009): $1705049
FASEB Summer Conference On Autoimmunity
Arlene H Sharpe
Federation Of Amer Soc For Exper Biology 9650 Rockville Pike Bethesda, Md 208143998
Grant 5R13AI065123-03 from National Institute Of Allergy And Infectious Diseases IRG: ZAI1
Abstract: This renewal proposal requests partial support for the 2005, 2007 and 2009 meetings of the Federation of American Societies of Experimental Biology (FASEB) Summer Conference on Autoimmunity which is normally held every other June at the Vermont Academy in Saxtons River, VT. Historically, this meeting has been fully subscribed attracting approximately 200 registrants (the upper limit accommodated at the Vermont venue) and alternates years with the FASEB Summer Conference on Lymphocytes and Antibodies . The purpose of the conference is to bring together basic top immunologists and clinical researchers from academia and the pharmaceutical industry at the professorial, post-doctoral and pre-doctoral levels from around the world to share the latest advancements in understanding of the pathogenesis and regulation of autoimmune disease. Autoimmune diseases together affect approximately 5% of the population targeting every major organ system and thus represent a significant health problem. However, there is not yet clear understanding of their etiologies and at present there are no cures and few useful therapies. The goal of this meeting is to merge data from animal models and patient studies on a broad range of autoimmune diseases; to share recent advances on the development of the T cell and B cell repertoires; mechanisms underlying the establishment and loss of self tolerance; the contribution of genetic and environmental (infectious) triggers to autoimmune disease development and progression; trafficking of autoreactive T cells to sites of inflammation; the pathogenetic mechanisms involved in tissue injury; and the latest therapeutic strategies for regulating autoimmune diseases. A major strength of the meeting is the informal forum that brings students and fellows together with established investigators who are international leaders in this highly disease-relevant and continually growing field. In addition to the oral presentations of the invited speakers and poster presentations by other attendees, the format of the meeting allows two short talks (15 minutes in length), selected from among the submitted s, to be interspersed into each of the eight sessions providing the opportunity for more formalized oral participation by selected graduate student and postdoctoral trainees. A major goal is to foster the initiation and strengthening of collaborations among scientists in the field. This conference serves as the definitive meeting for bringing together basic and clinical scientists with research interests focusing on the etiology and reaulation of autoimmune diseases.
Keywords: autoimmune disorder, meeting /conference /symposium, travel
Project start date: 2005-06-01
Project end date: 2010-05-31
5R13AI065123-03 (2007): $15000
New Costimulatory Pathways: Functions And Interactions
Arlene H Sharpe, Professor
Harvard University (medical School) Medical School Campus Boston, Ma 02115
Grant 5P01AI056299-05 from National Institute Of Allergy And Infectious Diseases IRG: AITC
Abstract: This Costimulation PPG grant is driven by the fundamental and therapeutic importance of T cell costimulation for regulating T cell activation and tolerance. The growing number of T cell costimulatory pathways together with the dynamic nature of the immune response suggests that there may be a functional hierarchy of costimulatory molecules for regulating responses of na ve, effector, and memory T cells. Understanding the functions of T cell costimulatory pathways in specific disease models should enable manipulation of costimulatory signals to promote T cell activation or T cell tolerance for therapeutic purposes. The major objectives of the Costimulation PPG is to develop an understanding of the roles of T cell costimulatory pathways in regulating T cell activation and tolerance in defined experimental models of transplantation, autoimmunity, allergy/asthma, and infections. We will address the following questions 1. Are T cell costimulatory pathways merely redundant or do they provide distinct and unique functions in different types of immune responses? 2. What are the important and unique interactions between the various pathways? 3. What are the effects and mechanisms of targeting of these pathways in vivo? Other objectives include fostering interactions between experts in the field, developing novel tools (animals and reagents) to share among investigators, and building a network of collaborations to share ideas, models and reagents. We plan to achieve these objectives by 1. identifying, targeting and studying the functions of new costimulatory pathways in well defined experimental models in vivo; 2) analyzing the interactions among the new, and with the well characterized T cell costimulatory pathways in these models. We are proposing 4 Projects (Transplantation, Autoimmunity, Allergy/Asthma, Infections) and 4 Cores (Administrative, Molecular/Signaling, Transgenic/Knockout, Biophysical Characterization). The Administrative Core will be responsible for providing scientific direction and coordination, fiscal oversight and administrative support for the PPG among 7 institutions in 5 different cities. This PPG should provide fundamental knowledge for developing novel translational research opportunities aimed at inducing T cell tolerance to prevent transplant rejection and ameliorate autoimmune and allergic diseases, as well as developing more effective immunity to microbes.
Keywords: T lymphocyte, biological signal transduction, leukocyte activation /transformation, surface antigen, clinical research
Project start date: 2003-09-30
Project end date: 2008-01-31
5P01AI056299-05 (2007): $1916340
5P01AI056299-04 (2006): $1916029
5P01AI056299-03 (2005): $1904918
7P01AI056299-02 (2004): $1942486
1P01AI056299-01 (2003): $579668
IN VIVO FUNCTION OF THE B7 FAMILY OF COSTIMULATORS
Arlene H Sharpe, Scholar, Hms Academy
Harvard University (medical School), Medical School Campus, Boston, Ma 02115
Grant 3R37AI038310-15S1 from Office Of The Director, National Institutes Of Health
Abstract: This award is issued in response to Notice OD-09-060, Recovery Act Administrative Supplements Providing Summer Research Experiences for Students and Science Educators.The overall goal of this application is to dissect the functional roles of the recently identified B7/CD28 family members ICOS and PD-L1 in regulating mucosal tolerance. This focus is driven by our recent studies that have identified essential, non-redundant roles for ICOS and PD-L1 in mucosal tolerance. We have found that ICOS and PD-L1 have similar roles in controlling the ability of orally-induced regulatory T cells to exert their protective effects. Each of these roles must be unique, since orally induced WT CD4+ Treg cannot function following transfer into ICOS-/- or PD-L1-/- mice. In contrast, PD-L1, but not ICOS, is required for the generation of functional orally induced CD4+ Treg. To investigate the relationships between ICOS and PD- L1 in regulating mucosal tolerance, we will analyze the 1) role of ICOS in the generation and/or function of pathogenic effector T cells (IL-12 driven IFN-g producing Th1 cells and IL-23 driven ThlL-17 cells), since the impaired function of orally induced WT CD4+ T reg could be a primary defect or secondary to enhanced pathogenicity of ICOS-/- effector cells 2) role of ICOS in controlling function of orally induced CD4+ Treg; and 3) relationships between ICOS and PD-L1 in controlling functions of self reactive effector and orally induced CD4+ T reg. These studies should reveal the relative roles of ICOS and PD-L1 in controlling the balance between regulatory and encephalitogenic Th1 cells in vivo. We have assembled a number of novel tools that will enable us to address these issues. To dissect the role of ICOS in mucosal tolerance, we have developed ICOS-/- mice. Our PD-L1-/- mice will serve as a definitive tool to examine how PD-L1 regulates the generation and function of orally-induced CD4+ Treg. We will use MOG35-55 specific TCR transgenic mice to visualize the effects of ICOS and PD-L1 dysregulation on activation, migration and expansion of naive and effector T cells in vivo, and development and behavior of orally induced Treg. These studies should lead to insights into how ICOS and PD-L1 regulate the responses of self-reactive T cells
Keywords: Address; Adoptive Transfer; Affect; Attenuated; Autoimmune Diseases; Autoimmune Status; Autoimmunity; Behavior; Body Tissues; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CSIF; CSIF-10; Cell Communication and Signaling; Cell Signaling; Cells; Cells, CD4; Clinical; Co-Stimulator; Costimulator; Cytokine Synthesis Inhibitory Factor; Cytokine formation-inhibiting factor (mouse clone F115 protein moiety reduced); Data; Defect; Development; Disease; Disorder; Dose; EAE; Edodekin Alfa; Effector Cell; Employee Strikes; Encephalomyelitis; Encephalomyelitis, Allergic; Environment; Epidermal Thymocyte Activating Factor; Equilibrium; Experimental Allergic Encephalitis; Experimental Allergic Encephalomyelitis; Experimental Autoimmune Encephalitis; Experimental Autoimmune Encephalomyelitis; Family; Family member; Gamma interferon; Generations; Goals; Grant; Homing; IFN-Gamma; IFN-g; IFNG; IL-10; IL-12; IL-2; IL-23; IL10; IL10A; IL12; IL2; IL2 Protein; Immune response; In Vitro; Interferon Gamma; Interferon Type II; Interferon gamma (human lymphocyte protein moiety reduced); Interferon, Immune; Interferon-gamma; Interleukin 10 Precursor; Interleukin 2; Interleukin 2 Precursor; Interleukin II; Interleukin-10; Interleukin-12; Interleukin-2; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Intracellular Communication and Signaling; Investigators; Lead; Ligands; Lymphocyte Mitogenic Factor; Lymphoid; MOG glycoprotein; Mammals, Mice; Mice; Mice, Transgenic; Mitogenic Factor; Murine; Mus; Myeloencephalitis; NKSF; Nasal; Natural Killer Cell Stimulatory Factor; Nose; Nose, Nasal Passages; Optic Neuritis; Oral; Organ; Pathogenicity; Pathway interactions; Pb element; Peptides; Peripheral; Production; Regulation; Relative; Relative (related person); Research Personnel; Researchers; Resistance; Respiratory System, Nose, Nasal Passages; Role; Secondary to; Signal Transduction; Signal Transduction Systems; Signaling; Strikes; Strikes, Employee; T cell growth factor; T-Cell Activation; T-Cell Growth Factor; T-Cell Stimulating Factor; T-Cells; T-Lymphocyte; T4 Cells; T4 Lymphocytes; Th-1 Cell; Th1 Cells; Thymocyte Stimulating Factor; Thymus-Dependent Lymphocytes; Tissues; Transgenic Mice; Transgenic Organisms; Type 1 Helper Cell; Wild Type Mouse; autoimmune disorder; autoimmune encephalomyelitis; balance; balance function; biological signal transduction; cytokine; disease/disorder; experiment; experimental research; experimental study; feeding; heavy metal Pb; heavy metal lead; helper T cell; host response; immunoresponse; in vivo; insight; interleukin-23; lFN-Gamma; migration; myelin oligodendrocyte glycoprotein; novel; oligodendrocyte-myelin glycoprotein; pathway; protective effect; research study; resistant; response; self recognition (immune); social role; thymus derived lymphocyte; tool; transgenic
Project start date: 2009-06-05
Project end date: 2010-09-30
Budget start date: 5-JUN-2009
Budget end date: 30-SEP-2010
3R37AI038310-15S1 (2009): $22535
PATHOGENESIS OF RETROVIRAL NEUROLOGIC DISEASE
Arlene H Sharpe, Professor
Brigham And Women´s Hospital
research Administration
boston, Ma 02115
Grant 5R01NS031065-03 from National Institute Of Neurological Disorders And Stroke IRG: ARRC
Abstract: The progressive neurologic syndromes caused by the Human Immunodeficiency Virus (HIV) are a serious complication of HIV infection and give impetus to the study of mechanisms of retroviral neurovirulence. During the course of HIV infection, a variety of diseases of the central and peripheral nervous system with diverse inflammatory, demyelinating, or degenerative pathologic features can develop. Whether these diseases are due to direct effects of virus upon specific nervous system cell types, or to indirect mechanisms mediated by induction of factors, such as cytokines, are questions currently under investigation. An understanding of the pathogenesis of retrovirus-mediated neurologic diseases is crucial for the design of rational therapy. The goal of this research program is to analyze mechanisms of retroviral neurovirulence. To gain insight into the pathogenesis of one retroviral neurologic disease, a murine model system is being employed. The neurodegenerative disease produced by the murine neurotropic type C retrovirus Cas-Br-E is being analyzed. Infection of mice with Cas-Br-E can serve as a model of HIV-associated encephalopathy in which HIV infection of the brain, without inflammation, leads to progressive cognitive deficits. This murine model enables the dissection of complex issues of retroviral neurovirulence relevant to advancing the understanding of mechanisms of AIDS neurologic disease syndromes. Central to the understanding of neurovirulence is the identification of viral target cells and the exploration of the role of each type of target cell in disease production. The Cas-Br-E model enables an examination of these issues on the organismal, cellular and molecular levels. The specific aims of this research program are (1) to achieve a precise identification of viral target cells using in situ hybridization with two probes, one for Cas-Br-E and the other for target cell type, temporally from the time of infection to the onset of disease and (2) to examine the interaction of Cas-Br-E with specific cell types in order to determine whether Cas-Br-E neurodegenerative disease is due to direct effects of virus upon neurons or indirect, resulting from viral infection of glia or endothelial cells using the following approaches a. Viral infection of aggregation chimeras containing virus-susceptible CNS cells and virus-resistant CNS cells in which resistant neurons can be visualized using a beta-galactosidase marker, will determine whether virus-resistant neurons degenerate as a consequence of infection of adjacent, virus-susceptible cells. b. Transgenic mouse studies will address whether neurodegenerative effects can be produced when the viral envelope gene, the primary determinant of Cas- Br-E neurovirulence, is targeted to specific DNS cell populations using cell type-specific promoters. c. A comparison of cytokine expression in the CNS of mice infected with neurovirulent Cas-Br-E and non-neurovirulent Moloney murine leukemia virus will be carried out to determine whether the expression of specific cytokines are unique to CNS tissue exhibiting neuropathologic changes. If specific cytokines are identified using this approach, then the effects of modifying disease with cytokine antagonists or using cytokine-deficient mice will be explored
Keywords: Retroviridae, host organism interaction, nervous system infection, neurotropic virus, virulence AIDS dementia complex, genetic promoter element, interleukin 1, interleukin 6, tumor necrosis factor alpha in situ hybridization, laboratory mouse, nucleic acid probe, transgenic animal
Project start date: 1992-07-01
Project end date: 1996-06-30
5R01NS031065-03 (1994): $241911
Sponsored Links Excellgen http://Excellgen.com
5R01NS031065-02 (1993): $193279
IN VIVO ROLE OF CTLA-4 IN COSTIMULATION AND AUTOIMMUNITY
Arlene H Sharpe, Scholar, Hms Academy
Harvard University (medical School), Medical School Campus, Boston, Ma 02115
Grant 5R01AI040614-13 from National Institute Of Allergy And Infectious Diseases
Abstract: The overall goal of this project is to dissect the roles of the PD-1 PD-1 ligand pathway in regulating tolerance and autoimmunity. During the current funding period, we have found that PD-1 and it ligands, PD-L1 (B7-H1) and PD-L2 (B7-DC), have critical roles in regulating the balance between T cell activation and tolerance. Our studies indicate that PD-1, PD-L1 and PD-L2 limit the responses of both naove and effector self-reactive T cells. We have found that PD-L1 and PD-L2 can have overlapping roles on APC, but that PD-L1 on nonhematopoietic cells has a unique role in mediating tissue tolerance. The therapeutic potential of manipulating PD-1 and its ligands to ameliorate autoimmune disease gives impetus to further investigation of how these important immunoregulatory molecules modulate tolerance and autoimmunity. Our finding that PD- L1 on nonhematopoietic cells can inhibit T cell activation and effector function compels us to investigate how PD-L1 mediates tissue tolerance, and dissect the contributions of PD-L1 on T cells, APC, endothelial and other cell types in regulating T cell responses. Our results lead us to hypothesize that PD-1 and its ligands critically regulate the balance between pathogenic vs. protective T cell responses at multiple levels, both in the lymphoid organs and in the target tissues. To investigate this hypothesis, our specific aims are 1) To compare the roles of PD-1 and its ligands in controlling the development and function of pathogenic myelin-reactive CD4 T cells. We will study the roles of PD-1 and its ligands in regulating the differentiation of myelin-reactive CD4 T cells to Th1, Th17 vs. FoxP3+ CD4 regulatory T cells, the effector functions of MOG-reactive Th1 vs. Th17 cells and the interplay between pathogenic Th1/Th17 effector cells and FoxP3+ regulatory T cells during the development and progression of EAE. 2) To investigate the role of the PD-1PD-L pathway in regulating autopathogenic B cells. PD-1 and PD-L1 are expressed on B cells as well as T cells, but their roles in controlling self-reactive T vs. B cell responses are not clear. Dysregulated B cell responses may play a role in the exacerbated EAE that develops in PD-1-/- and PD-L-/- mice. We will investigate the roles of PD-1 and its ligands in the APC function of B cells, T cell B cell collaboration and production of pathogenic antibodies by myelin-specific B cells. 3) To investigate the roles of PD-L1 and PD-L2 in tissue tolerance. We will study the roles of PD-L1 and PD-L2 in tolerance-inducing functions of dendritic cells and the role of PD-L1 on vascular endothelial cells in mediating tissue tolerance during EAE. We will use MOG 35-55/IAb tetramer together with MOG TCR transgenic, B cell IgH knockin mice and our PD-1-/-, PD-L1-/-, PD-L2-/- PD-L1/L2-/- mice to investigate how PD-1, PD-L1 and PD-L2 control tolerance and autoimmunity. These studies should further our understanding of mechanisms that control tolerance and autoimmunity, and provide insight into how PD-1 and its ligands may be effectively manipulated for therapy of autoimmune diseases. One of the most remarkable properties of the normal immune system is its ability to respond to and protect against a diversity of microorganisms, but not respond harmfully to cells or tissues of the human body. When regulatory mechanisms go awry, the immune system can attack the body and cause autoimmune disease. This project studies the mechanisms by which one important immunoregulatory pathway, the PD-1PD-1 ligand pathway, regulates the responses of white blood cells, called lymphocytes, and protects against autoimmunity
Keywords: APC; Address; Animal Welfare; Antibodies; Antigen-Presenting Cells; Autoimmune Diabetes; Autoimmune Diseases; Autoimmune Status; Autoimmunity; B blood cells; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; B-Cells; B-Lymphocytes; B7-DC; B7-DC antigen; BCDF; BSF-2; BSF2; BSF2 (B cell stimulating factor 2); Bibliography; Body Tissues; Bone Marrow; Bursa-Dependent Lymphocytes; Bursa-Equivalent Lymphocyte; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; Cell Communication and Signaling; Cell Function; Cell Process; Cell Signaling; Cell physiology; Cells; Cells, CD4; Cellular Function; Cellular Physiology; Cellular Process; Chimera; Chimera organism; Collaborations; Comment; Comment (PT); Comment [Publication Type]; Commentary; Commentary (PT); Country; Data; Dendritic Cells; Development; Diabetes Mellitus; Differentiation Factor, B-Cell; EAE; Ecological impact; Editorial Comment; Editorial Comment (PT); Effector Cell; Encephalomyelitis; Encephalomyelitis, Allergic; Environment; Environmental Impact; Equilibrium; Equipment; Ethics Committees, Research; Experimental Allergic Encephalitis; Experimental Allergic Encephalomyelitis; Experimental Autoimmune Encephalitis; Experimental Autoimmune Encephalomyelitis; Family; Family member; Frequencies (time pattern); Frequency; Funding; Generations; Goals; Grant; HPGF; Hematopoietic; Hepatocyte-Stimulating Factor; Hybridoma Growth Factor; IACUC; IFN-beta 2; IFNB2; IL-6; IL6 Protein; IRBs; Immunologic Accessory Cells; Impact, Environmental; Institutional Animal Care and Use Committee; Institutional Review Boards; Interleukin 6 (Interferon, Beta 2); Interleukin-6; International; Intracellular Communication and Signaling; Investigation; Knock-in; Knock-in Mouse; Lead; Ligands; Lymphocyte; Lymphocytic; Lymphoid; MGI-2; Mammals, Mice; Mediating; Mice; Mice, Transgenic; Modeling; Modification; Monocytes / Macrophages / APC; Mouse Strains; Murine; Mus; Myelin; Myeloencephalitis; Myeloid Differentiation-Inducing Protein; Organ; Pathway interactions; Pb element; Phase; Phenotype; Plasmacytoma Growth Factor; Play; Principal Investigator; Production; Programs (PT); Programs [Publication Type]; Published Comment; Regulatory T-Lymphocyte; Relative; Relative (related person); Research; Research Ethics Committees; Research Resources; Resources; Reticuloendothelial System, Bone Marrow; Risk; Role; Self-control as a personality trait; Signal Transduction; Signal Transduction Systems; Signaling; Subcellular Process; T-Cell Activation; T-Cells; T-Lymphocyte; T-Lymphocyte, Regulatory; T4 Cells; T4 Lymphocytes; Testing; Th-1 Cell; Th1 Cells; Therapeutic; Thymus-Dependent Lymphocytes; Tissues; Transgenic Mice; Transgenic Organisms; Type 1 Helper Cell; Vascular Endothelial Cell; Veiled Cells; Vertebrate Animals; Vertebrates; Viewpoint; Viewpoint (PT); Viral; Work; ing; accessory cell; autoimmune disorder; autoimmune encephalomyelitis; balance; balance function; base; biological signal transduction; cell type; cytokine; diabetes; expiration; heavy metal Pb; heavy metal lead; helper T cell; human subject; immunopathology; in vivo; insight; interest; interferon beta 2; lymph cell; macrophage; novel; pathway; programs; response; self control; self recognition (immune); social role; therapeutic target; thymus derived lymphocyte; tool; transgenic; tumor; vertebrata
Project start date: 1997-02-01
Project end date: 2013-03-31
Budget start date: 1-APR-2010
Budget end date: 31-MAR-2011
PFA/PA: PA-07-070
5R01AI040614-13 (2010): $419513
In Vivo Function Of The B7 Family Of Costimulators
Arlene H Sharpe, Professor
Harvard University (medical School) Medical School Campus Boston, Ma 02115
Grant 2R37AI038310-12 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: The overall goal of this application is to dissect the functional roles of the recently identified B7/CD28 family members ICOS and PD-L1 in regulating mucosal tolerance. This focus is driven by our recent studies that have identified essential, non-redundant roles for ICOS and PD-L1 in mucosal tolerance. We have found that ICOS and PD-L1 have similar roles in controlling the ability of orally-induced regulatory T cells to exert their protective effects. Each of these roles must be unique, since orally induced WT CD4+ Treg cannot function following transfer into ICOS-/- or PD-L1-/- mice. In contrast, PD-L1, but not ICOS, is required for the generation of functional orally induced CD4+ Treg. To investigate the relationships between ICOS and PD- L1 in regulating mucosal tolerance, we will analyze the 1) role of ICOS in the generation and/or function of pathogenic effector T cells (IL-12 driven IFN-g producing Th1 cells and IL-23 driven ThlL-17 cells), since the impaired function of orally induced WT CD4+ T reg could be a primary defect or secondary to enhanced pathogenicity of ICOS-/- effector cells 2) role of ICOS in controlling function of orally induced CD4+ Treg; and 3) relationships between ICOS and PD-L1 in controlling functions of self reactive effector and orally induced CD4+ T reg. These studies should reveal the relative roles of ICOS and PD-L1 in controlling the balance between regulatory and encephalitogenic Th1 cells in vivo. We have assembled a number of novel tools that will enable us to address these issues. To dissect the role of ICOS in mucosal tolerance, we have developed ICOS-/- mice. Our PD-L1-/- mice will serve as a definitive tool to examine how PD-L1 regulates the generation and function of orally-induced CD4+ Treg. We will use MOG35-55 specific TCR transgenic mice to visualize the effects of ICOS and PD-L1 dysregulation on activation, migration and expansion of naive and effector T cells in vivo, and development and behavior of orally induced Treg. These studies should lead to insights into how ICOS and PD-L1 regulate the responses of self-reactive T cells.
Keywords: CD28 molecule, T lymphocyte, antigen presenting cell, biological signal transduction, leukocyte activation /transformation, surface antigen, T cell receptor, cytokine, gene expression, gene mutation, genetic transcription, genetic mapping, genetically modified animal, laboratory mouse, tissue /cell culture
Project start date: 1995-07-15
Project end date: 2010-12-31
2R37AI038310-12 (2006): $423750
Arlene H Sharpe, Professor
Harvard University (medical School)
medical School Campus
boston, Ma 02115
Grant 5P01AI039671-130010 from National Institute Of Allergy And Infectious Diseases IRG: ZAI1
Abstract: The overall goal is to dissect the functional roles of the recently identified B7 family member, B7-H4, and the SLAM family member, CD48 (a CD2 ligand), in regulating organ-specific autoimmune diseases. This focus is driven by recent genetic studies of Multiple Sclerosis and murine type 1 diabetes that have implicated the genetic locus that contains these costimulatory molecules (human or mouse homologues) with disease susceptibility, together with our recent studies that point to important roles for B7-H4 and CD48 in regulating T cell activation and tolerance. To investigate the roles of B7-H4 and CD48-mediated signals in the afferent arm of the response where T cells become activated in the periphery, and in the effector arm, where potentially pathogenic T cells are driven to mediate tissue destruction, we are proposing a multifaceted approach. We will 1)investigate the role of the B7-H4 in regulating T cell tolerance and autoimmunity; 2)analyze the role of CD48 in regulating the induction and effector phases of EAE; and 3)examine the roles of CD48 and B7-H4 in regulating T and B cell tolerance. We have assembled a number of novel tools that will enable us to address these important issues. To dissect the role of B7-H4 in EAE, we have developed B7-H4lg and anti-B7-H4 mAb. We also have available B7-H4-/- mice and are in the process of generating transgenic mice that inducibly express B7-H4. Our CD48-/- mice, and anti-CD48 mAb will serve as definitive tools for examining the role of CD48 during EAE. We will use MOG 35-55 specific TCR transgenic mice to visualize the effects of B7-H4 and CD48 dysregulation on the activation, migration and expansion of naive and activated T cells in vivo, and MOG 35-55 TCR x Th double transgenic mice to analyze the roles of B7-H4 and CD48 in regulating B and T cell tolerance to MOG. Taken together, these studies should lead to insights into how B7-H4 and CD48 costimulatory regulate the responses of self-reactive T cells
Keywords: CD antigen, T lymphocyte, experimental allergic encephalomyelitis, leukocyte activation /transformation, surface antigen B lymphocyte, genetic polymorphism, genetic susceptibility, immune tolerance /unresponsiveness, monoclonal antibody genetically modified animal, laboratory mouse
Project start date: 2008-02-01
Project end date: 2010-01-31
VISUALIZING EFFECTS OF COSTIMULATION ON ANTIVIRAL IMMUNITY
Arlene H Sharpe, Scholar, Hms Academy
Harvard University (medical School), Medical School Campus, Boston, Ma 02115
Abstract: The major goal of this project is to define the functions and mechanisms by which T cell costimulatory pathways regulate anti-viral immunity. To achieve this goal we are using an established model of influenza infection. Our studies indicate that one of the newer pathways in the B7CD28 family, the PD-1 PD-1/PD-L2 pathway, delivers inhibitory signals that that play a critical role in regulating the interplay between host defenses aimed at eradicating pathogenic microbes and microbial strategies that evolved to resist immune responses The therapeutic potential of manipulating PD-1 and its ligands to enhance immune responses during infection gives impetus to further investigation of how these important immunoregulatory molecules modulate antimicrobial immunity and immunopathology. The discovery of the new PD-L1 B7-1 pathway compels us to investigate how B7-1PD-L1 interactions are involved in regulating anti-microbial immunity, and dissect the roles of PD-L1PD-1 vs. PD-L1B7-1 interactions during infection. Our specific aims are 1 To analyze the functional significance of PD-L1B7-1 and PD-L1PD-1 interactions in controlling the activation and differentiation of na´i´ve CDS T cells. We will investigate the roles of PD-L1B7-1 interactions, PD-L1PD-1 interactions individually and together in controlling the CDS T activation, differentiation, and fate as memory cells or more differentiated effector cells. We will visualize the roles of these pathways in controlling activation of CDS T cells. 2. To investigate the roles of PD-L1PD-1 and PDL1 B7-1 interactions in controlling responses of CDS effector T cells. We will dissect the roles of these pathways in controlling CDS effector T cell function. We will visualize the dynamics of the effector response in the lymph node by intravital microscopy 3 To analyze the roles of the PD-1PD-L and PD-L1B7-1 pathways in controlling protective immunity to influenza virus. We will evaluate how PD-L1PD-1 and PD-L1B7-1 interactions control activation and fates of memory T cells. We will perform challenge infection intranasally to evaluate protective immunity or s.c. to examine the dynamics of the secondary response by intravital microscopy/2 photon imaging approaches.Insights from these studies may lead to improved prophylactic and/or therapeutic vaccination strategies
Budget start date: 1-AUG-2010
Budget end date: 31-JUL-2011
5P01AI078897-03_0002 (2010): $407712
5P01AI078897-02_0002 (2009): $399833
CORE--TRANSGENIC MODELS OF SKIN DISEASE
Arlene H Sharpe
Institution:
Grant 5P30AR042689-039001 from National Institute Of Arthritis And Musculoskeletal And Skin Diseases
Abstract: The long-term objective of this core is to integrate transgenic technology into the realm of investigative dermatology, so that this scientific approach becomes a standard and accessible means of addressing the function of genes thought to be important in skin disease. Currently, hypotheses linking skin disease and the function of certain gene products in vivo are based on two types of observations l) the production or unique regulation of the gene product by cultured skin- derived cells in vitro; and 2) the observation that the gene product is aberrantly expressed in diseased skin, based on analysis of a histopathological specimen derived from biopsy material. The first class of observation, though useful, is inherently flawed, since innumerable variables can intervene between in vitro culture systems and the complexity of organized tissue. The second class of observation has a distinct inherent flaw. While it does accommodate the complexity of gene regulation in organized tissue, it cannot discriminate between cause, effect and epiphenomenon, and is fundamentally a retrospective approach. A different approach is now available to complement the first two. This approach involves manipulating the mouse genome by introducing into early embryonic cells genetic constructs that result in new expression, or specific deletion, of certain genes. This prospective approach to enabling the analysis of a particular gene product in skin disease is uniquely powerful and is likely to change, in a fundamental way, how we think about skin disease.The following Specific Aims are proposed 1. To provide a service that will micro inject pronuclei of fertilized eggs with purified DNA constructs containing genes relevant to skin disease, and implant injected cells into pseudo-pregnant recipients, towards the generation of transgenic mice. 2. To provide a service that will transfect embryonic stem cells with targeted homologous recombination vectors containing genes or gene elements relevant to skin disease, isolate successfully modified cells after drug selection, and inject such modified ES cells into blastocysts, towards the generation of targeted gene "knockout" mice. 3. To provide dedicated space for, and to subsidize per diem housing costs of, unique transgenic mice (that currently exist or will be generated in the context of the HSDRC) that display either tissue-specific overexpression or targeted deletion of genes that may be relevant to the pathogenesis of skin disease. 4. To provide education about experimental approaches involving transgenic mice that assists HSDRC investigators in asking succinct and focused experimental questions in this powerful system.
Keywords: animal colony, biomedical facility, disease model, model design /development, skin disorder, transgenic animal, embryonic stem cell, gene targeting, laboratory mouse, microinjection
Sponsored Links Excellgen http://Excellgen.com
Costimulation And Regulation Of Anti-Microbial Immunity
Arlene H Sharpe, Professor
Brigham And Women s Hospital Research Administration Boston, Ma 02115
Grant 1P01AI056299-010004 from National Institute Of Allergy And Infectious Diseases IRG: AITC
Abstract: The long term goal of this project is to understand the function of costimulatory pathways in regulating anti-microbial T cell immunity. To achieve this goal, two established models of infection, Leishmania major (L. major) and Lymphocytic choriomeningitis virus (LCMV), will be used to dissect functions of newly discovered T cell costimulatory pathways individually and analyze interactions with well-characterized pathways in regulating anti-microbial immune responses. The L. major model will enable us to dissect the roles of T cell costimulatory pathways in regulating CD4 T helper commitment to a Thl/Th2 response, and CD4 and CD8 memory responses during this well characterized parasitic infection. The LCMV model enables us to investigate the roles of T cell costimulatory pathways in regulating CD8 T cell activation, differentiation, effector and memory responses during acute viral infection and in regulating "exhausted" CD8 T cells during chronic viral infection. Our specific aims are 1. To investigate the roles of the PD-IPD-LI/PD-L2 and CTLA-4 costimulatory pathways in regulating the pathogenesis of L. Major. We will compare the roles of PD-IPD-L1/PD-L2 pathway during the induction, differentiation, and effector responses to L. major and to study its interactions with the B7CTLA-4 costimulatory pathway, and the interplay between the PD-1 and CTLA-4 pathways during the development of immunity to L. major. 2. To analyze the roles of the PD-IPD-L1/PD-L2 and CTLA-4 costimulatory pathways in regulating the function of LCMV-specifie CD8 T cells. We will examine whether signals from PD-L1 or PD-L2 or both are involved in inhibiting the function of these exhausted CD8 T cells in chronic LCMV infection, and investigate the role of the PD-1 pathway and its interaction with the CTLA-4 pathway in regulating virus specific T cell responses during both acute and chronic LCMV infection. 3 To dissect the roles of novel and characterized costimulatory pathways in T cell differentiation, effector, and memory responses to infection with L. major and LCMV. As novel reagents (mAbs, Ig fusion proteins, transgenic / knockout mouse strains) to dissect new and well characterized T cell costimulatory pathways become available, we will build on the studies in Aims 1 and 2 to further investigator how T cell costimulatory pathways regulate the outcome of infections with L. major and LCMV. Taken together, studies in aims 1-3 should provide insight into the role of costimulatory pathways in regulating anti-microbial CD4 and CD8 T cell responses and may reveal how manipulation of costimulatory pathways can enhance anti-microbial immunity.
Keywords: CD28 molecule, Leishmania major, T lymphocyte, biological signal transduction, lymphocytic choriomeningitis virus, microorganism immunology, surface antigen, B lymphocyte, cell differentiation, cytokine, cytotoxic T lymphocyte, helper T lymphocyte, immunologic memory, leukocyte activation /transformation, macrophage, laboratory mouse
Project start date: 2003-07-01
Project end date: 2008-06-30
IN VIVO ROLE OF CTLA-4 IN COSTIMULATION AND AUTOIMMUNITY
Arlene H Sharpe, Professor
Brigham And Women´s Hospital
research Administration
boston, Ma 02115
Grant 5R01AI040614-05 from National Institute Of Allergy And Infectious Diseases IRG: IMS
Abstract: The investigator will test the hypothesis that CTLA-4 downregulates T-cell activation and is normally involved in the prevention of autoimmunity. Evidence for this premise comes from the investigator´s finding that the CTLA-4-deficient mice develop splenomegaly and lymphadenopathy, multi-organ lymphocytic infiltration and tissue destruction with severe myocarditis and pancreatitis, and die by 3-4 weeks of age. Three specific aims will be tested. The role of CTLA-4 in regulation of T-cell dependent immune responses will be analyzed by determining how CTLA-4 deficiency affects T-cell responses in vitro and whether CTLA-4 mediates its inhibitory effects solely through interactions with B7-1 and B7-2. The mechanisms of CTLA-4-mediated inhibition will be studied using naive and activated T-cells from CTLA-4-deficient, TCR transgenic mice. Emphasis will be placed on susceptibility to apoptosis and lymphokine production. The contribution of CTLA-4 to systemic autoimmune responses will be addressed by assessment of the pathology of in CTLA-4-deficient mice, determination of whether self-reactive T-cells appear in CTLA-4-deficient mice, and whether the course of EAE in MBP-specific TCR transgenic mice is altered when these mice lack CTLA-4
Keywords: CD28 molecule, autoimmune disorder, helper T lymphocyte, leukocyte activation /transformation B lymphocyte, T cell receptor, experimental allergic encephalomyelitis, lymphokine, myelin basic protein, programmed cell death, protein biosynthesis laboratory mouse, tissue /cell culture, transgenic animal
Project start date: 1997-02-01
Project end date: 2002-01-31
5R01AI040614-05 (2001): $246459
5R01AI040614-04 (2000): $239280
Sponsored Links Excellgen http://Excellgen.com
5R01AI040614-03 (1999): $232313
5R01AI040614-02 (1998): $225546
Role Of ICOS And B7 On T Cells In Regulating Autoimmunity
Arlene H Sharpe, Professor
Brigham And Women s Hospital Research Administration Boston, Ma 02115
Grant 5P01AI039671-090004 from National Institute Of Allergy And Infectious Diseases IRG: ZAI1
Abstract: The BY-CD28/CTLA-4 co-stimulatory pathway has a critical role in T cell activation, differentiation and tolerance. For this reason, methods directed toward manipulating this pathway have received considerable attention for the treatment of autoimmunity, and appear to have great therapeutic potential. Our finding that B7-1 on T cells influences IL-4 production, together with the discovery of the CD28 homologous ICOS, which appears to be particularly important for IL-10 production, have raised new questions about how co-stimulation regulates the responses of elf-reactive T cells. The regulation of IL-4 by b7-1 on T cells suggests that B7-1 on T cells may regulate the differentiation and encephalitogenic potential of self-reactive T cells. Because IL-10 is a critical regulator of autoimmune disease, engagement of ICOS may have important influences on the initiation and progress of autoimmune diseases. In this proposal we will investigate the role of B7 and ICOS-mediated signals in both the afferent arm of the autoimmune response where T cells are driven to mediate tissue destruction 1. We will investigate the role of ICOS in the induction of autoimmune responses in the CNS. We will examine how anti-ICOS mAbs and ICOS-Ig affect the initiation of EAE and determine whether ICOS deficient mice are susceptible to EAE. 2. We will analyze the role of ICOS in the function of encephalitogenic and regulatory T cells. We will use ICOS deficient ICOS deficient mice to study to determine whether ICOS provides co-stimulatory signals needed by regulatory T cells. 3. We will investigate the role of B7 on T cells during the induction and effector phases of EAE. Our B7 deficient strains are the definitive tools for examining B7 on T cells regulates the pathogenic potential of naive self reactive T cells and/or affects the function of activated of activated self reactive T cells. We also investigate how interactions between ICOS and the B7-CD28/CTLA-4 pathway affect the initiation and progression of autoimmune disease. In collaboration with Project 2, we will use MOG, 35-55 specific TCR transgenic mice to visualize the effects of ICOS dysregulation on the activation, migration and expansion of naive and activated T cells in vivo. We will also generate B7 deficient, MOG TCR transgenic and ICOS deficient, MOG TCR transgenic strains as a tools for studying the responses of B7-/- T cells and ICOS-/- T cells and ICOS-/- T cells in vivo during the induction and effector phases of EAE. Taken together, these studies should lead to new insight into how the B7/CD28/CTLA-4 and ICOS pathway regulate the responses of self-reactive T cells, and hopefully will facilitate manipulation of these pathways to effectively treat autoimmune disease.
Keywords: T lymphocyte, autoimmune disorder, immunoregulation, leukocyte activation /transformation, pathologic process, CD28 molecule, biological signal transduction, experimental allergic encephalomyelitis, interleukin 10, interleukin 4, genetically modified animal, laboratory mouse, monoclonal antibody
In Vivo Role Of CTLA-4 In Costimulation And Autoimmunity
Arlene H Sharpe, Professor
Harvard University (medical School) Medical School Campus Boston, Ma 02115
Grant 5R01AI040614-10 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: The B7CD28/CTLA-4 costimulatory pathway has a critical role in regulating T cell activation, differentiation and tolerance, and is a promising therapeutic target. PD-1 is structurally related to CTLA-4 and has an ITIM motif in its cytoplasmic tail. PD-1 deficient mice develop an autoimmune-like disease. Our recent studies show that the newly discovered B7 homologues, PD-L1 and PD-L2, are ligands for PD-1, and can inhibit T cell proliferation and cytokine production in vitro. The expression of PD-L1 and PD-L2 on nonlymphoid tissues, as well as professional APCs, supports a role for this pathway in regulating peripheral T cell tolerance. The delineation of this pathway has revealed a new means by which T cell responses are regulated, and raised questions about its role in regulating T cell activation and tolerance, and its relationship with the B7CD28/CTLA-4 pathway. The goals of this project are to investigate the roles of PD-L1 and PD-L2 in regulating T cell activation and tolerance, and interactions between the B7CD28/CTLA-4 and PD-lPD-L1/PD-L2 pathways We will 1) analyze the function of PD-Li and PD-L2 in regulating naive and activated antigen-specific T cells and helper T cell dependent humoral immune responses. We have generated anti-PD-Ll and anti-PD-L2 mAbs and are generating mice lacking PD-L1 and/or PD-L2. These tools provide a definitive means for determining when and how PD-L1 and PD-L2 exert their effects during an immune response, 2) investigate the roles of PD-L1 and PD-L2 in regulating peripheral T cell tolerance. We will use DO.11 TCR Tg T cells to visualize the impact of blockade or elimination of PD-L1 and/or PD-L2 on the responses of antigen-specific CD4+ T cells to immunogenic and tolerogenic stimuli. 3) Analyze the interactions between the PD-1PD-L1/PD-L2 and B7CD28/CTLA-4 pathways. We will examine whether these pathways regulate the expression of each other, and evaluate functional interactions. The availability of mice lacking B7-1 and/or B7-2, together with mice lacking CD28 and/or CTLA-4, provide us with unique opportunities to analyze these interactions. These approaches should provide fundamental information about the role of the PD-1PDL1/PD-L2 pathway in regulating T cell activation and tolerance, and its interactions with the B7CD28/CTLA-4 pathway. These studies may thereby assist in the design of optimal therapeutic strategies for manipulating the B7CD28/CTLA-4 pathway and indicate the therapeutic potential of PD-1PD-L1/PD-L2 pathway manipulation.
Keywords: CD28 molecule, autoimmune disorder, helper T lymphocyte, leukocyte activation /transformation, T cell receptor, apoptosis, biological signal transduction, cell cell interaction, cell differentiation, cell proliferation, cytokine, glomerulonephritis, humoral immunity, immune tolerance /unresponsiveness, ligand, genetically modified animal, laboratory mouse, tissue /cell culture
Project start date: 1997-02-01
Project end date: 2008-01-31
5R01AI040614-10 (2006): $331034
5R01AI040614-09 (2005): $339000
7R01AI040614-08 (2004): $337750
Sponsored Links Excellgen http://Excellgen.com
5R01AI040614-07 (2003): $300375
2R01AI040614-06 (2002): $299458
IN VIVO FUNCTION OF THE B7 FAMILY OF COSTIMULATORS
Arlene H Sharpe, Professor
Harvard University (medical School) Medical School Campus Boston, Ma 02115
Grant 5R01AI038310-11 from National Institute Of Allergy And Infectious Diseases IRG: IMB
Abstract: The B7-CD28/CTLA-4 costimulatory pathway has a critical role in regulating T cell activation, differentiation and tolerance, and is a promising therapeutic target. The recent discovery of the CD28 homologue ICOS, an inducible T cell costimulatory receptor, and its ligand, which is a B7 homologue, has revealed a new means by which T cell responses may be regulated, and raised questions about the functional significance of ICOS and its relationship with the B7-CD28/CTLA-4 pathway. Because ICOS is expressed only after TCR engagement, and ICOS costimulation induces IL-4 and IL- 10, which are important immunoregulatory cytokines, ICOS may have important influences on the amplification and/or regulation of an immune response. The goals of this project are to investigate the in vivo functions of ICOS and its functional relationship with the B7-CD28/CTLA-4 pathway 1) We will examine the importance of ICOS for the generation of immune responses in vivo, by examining the functional consequences of ICOS dysregulation. We have generated anti-ICOS mAbs and ICOS-Ig and are generating mice lacking ICOS and transgenic mice that constitutively overexpress ICOS in T cells. These tools provide a means for determining when during an immune response ICOS exerts its effects. 2) We will use DO.11 TCR Tg T cells to visualize the impact of ICOS dysregulation on the activation, expansion, differentiation, and effector functions of antigen- specific CD4+ T cells. 3) We will analyze the inter- relationships between ICOS and the B7-CD28/CTLA-4 pathways during an immune response. We will examine whether these pathways reciprocally regulate the expression of each other, and evaluate functional relationships between the pathways. The availability of mouse strains lacking B7-1, B7-2 or both B7 costimulators, together with mouse strains lacking CD28, CTLA-4 or both receptors, provides us with unique opportunities to analyze the interactions between the ICOS-ICOS-CR and B7-CD28/CTLA-4 pathways. Taken together, these approaches should provide fundamental information regarding when during an immune response ICOS is needed and how ICOS interacts with the B7-CD28/CTLA-4 pathway. These studies may thereby assist in the design of optimal therapeutic strategies for manipulation of the B7- CD28/CTLA-4 pathway and also indicate the therapeutic potential of ICOS pathway manipulation.
Keywords: CD28 molecule, T lymphocyte, antigen presenting cell, biological signal transduction, leukocyte activation /transformation, surface antigen, T cell receptor, cytokine, gene expression, gene mutation, genetic transcription, genetic mapping, genetically modified animal, laboratory mouse, tissue /cell culture
Project start date: 1995-07-15
Project end date: 2005-12-31
5R01AI038310-11 (2004): $381375
5R01AI038310-09 (2003): $349335
5R01AI038310-08 (2002): $350268
5R01AI038310-07 (2001): $351174
2R01AI038310-06 (2000): $352054
5R01AI038310-05 (1999): $263996
5R01AI038310-04 (1998): $253843
5R01AI038310-03 (1997): $244079
Sponsored Links Excellgen http://Excellgen.com