Doina Ganea
Temple University
Project start date: 2000-04-01
Project end date: 2014-12-31
Sponsored Links Excellgen http://Excellgen.com
Neuropeptides And Regulatory T Cells
Doina Ganea, Professor And Chair
Temple University 1601 N. Broad Street Philadelphia, Pa 19122
Grant 5R01AI047325-08 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: Autoimmune diseases are thought to result from breaks in tolerance, brought upon by abnormalities in the recognition of exogenous or endogenous antigens. A network of cellular and molecular mechanisms constantly adjusts the immune response within the limits of tolerance for self-antigens. Recently, regulatory T cells (Treg) have been recognized as essential in maintaining tolerance, and in re-establishing immune homeostasis. In spite of recent efforts, many unanswered questions remain however, particularly regarding the nature of cells/factors/mechanisms that control the generation and/or activity of antigen-specific Treg. Neuroimmune interactions between the CNS and the immune system are mediated through soluble factors such as cytokines, chemokines, neuropeptides, and neurotransmitters. Although a large number of studies attest to the role of neuropeptides as immunomodulators, the question whether they contribute to the generation and/or activation of Treg has not been addressed. We reported previously on the potent anti-inflammatory effect of the neuropeptides vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase activating polypeptide (PACAP) both in vivo and in vitro. The central hypothesis of this proposal is that VIP and PACAP induce the generation and/or activation of Treg, which then play an essential role in implementing the VIP/PACAP anti-inflammatory functions. In the first two specific aims, we propose to investigate the generation and/or activation of Treg by VIP/PACAP in vivo and in vitro, to characterize the VIP/PACAP-induced Treg in terms of phenotype, antigen-specificity, and mechanisms for suppression, and to evaluate the role of dendritic cells in the induction of Treg by VIP/PACAP. In the third specific aim, we propose to extend our investigation into two models of Th1-dominated autoimmune diseases. We will evaluate the role of Treg in the protective effect of VIP/PACAP in EAE and collagen-induced arthritis, with the ultimate goal of establishing new therapeutic avenues for the treatment of autoimmune diseases.
Keywords: chemical structure function, developmental immunology, inflammation, neuroimmunomodulation, neuropeptide, neuroregulation, suppressor T lymphocyte, CD4 molecule, autoimmunity, cell cell interaction, cell differentiation, cell growth regulation, cell migration, dendritic cell, experimental allergic encephalomyelitis, immune tolerance /unresponsiveness, leukocyte activation /transformation, lymphocyte proliferation, neuropeptide receptor, rheumatoid arthritis, vasoactive intestinal peptide, flow cytometry, genetically modified animal, laboratory mouse
Project start date: 2004-08-01
Project end date: 2008-05-31
5R01AI047325-08 (2007): $298029
5R01AI047325-07 (2006): $319136
5R01AI047325-05 (2005): $316788
REGULATION OF IMMUNE CELL APOPTOSIS BY NEUROPEPTIDES
Doina Ganea, Professor
Rutgers The State Univ Of Nj Newark 249 University Ave. Newark, Nj 07102
Grant 5R01AI047325-03 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: adapted from applicant s ) A functional connection, partially mediated through cytokines and neuropeptides, exists between the neuroendocrine and the immune system. Cytokines released in the CNS regulate the growth and differentiation of neuronal and glial cells, and neuropeptides or neurotransmitters released within the lymphoid organs regulate the development and function of immune cells. The vasoactive intestinal peptide (VIP) and the related neuropeptide the pituitary adenylate cyclase activating polypeptide (PACAP) are present in the lymphoid organs, and act as immunomodulators, exhibiting primarily antiinflammatory activities. The investigators showed previously that VIP and PACAP inhibit T cell- and macrophage-derived cytokine production in vivo and in vitro, that immune cells express VIP/PACAP receptors, and that VIP/PACAP exert protective effects in animal models for septic shock. However, the role of neuropeptides in lymphocyte homeostasis, and particularly in activation-induced T cell apoptosis is not known. The in vitro preliminary studies indicate that VIP/PACAP protect CD4+ T cells against activation-induced cell death (AICD), and suggest the downregulation of Fas ligand (FasL) expression as a possible mechanism. This project proposes to investigate the in vivo and in vitro roles of VIP and PACAP in FasL-induced apoptosis, i.e. in the activation-induced apoptosis of CD4+ T cells, and the cytotoxic activity of T cells against Fas-bearing targets, and to investigate the molecular mechanisms by which VIP and PACAP inhibit FasL expression. Based on their previous studies, and on the preliminary results, they postulate that VIP and PACAP released within the lymphoid organs following antigenic stimulation, regulate the immune response at several stages. First, they act as "macrophage deactivating factors," inhibiting the secretion of proinflammatory agents and downregulating the expression of B7. Through their effects on macrophages, VIP and PACAP reduce the further induction of both nonspecific and specific immune responses. In addition, VIP/PACAP inhibit directly IL-2 production by T cells, further reducing T cell proliferation. Also, as proposed here, VIP/PACAP reduce the cytotoxic function of both CD4+ T cells primarily through the downregulation of FasL. Finally, they propose that VIP and PACAP also regulate activation induced T cell apoptosis (AICD), acting as survival factors which might be important for the generation of long-lived memory T cells. Since failure to maintain a balance between cell proliferation and apoptotic cell death leads to the development of either proliferative or degenerative pathological conditions, VIP and PACAP play an important physiological role through the regulation of FasL/Fas-mediated apoptosis. Also, by limiting CD4+ T cell cytoxicity against bystander targets, VIP/PACAP may preserve cell viability in tissues with low MHCII expression such as brain, or of uninfected CD4+ T cells in AIDS.
Keywords: CD95 molecule, T lymphocyte, apoptosis, cellular immunity, neuroimmunomodulation, neuropeptide, neuroregulation, cytotoxic T lymphocyte, helper T lymphocyte, immunologic memory, interleukin 2, lymphocyte proliferation, macrophage, receptor expression, transcription factor, vasoactive intestinal peptide, laboratory mouse, tissue /cell culture
Project start date: 2001-01-01
Project end date: 2003-12-31
5R01AI047325-03 (2003): $233250
Grants awarded to Doina Ganea
TRAINING PROGRAMS IN MICROBIOLOGY AND IMMUNOLOGY
Doina Ganea, Professor And Chair
Temple University 1601 N. Broad Street Philadelphia, Pa 19122
Grant 5T32AI007101-29 from National Institute Of Allergy And Infectious Diseases IRG: MID
Abstract: This program provides background and training is the areas of molecular and cellular immunology, molecular and biochemical microbiology, and eukaryotic and procaryotic molecular genetics. The goal is to develop highly competent investigators capable of performing and eventually directing research in basic modem microbiology and immunology. Trainees are exposed to a variety of perspectives, ideas, and methodologies which can be utilized in their dissertation research and careers as investigators. Rigorous research training is provided in studies of eukaryotic and prokaryotic systems using combinations of molecular, biochemical, genetic, and cellular approaches. While relationships to human diseases is emphasized, trainees receive experience in the most modem molecular and biochemical technologies. Research disciplines include molecular and cellular immunology, microbial biochemistry, molecular genetics, mycology, virology, bacteriology, and cell biology. Predoctoral trainees complete a rigorous series of graduate courses providing them with a thorough background in microbiology and immunology. First year students complete courses in the molecular basis of pathogenic microbiology, molecular and cellular immunology, and microbial genetics and physiology. This is followed by advanced elective courses, several series of seminars by outside speakers and faculty, and by journal club participation. Trainees are required to complete rotations in three laboratories prior to the selection of a permanent advisor and a dissertation research topic. Applicants must have a bachelor s degree from an accredited institution, and a solid background in biological and chemical sciences. Only full time students are accepted. Postdoctoral trainees are offered the opportunity to work in collaboration with several preceptors as a part of this training program. The post-doctoral trainee is encouraged to utilize resources available throughout the Health Sciences Center. Postdoctoral trainees must have received a Ph.D. or M.D. degree, and past productivity as assessed by publication record is used, at least in part, as the basis for evaluating applicants.
Project start date: 2004-07-01
Project end date: 2009-06-30
5T32AI007101-29 (2007): $342683
ROLE OF PGE2 IN CNS AND PERIPHERAL AUTOIMMUNE DISORDERS
Doina Ganea
Temple University, 1938 Liacouras Walk, Philadelphia, Pa 19122
Grant 3R01AI052306-08S1 from National Institute Of Allergy And Infectious Diseases
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. Pathogenic Th1-type immune responses to self-antigens are thought to play an essential role in a number of organ-specific autoimmune diseases. However, recent developments in animal models of multiple sclerosis, Crohn´s disease, and rheumatoid arthritis, suggest that IL-17 producing T cells (ThlL-17) rather than the IFNg-producing Th1 cells are the most relevant participants in autoimmunity. Activated antigen-presenting cells (ARC) control the development of Th1 effectors through IL-12p70 release, and of ThlL-17 through IL- 23. In contrast to most ARC activators that induce both IL-23 and IL-12, we identified PGE2 as an inducer of IL-23 at the expense of IL-12p70. The central hypothesis in this proposal is that PGE2 released in inflammatory conditions promotes the expression and production of IL-23, while reducing IL-12p70 release from dendritic cells and microglia, and induces the subsequent generation and/or proliferation of ThlL-17. We propose that, through the IL-23-->IL-17 axis, PGE2 contributes to the maintenance of an autoimmune-prone environment in the affected tissues. In Specific Aim 1 we propose to characterize dendritic cells (DC) and microglia (MG) exposed to or generated in the presence of PGE2 in terms of IL-23/IL-12 production and to assess their in vitro and in vivo capacity to generate ThlL-17 cells. Specific Aim 2 is focused on the PGE2- induced signaling in DC and the identification of the relevant signaling molecules and transcription factors involved in the PGE2 regulation of p19, p40, and p35 gene transcription. In Specific Aim 3 we propose to evaluate the role of PGE2 in vivo in two models of autoimmune diseases, the collagen-induced arthritis and the experimental autoimmune encephalomyelitis by assessing clinical symptoms, the relevant histopathology, the development of IL-17 producing T cells, and the cytokine profile in the affected tissues and in the peripheral lymphoid organs. The identification of the molecular and cellular factors involved in the generation, activation, and maintenance of IL-23-producing APC and of pathogenic ThlL-17 will have a significant impact on our understanding and intervention in autoimmune diseases. The ultimate goal for the clarification of the molecular mechanisms involved in the PGE2 control of the IL-23/IL-12 balance and for the identification of the functional PGE2 receptors on DCs and microglia is the development of new therapeutic avenues in autoimmunity
Keywords: 3`5`-cyclic ester of AMP; 3, 5 cyclic AMP synthetase; A-152E5.1; ABCD-1; ACT2; APC; AT744.1; ATGN; ATP pyrophosphate-lyase (cyclizing); Act-2; Adenosine Cyclic 3`, 5`-Monophosphate; Adenosine Cyclic Monophosphate; Adenosine, cyclic 3`, 5`-(hydrogen phosphate); Adenyl Cyclase; Adenylate Cyclase; Adenylyl Cyclase; Affect; Animal Model; Animal Models and Related Studies; Anti-Inflammatories; Anti-Inflammatory Agents; Antigen-Presenting Cells; Antigens; Antiinflammatories; Antiinflammatory Agents; Applications Grants; Atrophic Arthritis; Autoantigens; Autoimmune; Autoimmune Diseases; Autoimmune Process; Autoimmune Status; Autoimmunity; Autologous Antigens; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; BSF2 (B cell stimulating factor 2); Blood (Leukemia); Body Tissues; Brain; CCL22; CCL22 gene; CCL3; CCL3 gene; CCL4; CCL4 gene; CD154; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CD40L; CD40LG; CRG-2; CTLA-8; CTLA8; CXCL10; CXCL10 gene; Cell Communication and Signaling; Cell Signaling; Cells; Cells, CD4; Chemoattractants; Chemotactic Factors; Chemotaxins; Clinical; Collagen Arthritis; Collagen-Induced Arthritis; Common Rat Strains; Crohn`s disease; Crohn`s disorder; Cyclic AMP; Cytokines, Chemotactic; Cytotoxic T-Lymphocyte-Associated Antigen 8; Cytotoxic T-Lymphocyte-Associated Serine Esterase 8; DC/B-CK; DIF; Dendritic Cells; Development; Differentiation Factor, B-Cell; Dinoprostone; Down-Regulation; Down-Regulation (Physiology); Downregulation; EAE; Edodekin Alfa; Encephalomyelitis, Allergic; Encephalon; Encephalons; Enteritis, Granulomatous; Environment; Equilibrium; Experimental Allergic Encephalitis; Experimental Allergic Encephalomyelitis; Experimental Autoimmune Encephalitis; Experimental Autoimmune Encephalomyelitis; Figs; Figs - dietary; Funding; G0S19-1; GM-CSF; GMCSF; Gene Expression; Gene Transcription; Generations; Genetic Transcription; Goals; Graft vs Host Reaction; Grant; Grant Proposals; Grants, Applications; Granulocyte-Macrophage Colony-Stimulating Factor; HPGF; Hepatocyte-Stimulating Factor; His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn; Histamine-Producing Cell-Stimulating Factor; Histopathology; Homologous Chemotactic Cytokines; Hortega cell; Human; Human, General; Hybridoma Growth Factor; IFI10; IFN-beta 2; IFNB2; IL-12; IL-17; IL-17A; IL-23; IL-6; IL12; IL17; IL17 Protein; IL17A; IL6 Protein; INFLM; INP10; IP-10; Idiopathic Parkinson Disease; Immune response; Immunity; Immunity, Innate; Immunity, Native; Immunity, Natural; Immunity, Non-Specific; Immunologic Accessory Cells; In Vitro; Inflammation; Inflammatory; Inflammatory Arthritis; Intercrines; Interleukin 17 (Cytotoxic T-Lymphocyte-Associated Serine Esterase 8); Interleukin 17 Precursor; Interleukin 6 (Interferon, Beta 2); Interleukin-12; Interleukin-17; Interleukin-6; Intervention; Intervention Strategies; Intracellular Communication and Signaling; LAG1; LD78ALPHA; Leukemias, General; Lewy Body Parkinson Disease; Ligands; Lymphoid; MDC; MGC34554; MGI-2; MIP-1-alpha; MIP-1-beta; MIP1A; MIP1B; MOB-1; MS (Multiple Sclerosis); Maintenance; Maintenances; Mammals, Mice; Mammals, Rats; Man (Taxonomy); Man, Modern; Mediator; Mediator of Activation; Mediator of activation protein; Mice; Microglia; Modeling; Molecular; Molgramostin; Monocytes / Macrophages / APC; Multiple Sclerosis; Murine; Mus; Myeloid Differentiation-Inducing Protein; NIH; NKSF; National Institutes of Health; National Institutes of Health (U.S.); Natural Immunity; Natural Killer Cell Stimulatory Factor; Nervous System, Brain; Neuropeptides; Organ; PACAP; PGE2; PGE2 alpha; PGE2alpha; PHM27; Paralysis Agitans; Parkinson; Parkinson Disease; Parkinson`s; Parkinson`s disease; Parkinsons disease; Participant; Peripheral; Plasmacytoma Growth Factor; Play; Primary Parkinsonism; Production; Progress Reports; Prosta-5, 13-dien-1-oic acid, 11, 15-dihydroxy-9-oxo-, (5Z, 11alpha, 13E, 15S)-; Prostaglandin E2; Prostaglandin E2 alpha; Prostaglandin E2alpha; Publications; RNA Expression; Rat; Rattus; Receptor Protein; Regulation; Reporting; Reports, Progress; Resistance; Rest; Rheumatoid Arthritis; Role; SCYA22; SCYA3; SCYA4; SCYB10; SIS cytokines; STCP-1; Scientific Publication; Sclerosis, Disseminated; Self-Antigens; Signal Transduction; Signal Transduction Systems; Signaling; Signaling Molecule; Stab Wounds; Symptoms; T-Cell Subsets; T-Cells; T-Lymphocyte; T-Lymphocyte Subsets; T4 Cells; T4 Lymphocytes; TC-GM-CSF; TLR protein; TNF; TNF A; TNF gene; TNFSF2; TNFSF5; TNFSF5 gene; TRAP Gene; Testing; Th-1 Cell; Th1 Cells; Th1/Th2 Differentiation; Th1/Th2 Differentiation Pathway; Thymus-Dependent Lymphocytes; Tissues; Toll-like receptors; Transcription; Transcription, Genetic; Tumor Necrosis Factor Gene; Tumor-Cell Human GM Colony-Stimulating Factor; Type 1 Helper Cell; United States National Institutes of Health; Up-Regulation; Up-Regulation (Physiology); Upregulation; VIP; Vasoactive Intestinal Peptide; Vasoactive Intestinal Polypeptide; Vasointestinal Peptide; Veiled Cells; Wounds, Stab; accessory cell; adenosine 3`5` monophosphate; adenylcyclase; autoimmune disorder; autoimmune encephalomyelitis; balance; balance function; biological signal transduction; cAMP; chemoattractant cytokine; chemokine; complement chemotactic factor; cytokine; eleocolitis; experiment; experimental research; experimental study; gIP-10; gitter cell; graft versus host reaction; granulocyte macrophage colony stimulating factor; granulomatous enterocolitis; helper T cell; host response; immunogen; immunoresponse; in vivo; insular sclerosis; interferon beta 2; interleukin-23; interventional strategy; leukemia; macrophage; mesoglia; microglial cell; microgliocyte; model organism; new therapeutics; next generation therapeutics; novel therapeutics; perivascular glial cell; pituitary adenylate cyclase activating peptide; pituitary adenylate cyclase activating polypeptide; prevent; preventing; receptor; regional enteritis; research study; resistant; resistant strain; self recognition (immune); social role; thymus derived lymphocyte; transcription factor
Project start date: 2009-07-14
Project end date: 2010-09-30
Budget start date: 14-JUL-2009
Budget end date: 30-SEP-2010
3R01AI052306-08S1 (2009): $17400
FASEB Summer Conference On Neuroimmunology
Doina Ganea, Professor
Federation Of Amer Soc For Exper Biology 9650 Rockville Pike Bethesda, Md 208143998
Grant 1R13AG024223-01 from National Institute On Aging IRG: NIA
Abstract: This application is a request for support for the 8th FASEB Neuroimmunology Summer Research Conference to be held in Tucson, AZ, August 7-12, 2004. In the last decade, scientists from different disciplines became interested in the cross talk between the immune and nervous system. Accumulating evidence suggests that immune factors and cells play a role in the CNS in normal and pathological conditions, and that the CNS regulates peripheral immune responses. Rapid advances make it necessary to reassess a number of basic aspects of CNS-immune interactions, including anatomical, physiological, and functional aspects. Previously, interest in the immune involvement in the CNS was limited to brain autoimmune diseases. However, CNS trauma and neurodegenerative diseases are recognized today as having inflammatory components. Examples include Alzheimer s disease, HIV associated dementia, Parkinson s disease, brain trauma, and spinal cord injury. On the other hand, several CNS products downregulate peripheral immunity, having a beneficial effect on pathological conditions such as septic shock and autoimmune diseases. This alters our view of therapeutic approaches for the treatment of both autoimmune and neurodegenerative diseases. At the 2004 FASEB meeting, we plan to expand on basic issues regarding the role of immune mediators in CNS inflammation and neuroprotection, on the immunomodulatory role of CNS products, and on the molecular mechanisms related to immune cell CNS trafficking and the functional establishment of the immune privileged sites. Questions will be raised regarding the origin and function of CNS antigen presenting cells, viral targeting of the CNS, beneficial and detrimental effects of CNS autoimmunity. Finally, a major thrust of this conference will be to explore the role and mechanisms of inflammation in CNS trauma and neurodegenerative diseases. This meeting provides a much needed platform for scientific discussions in both basic and clinical neuroimmunology.
Keywords: central nervous system, meeting /conference /symposium, neuroimmunomodulation, antigen presenting cell, brain injury, inflammation, neural degeneration, travel
Project start date: 2004-06-01
Project end date: 2004-08-31
1R13AG024223-01 (2004): $25000
Role Of PGE2 In CNS And Peripheral Autoimmune Disorders
Doina Ganea, Professor And Chair
Temple University 1601 N. Broad Street Philadelphia, Pa 19122
Grant 2R01AI052306-06 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: Pathogenic Th1-type immune responses to self-antigens are thought to play an essential role in a number of organ-specific autoimmune diseases. However, recent developments in animal models of multiple sclerosis, Crohn s disease, and rheumatoid arthritis, suggest that IL-17 producing T cells (ThlL-17) rather than the IFNg-producing Th1 cells are the most relevant participants in autoimmunity. Activated antigen-presenting cells (ARC) control the development of Th1 effectors through IL-12p70 release, and of ThlL-17 through IL- 23. In contrast to most ARC activators that induce both IL-23 and IL-12, we identified PGE2 as an inducer of IL-23 at the expense of IL-12p70. The central hypothesis in this proposal is that PGE2 released in inflammatory conditions promotes the expression and production of IL-23, while reducing IL-12p70 release from dendritic cells and microglia, and induces the subsequent generation and/or proliferation of ThlL-17. We propose that, through the IL-23-->IL-17 axis, PGE2 contributes to the maintenance of an autoimmune-prone environment in the affected tissues. In Specific Aim 1 we propose to characterize dendritic cells (DC) and microglia (MG) exposed to or generated in the presence of PGE2 in terms of IL-23/IL-12 production and to assess their in vitro and in vivo capacity to generate ThlL-17 cells. Specific Aim 2 is focused on the PGE2- induced signaling in DC and the identification of the relevant signaling molecules and transcription factors involved in the PGE2 regulation of p19, p40, and p35 gene transcription. In Specific Aim 3 we propose to evaluate the role of PGE2 in vivo in two models of autoimmune diseases, the collagen-induced arthritis and the experimental autoimmune encephalomyelitis by assessing clinical symptoms, the relevant histopathology, the development of IL-17 producing T cells, and the cytokine profile in the affected tissues and in the peripheral lymphoid organs. The identification of the molecular and cellular factors involved in the generation, activation, and maintenance of IL-23-producing APC and of pathogenic ThlL-17 will have a significant impact on our understanding and intervention in autoimmune diseases. The ultimate goal for the clarification of the molecular mechanisms involved in the PGE2 control of the IL-23/IL-12 balance and for the identification of the functional PGE2 receptors on DCs and microglia is the development of new therapeutic avenues in autoimmunity.
Project start date: 2002-07-01
Project end date: 2011-03-31
2R01AI052306-06 (2007): $366500
5R01AI052306-08 (2009): $347274
CB2 RECEPTOR REGULATIN OF INFLAMMATORY RESPONSE IN EAE
Doina Ganea
Temple University, 1938 Liacouras Walk, Philadelphia, Pa 19122
Grant 5R01AI084065-02 from National Institute Of Allergy And Infectious Diseases
Abstract: Multiple sclerosis (MS), a chronic demyelinating disease of the central nervous system, is a major cause of neurological disability in Western countries. In spite of intensive and sustained research efforts, existing treatment options do not substantially prevent tissue damage and clinical disability. MS is increasingly recognized as an autoimmune neurodegenerative disease triggered by inflammatory attacks of the CNS. We propose to study a newly synthesized molecule (O-1966) that may significantly reduce the contribution of immune cells to CNS damage. O-1966 is a member of the cannabinoid class of molecules. While cannabinoids derived from the plant Cannabis Sativa have been used for thousands of years, their value in the treatment of diseases such as MS has been limited by their psychoactive properties. Presently, it is possible to target the CB2 receptors, primarily expressed on immune cells, which exhibit immunomodulatory functions. O-1966, a selective CB2 agonist, alters immune functions without psychoactive effects. Preliminary results showed that stimulation of CB2 receptors decreases CNS damage in experimental autoimmune encephalomyelitis (EAE). Our preliminary data suggest that the protective action of O-1966 in EAE occurs through effects on inflammation. In this proposal we will investigate the molecular mechanisms by which O-1966 specifically influences the function of immune cells. The proposed studies will be conducted at both molecular/cellular and whole animal level, to allow a better evaluation of the therapeutic potential of O- 1966. We propose that CB2 receptor activation by the selective CB2R agonist O-1966 results in 1. changes in the phenotype of effector T cells through the induction of regulatory T cells; and 2. inhibition of encephalitogenic T cell traffic to the CNS through a reduction in T cell rolling and adhesion to the vascular CNS endothelium. In Specific Aim 1 we will evaluate the effect of O-1966 in EAE and characterize the CNS infiltrating cells, based on the hypothesis that CB2 activation results in a shift in T cell differentiation from encephalitogenic Th17/Th1 to regulatory T cells. Based on preliminary studies, we propose that the CB2 selective agonist O-1966 affects T cell differentiation through the induction of tolerogenic dendritic cells. This represents a new research area, since the role of cannabinoids on DC differentiation has not been addressed. In Specific Aim 2 we will examine the effects of O-1966 on encephalitogenic Teffector and Treg cell rolling and adhesion to CNS postcapillary venules by intravital microscopy, its effect on the expression of adhesion molecules in Teff/Treg cells and in CNS endothelial cells, and on the expression of chemokines involved in the recruitment of activated T cells to the perivascular space and CNS parenchyma. The identification of molecular/cellular factors and of the mechanisms involved in the anti-inflammatory effect of CB2 receptor ligands will have a significant impact on the understanding and intervention in CNS autoimmune/inflammatory diseases. The ultimate goal of this proposal is the development of new effective therapeutic agents targeted at modification of the inflammatory responses that contribute to MS. Multiple sclerosis, the most common chronic demyelinating disease of the central nervous system, is a major cause of disability in Western countries. Approximately 2.5 million people worldwide and 400,000 Americans suffer from MS. In addition to the often devastating consequences for quality of life for individuals suffering from MS, the economic impact at both the personal and national level is substantial. It is estimated that the annual costs for the treatment of MS is in excess of $2.5 billion. In spite of intensive and sustained research efforts, existing treatment options do not substantially prevent tissue damage and clinical disability. The ultimate goal of the current proposal is the development of new effective therapeutic agents for the treatment of MS
Keywords: 6H-Dibenzo(b, d)pyran-1-ol, 6a, 7, 8, 10a-tetrahydro-6, 6, 9-trimethyl-3-pentyl-, (6aR-trans)-; 9-ene-Tetrahydrocannabinol; ATGN; Address; Adhesion Molecule; Adhesions; Affect; Agonist; Allogenic; American; Animal Model; Animal Models and Related Studies; Animals; Anti-Inflammatories; Anti-Inflammatory Agents; Anti-inflammatory; Antigens; Antiinflammatories; Antiinflammatory Agents; Area; Attenuated; Autoimmune; Autoimmune Process; Blood Vessels; Blood leukocyte; Body Tissues; Brain; C57BL/6 Mouse; CB1 Receptor; CB2 Receptor; CD106; CD106 Antigens; CD183; CD4 Positive T Lymphocytes; CD4 T cells; CD4 lymphocyte; CD4+ T cell; CD4+ T-Lymphocyte; CD4-Positive Lymphocytes; CKR-L2; CMKAR3; CXCR3; CXCR3 gene; Cannabinoids; Cannabis; Cannabis sativa; Cannabis sativa plant; Cell Adhesion Molecules; Cell Communication and Signaling; Cell Signaling; Cells; Cells, CD4; Cerebral Infarction; Cerebrum; Chemotherapy-Hormones/Steroids; Chronic; Clinical; Co-culture; Cocultivation; Coculture; Coculture Techniques; Country; Cytokines, Chemotactic; Data; Degenerative Diseases, Nervous System; Degenerative Neurologic Disorders; Delta-9-Tetrahydrocannabinol; Demyelinating Disease of Central Nervous System; Demyelinating Disorder of Central Nervous System; Dendritic Cells; Development; Disease; Disorder; Dose; Dronabinol; EAE; Encephalomyelitis; Encephalomyelitis, Allergic; Encephalon; Encephalons; Endocrine Gland Secretion; Endogenous Factors; Endothelial Cells; Endothelium; Eragrostis; Exhibits; Experimental Allergic Encephalitis; Experimental Allergic Encephalomyelitis; Experimental Autoimmune Encephalitis; Experimental Autoimmune Encephalomyelitis; Exposure to; Fluorescence; GPR9; Goals; Hemp Plant; Homologous Chemotactic Cytokines; Hormones; INCAM-110; INFLM; IP10; IP10-R; IVM; Immune; Immune Function, Cellular; Immunization; Immunologic Stimulation; Immunological Stimulation; Immunostimulation; In Vitro; Individual; Inducible Cell Adhesion Molecule 110; Infiltration; Inflammation; Inflammatory; Inflammatory Response; Intercrines; Intervention; Intervention Strategies; Intracellular Communication and Signaling; Label; Leukocyte Rolling; Leukocytes; Ligands; MS (Multiple Sclerosis); Mammals, Mice; Marinol; Marrow leukocyte; Mediating; Medulla Spinalis; Mice; Microscopy, Video; Middle Cerebral Artery Occlusion; Mig-R; MigR; Modeling; Modification; Molecular; Motor; Multiple Sclerosis; Murine; Mus; Myeloencephalitis; Myelogenous; Myeloid; Nerve Impulse Transmission; Nerve Transmission; Nervous System, Brain; Neurodegenerative Diseases; Neurodegenerative Disorders; Neurologic; Neurologic Degenerative Conditions; Neurologic Diseases, Degenerative; Neurological; Neuronal Transmission; Neuropeptides; Peripheral; Phenotype; Postcapillary Venule; Property; Property, LOINC Axis 2; QOL; Quality of life; Receptor Activation; Receptor Protein; Receptor, Cannabinoid, CB1; Receptor, Cannabinoid, CB2; Regulation; Regulatory T-Lymphocyte; Reporting; Research; Reticuloendothelial System, Leukocytes; Reticuloendothelial System, Spleen; Role; SIS cytokines; Sclerosis, Disseminated; Sensitization, Immunologic; Sensitization, Immunological; Signal Transduction; Signal Transduction Systems; Signaling; Spinal Cord; Spleen; Structure of postcapillary venule; Synapses; Synaptic; T cell differentiation; T-Cell Proliferation; T-Cells; T-Lymphocyte; T4 Cells; T4 Lymphocytes; Teff; Testing; Tetrahydrocannabinol; Therapeutic Agents; Therapeutic Hormone; Thymus-Dependent Lymphocytes; Tissues; Treatment Cost; VCAM; VCAM-1; Vascular Cell Adhesion Molecule; Vascular Cell Adhesion Molecule-1; Vascular Endothelial Cell; Veiled Cells; Video Microscopy; Videomicrography; Videomicroscopy; White Blood Cells; White Cell; analog; attenuation; autoimmune encephalomyelitis; base; biological signal transduction; cannabinoid receptor; cell adhesion protein; central nervous system demyelinating disorder; chemoattractant cytokine; chemokine; chemokine receptor; cytokine; delta(1)-THC; delta(1)-Tetrahydrocannabinol; delta(9)-THC; delta(9)-Tetrahydrocannabinol; disability; disease/disorder; economic impact; experiment; experimental research; experimental study; helper T cell; immune function; immunogen; improved; in vivo; insular sclerosis; interventional strategy; intravital microscopy; marijuana; member; migration; model organism; neurodegenerative illness; neurotransmission; new therapeutics; next generation therapeutics; novel therapeutics; postcapillary venule; prevent; preventing; protective effect; public health relevance; receptor; research study; response; social role; therapeutic evaluation; thymus derived lymphocyte; trafficking; vascular; white blood cell; white blood corpuscle
Relevance: Narrative Multiple sclerosis, the most common chronic demyelinating disease of the central nervous system, is a major cause of disability in Western countries. Approximately 2.5 million people worldwide and 400,000 Americans suffer from MS. In addition to the often devastating consequences for quality of life for individuals suffering from MS, the economic impact at both the personal and national level is substantial. It is estimated that the annual costs for the treatment of MS is in excess of $2.5 billion. In spite of intensive and sustained research efforts, existing treatment options do not substantially prevent tissue damage and clinical disability. The ultimate goal of the current proposal is the development of new effective therapeutic agents for the treatment of MS
Project start date: 2009-06-15
Project end date: 2013-05-31
Budget start date: 1-JUN-2010
Budget end date: 31-MAY-2011
PFA/PA: PA-07-070
5R01AI084065-02 (2010): $371250
1R01AI084065-01A2 (2009): $375000
Neuropeptides As Mediators Of Th2-type Immunity
Doina Ganea, Professor
Temple University 1601 N. Broad Street Philadelphia, Pa 19122
Grant 5R01AI052306-05 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: Bi-directional communications between the CNS and the immune system are mediated through common ligands and receptors, i.e. cytokines, hormones, and neuropeptides. There is ample evidence that the neuropeptides VlP and PACAP affect innate immunity through their effect on macrophages. However, the role of VlP/PACAP in the maturation and activity of dendritic cells (DC) and microglia, major participants in innate immunity and antigen presentation in the periphery and CNS, is not known. Although DCs and microglia are essential for pathogen elimination, unrestrained activation leads to tissue destruction. There are numerous examples of DCs involvement in autoimmune diseases, such as SLE, RA, MS, insulin-deficient diabetes. DCs and microglia stimulate and reactivate T cells, and promote the generation and accumulation of pro-inflammatory Th1 effectors. Endogenous agents such as anti-inflammatory cytokines, glucocorticoids, prostaglandins, limit the immune response by deactivating the antigen presenting cells, and promoting Th2 immunity. The central hypothesis in this proposal is that VlP and PACAP inhibit the innate immune response of DCs and microglia, preventing pro-inflammatory cytokine and chemokine (CK) production, reduce their capacity to activate T cells, and bias effector T cells towards Th2 responses. Specific Aim I is focused on the effects of VlP/PACAP on DCs, including production of specific cytokines and CK, expression of CK receptors and directed migration of DCs, expression of stimulatory/costimulatory molecules and T cell activation. Specific Aim II addresses similar questions in two models of microglial activation, LPS stimulation that induces primarily an innate immune response, and GM-CSF treatment resulting in DC-resembling microglia. In Specific Aim Ill we evaluate VlP/PACAP as agents that induce DCs and microglia to promote the Th2 effector accumulation and response. These studies will contribute to a better understanding of the physiological relevance of neuropeptides, particularly in establishing and maintaining immune deviation, and to the future development of appropriate receptor agonists with the capacity to limit innate inflammatory responses, and to reverse the predominant Th1 response in autoimmune diseases in the periphery and the CNS.
Keywords: cellular immunity, dendritic cell, microglia, neuroimmunomodulation, neuropeptide, vasoactive intestinal peptide, T lymphocyte, antibody specificity, antigen presentation, antigen receptor, cell migration, chemokine, cytokine, cytokine receptor, helper T lymphocyte, leukocyte activation /transformation, protein biosynthesis, receptor expression, colony stimulating factor, enzyme linked immunosorbent assay, flow cytometry, immunocytochemistry, laboratory mouse, polymerase chain reaction
Project start date: 2003-04-01
Project end date: 2007-03-31
5R01AI052306-05 (2006): $330057
5R01AI052306-03 (2005): $314910
Sponsored Links Excellgen http://Excellgen.com
5R01AI052306-02 (2004): $314910
1R01AI052306-01A1 (2003): $328785
NEUROPEPTIDES AND REGULATORY T CELLS
Doina Ganea
Temple University, 1938 Liacouras Walk, Philadelphia, Pa 19122
Grant 2R01AI047325-09A2 from National Institute Of Allergy And Infectious Diseases
Abstract: Autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) are thought to result from breaks in tolerance. In the early stages, self-reactive T cells play a major role. Late stage progression is due primarily to the chronic inflammatory environment created by innate immune cells, i.e. macrophages and synoviocytes in RA and macrophages/microglia in MS. Effective therapies should address both early and late stages, avoid generalized immunosuppression, and have local rather than systemic effects. We showed previously that dendritic cells (DC) differentiated in the presence of the neuropeptide vasoactive intestinal peptide (VIP) become tolerogenic, and induce regulatory T cells (Treg). The VIP-induced DC (DCVIP) prevent collagen induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE), stop disease progression in early stages, but do not affect innate immune cells responsible for later stages. Systemic VIP administration affects both T cells and suppresses the inflammatory activity of macrophages, synoviocytes, and microglia. However, the requirement for repeated, high VIP doses leads to side effects due to its pleiotropic functions. Therefore we propose to evaluate the therapeutic potential of genetically altered VIP expressing DC, which in addition to being tolerogenic, will deliver VIP locally, inhibiting the release of proinflammatory agents. The VIP-expressing DC (LentiVIP-DC) will be tested in EAE and CIA models. In Specific Aim 1, we propose to establish the best conditions for DC transduction. LentiVIP-DC will be analyzed in terms of phenotype, migration, cytokine profile and effects on T cells and macrophages. In Specific Aim 2 and 3 we propose to use LentiVIP-DC in EAE and CIA models. We will assess LentiVIP-DC migration to spleen, CNS, and affected joints, and investigate the effects on clinical disease, on splenic and local cytokine/chemokine expression and on T cell differentiation. The combined therapeutic approach using tolerogenic DC transduced with VIP-expressing lentiviral vectors should allow for the generation of antigen- specific Treg, as well as the local release of immunosuppressive VIP. This double-directional system represents a novel approach in the treatment of autoimmune diseases. Autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) affect more than 2 million Americans and represent a serious health problem and a major cause of disability in the US and other Western countries. In addition to the often devastating consequences for the quality of life of individuals suffering from MS or RA, the economic impact at both personal and national level is substantial. In spite of intensive and sustained research efforts, existing treatment options do not substantially prevent tissue damage and clinical disability. The ultimate goal of the present proposal is the development of a combined therapy based on genetically modified tolerogenic dendritic cells, which represents a novel therapeutic approach for the treatment of autoimmune diseases
Keywords: No Project Terms available
Relevance: Autoimmune diseases such as rheumatoid arthritis (RA) and multiple sclerosis (MS) affect more than 2 million Americans and represent a serious health problem and a major cause of disability in the US and other Western countries. In addition to the often devastating consequences for the quality of life of individuals suffering from MS or RA, the economic impact at both personal and national level is substantial. In spite of intensive and sustained research efforts, existing treatment options do not substantially prevent tissue damage and clinical disability. The ultimate goal of the present proposal is the development of a combined therapy based on genetically modified tolerogenic dendritic cells, which represents a novel therapeutic approach for the treatment of autoimmune diseases
Project start date: 2000-04-01
Project end date: 2014-12-31
Budget start date: 1-JAN-2010
Budget end date: 31-DEC-2010
PFA/PA: PA-07-070
2R01AI047325-09A2 (2010): $375000
2R01AI047325-04 (2004): $289013
VIP--A MEDIATOR OF NEUROIMMUNE INTERACTIONS
Doina Ganea, Professor
Biological Sciencesrutgers The State Univ Of Nj Newark
249 University Ave.
newark, Nj 07102
Grant 5R01AI041786-03 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: Applicant´s ) Experimental and clinical observations suggest a functional crosstalk between the nervous and the immune system, largely mediated through shared ligands and receptors. Cytokines generated or gaining access to the CNS regulate the growth, survival, an d function of the CNS cells. Conversely, neuropeptides/ neurotransmitters released or produced within the lymphoid organs may regulate the function of immune cells. Previous studies reported in vitro immuno-modulation by neuropeptides. Several reports, including Dr Ganea´s studies, indicate that some neuropeptides such as substance P stimulate immune functions, whereas other neuropeptides such as the vasoactive intestinal peptide (VIP) exert primarily an anti-inflammatory action. The in vitro anti-inflammatory role of VIP is supported by clinical data, which indicate an association of low VIP levels with highly reactive immune responses, and of high VIP levels with certain immunodeficiencies. Although several authors reported effects of VIP on immune responses little is known about the VIP immunomodulatory role in vivo, the regulation of VIP and VIP receptor expression in immune cells, and about the molecular mechanisms involved in VIP immunomodulation. Dr Ganea´s studies indicate that VIP and the pituitary adenylate cyclase-activating polypeptide (PACAP), a recently discovered VIP-related neuropeptide, inhibit the production of selected cytokines such as IL-2 and IL-4 by unprimed CD4+ T cells stimulated in vitro through the T cell receptor. We hypothesize that antigenic stimulation upregulates VIP production and/or VIP receptor expression in vivo within the lymphoid organs, and that VIP/VIP-R interactions inhibit CD4+ T cell proliferation and cytokine production. In Specific Aim A we propose to examine whether antigenic stimulation induces VIP release in vivo, and whether antigen-stimulated CD4+ T cells function as VIP sources. In Specific Aim B we propose to study the regulation of VIP-R1 and VIP-R2 expression in antigen-stimulated CD4+ T cells and T cell lines, and the involvement of these receptors in mediating the inhibitory effect of VIP/PACAP on IL-2 production. In Specific Aim C we propose to investigate the nature of the VIP cellular targets, and the molecular mechanisms, including the transduction pathways and transcriptional factors involved in the inhibitory effect of VIP/PACAP on IL-2 gene expression. The establishment of VIP and related neuropeptides as active participants in limiting a normal immune response and therefore preventing excessive tissue damage, and the elucidation of the molecular mechanisms involved, could have significant therapeutical consequences, particularly in autoimmune diseases
Keywords: cytotoxic T lymphocyte, hormone regulation /control mechanism, leukocyte activation /transformation, neuroimmunomodulation, vasoactive intestinal peptide drug receptor, gene induction /repression, hormone receptor, interleukin 2, interleukin 4, neuropeptide receptor, receptor expression, transcription factor animal genetic material tag, laboratory mouse, polymerase chain reaction, tissue /cell culture
Project start date: 1998-04-01
Project end date: 2002-03-31
5R01AI041786-03 (2000): $167564
5R01AI041786-02 (1999): $162683
1R01AI041786-01A1 (1998): $85407
MOLECULAR MECHANISMS INVOLVED IN THE IMMUNOMODULATORY ROLE OF SUBSTANCE P
Doina Ganea, Professor
Rutgers The State Univ Of Nj Newark 249 University Ave. Newark, Nj 07102
Grant 5S06GM008223-150036 from National Institute Of General Medical Sciences
Abstract: Although recent clinical and experimental observations indicate the existence of mutual relationship between the nervous and immune system, the molecular mechanisms by which the two systems interact are just beginning to be studied. Neuropeptides that belong to the tachykinin family, such as substance P, neurokinin A and neurokinin B, could play an important immunoregulatory role in vivo based on the following observations a) the presence of SP and NKA in the microenvironment of the lymphoid orgens; b) the existence of SP receptors on immune cells; and c) the in vitro immunomodulatory activity of SP and NKA. The major objective of this proposal is to determine whether SP and related tachykinins modulate the immune response through the regulation of cytokine expression. Preliminary results indicated that SP induced the production of IL-2 in murine T cells and T cells lines in a dose-dependent and specific manner, that SP induced the expression of IL-3 and GM-CSF, affecting the development of myeloid and erythroid colonies in vitro, and that the specific message for the NK-1R (high-affinity receptor for SP) can be identified in purified CD4+ T lymphocytes by RT-PCR. We propose to continue and expand the molecular analysis of the immunoregulatory effect of SP and related neurokinins by a) determining whether SP and related neurokinins stimulate IL-4 and IFNgamma production, in addition to the established stimulatory effect on IL-2 production; b) investigating the molecular mechanisms, including transcriptional and posttranscriptional regulation, by which SP and NKA stimulate IL-2 production in normal splenocytes and T cell lines; and c) identifying and characterizing the NK-1R present on lymphocytes, in terms of sequence, cellular distribution, and functionality. The study of the molecular mechanisms by which neuropeptides regulate the expression of interleukins, and therefore affect the outcome of the immune response, will offer new insights in the immunomodulatory activity of the nervous system, and could lead to new ways of controlling and manipulating the immune system, especially in pathological conditions.
Keywords: immunomodulator, immunoregulation, molecular biology, substance K, substance P, tachykinin, antigen presentation, cytokine, gene expression, genetic transcription, interferon gamma, interleukin 2, interleukin 4, posttranscriptional RNA processing, protein biosynthesis, laboratory mouse, molecular cloning, polymerase chain reaction
Project start date: 1998-07-01
Project end date: 1999-12-31
Sponsored Links Excellgen http://Excellgen.com
NEUROMODULATION OF LYMPHOCYTE ACTIVATION
Doina Ganea, Professor
Biological Sciencesrutgers The State Univ Of Nj Newark
249 University Ave.
newark, Nj 07102
Grant 5R01MH049079-02 from National Institute Of Mental Health IRG: MHAI
Abstract: Although recent clinical and experimental observations indicate the existence of a mutual relationship between the nervous and the immune system, the molecular mechanisms by which the two systems interact are just beginning to be studied. Neuropeptides that belong to the tachykinin family, such as substance-P, neurokinin A, and neurokinin B, could play an important immunoregulatory role in vivo, based on the following observations a) the presence of SP and NKA in the lymphoid organs; b) the existence of SP receptors on lymphocytes; and c) the in vitro immunomodulatory activity of SP and NKA. The major objective of this proposal is to determine whether SP and related neurokinins modulate the immune response through the regulation of cytokine expression. Preliminary results indicated that a) SP induced the production of IL-2 in murine T cell lines and murine normal lymphocyte cell cultures in a dose-dependent and specific manner; b) SP induced de novo synthesis of IL-2; and c) SP induced the expression of IFNgamma in murine splenocytes, in the absence or presence of suboptimal doses of ConA. We propose to continue and expand the molecular analysis of the immunoregulatory activity of SP and related neurokinins by a) investigating the molecular mechanisms, including transcriptional and posttranscriptional regulation, by which SP and NKA stimulate IL-2 and IFNgamma production in murine splenocytes and T cell lines; b) investigating the cellular target(s) for SP action within the normal lymphocyte/macrophage population, and the intercellular communications leading to IL-2 or IFNgamma production as a result of SP stimulation; c) studying the expression of SP receptors in murine T lymphocytes. The study of the molecular mechanisms by which neuropeptides regulate the expression of interleukins, and therefore affect the outcome of the immune response, will offer new insights in the immunomodulatory activity of the nervous system in normal and pathological conditions. This could lead to new ways of controlling and manipulating the activity of the immune system, which in turn could become significant for the development of new treatments for AIDS patients
Keywords: T lymphocyte, gene expression, immunoregulation, interferon gamma, interleukin 2, neuroimmunomodulation, substance P cell growth regulation, genetic transcription, immunogenetics, immunomodulator, leukocyte activation /transformation, lymphocyte proliferation, neuropeptide receptor, phorbol, posttranscriptional RNA processing, protein biosynthesis, receptor expression antibody neutralization test, bioassay, enzyme linked immunosorbent assay, human tissue, laboratory mouse, laboratory rat, northern blotting, nuclear runoff assay, radioimmunoassay, tissue /cell culture
Project start date: 1993-03-01
Project end date: 1996-02-29
5R01MH049079-02 (1994): $126103
1R01MH049079-01A1 (1993): $122890
REGULATION OF IMMUNE CELL APOPTOSIS BY NEUROPEPTIDES
Doina Ganea, Professor
Biological Sciencesrutgers The State Univ Of Nj Newark
249 University Ave.
newark, Nj 07102
Grant 1R01AI047325-01A1 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Abstract: adapted from applicant´s ) A functional connection, partially mediated through cytokines and neuropeptides, exists between the neuroendocrine and the immune system. Cytokines released in the CNS regulate the growth and differentiation of neuronal and glial cells, and neuropeptides or neurotransmitters released within the lymphoid organs regulate the development and function of immune cells. The vasoactive intestinal peptide (VIP) and the related neuropeptide the pituitary adenylate cyclase activating polypeptide (PACAP) are present in the lymphoid organs, and act as immunomodulators, exhibiting primarily antiinflammatory activities. The investigators showed previously that VIP and PACAP inhibit T cell- and macrophage-derived cytokine production in vivo and in vitro, that immune cells express VIP/PACAP receptors, and that VIP/PACAP exert protective effects in animal models for septic shock. However, the role of neuropeptides in lymphocyte homeostasis, and particularly in activation-induced T cell apoptosis is not known. The in vitro preliminary studies indicate that VIP/PACAP protect CD4+ T cells against activation-induced cell death (AICD), and suggest the downregulation of Fas ligand (FasL) expression as a possible mechanism. This project proposes to investigate the in vivo and in vitro roles of VIP and PACAP in FasL-induced apoptosis, i.e. in the activation-induced apoptosis of CD4+ T cells, and the cytotoxic activity of T cells against Fas-bearing targets, and to investigate the molecular mechanisms by which VIP and PACAP inhibit FasL expression. Based on their previous studies, and on the preliminary results, they postulate that VIP and PACAP released within the lymphoid organs following antigenic stimulation, regulate the immune response at several stages. First, they act as "macrophage deactivating factors," inhibiting the secretion of proinflammatory agents and downregulating the expression of B7. Through their effects on macrophages, VIP and PACAP reduce the further induction of both nonspecific and specific immune responses. In addition, VIP/PACAP inhibit directly IL-2 production by T cells, further reducing T cell proliferation. Also, as proposed here, VIP/PACAP reduce the cytotoxic function of both CD4+ T cells primarily through the downregulation of FasL. Finally, they propose that VIP and PACAP also regulate activation induced T cell apoptosis (AICD), acting as survival factors which might be important for the generation of long-lived memory T cells. Since failure to maintain a balance between cell proliferation and apoptotic cell death leads to the development of either proliferative or degenerative pathological conditions, VIP and PACAP play an important physiological role through the regulation of FasL/Fas-mediated apoptosis. Also, by limiting CD4+ T cell cytoxicity against bystander targets, VIP/PACAP may preserve cell viability in tissues with low MHCII expression such as brain, or of uninfected CD4+ T cells in AIDS
Keywords: CD95 molecule, T lymphocyte, cellular immunity, neuroimmunomodulation, neuropeptide, neuroregulation, programmed cell death cytotoxic T lymphocyte, helper T lymphocyte, immunologic memory, interleukin 2, lymphocyte proliferation, macrophage, receptor expression, transcription factor, vasoactive intestinal peptide laboratory mouse, tissue /cell culture
Project start date: 2001-01-01
Project end date: 2003-12-31
1R01AI047325-01A1 (2001): $258250
VIP--A MEDIATOR OF NEUROIMMUNE INTERACTIONS
Doina Ganea, Professor
Biological Sciencesrutgers The St Univ Of Nj New Brunswick
asb Iii
new Brunswick, Nj 08901
Grant 1R21AI041786-01 from National Institute Of Allergy And Infectious Diseases IRG: ZRG1
Keywords: cytotoxic T lymphocyte, hormone regulation /control mechanism, leukocyte activation /transformation, neuroimmunomodulation, vasoactive intestinal peptide drug receptor, gene induction /repression, hormone receptor, interleukin 2, interleukin 4, neuropeptide receptor, receptor expression, transcription factor laboratory mouse, polymerase chain reaction, tissue /cell culture
Project start date: 1997-09-30
Project end date: 1999-09-29
1R21AI041786-01 (1997): $137355