Genomes and Genes
Innate and Adaptive Immune Mechanisms in Arthritis
Principal Investigator: RICHARD J BUCALA
Abstract: ABSTRACT Rheumatoid arthritis results from a dysregulation in host immunity. Since our initial cloning of murine macrophage migration inhibitory factor (MIF), we have focused on the role of this mediator in the pathogenesis of rheumatoid arthritis. We showed that anti-MIF is protective in experimental arthritis and we reported on MIF's ability to override glucocorticoid immunosuppression, induce sustained activation of ERK1/2 MAP kinases, and promote inflammation by inhibiting activation-induced apoptosis. The importance of MIF in human disease was validated by our discovery of high-expression MIF alleles and their association with rheumatoid arthritis severity;these data were confirmed recently in a larger multi- center study and extended to juvenile idiopathic arthritis. In the currently funded period, we elucidated MIF function by creating genetic models for the complete and cell-lineage specific deletion of MIF (MIF-KO, mif flox), and we developed a "knock-in" mouse encoding a mutant MIF that resolved questions about the protein's enigmatic tautomerase activity. We also established that MIF signal transduction requires a complex of two proteins: CD74, which binds MIF, and CD44, which initiates signaling by activating Src family tyrosine kinases. In this competitive renewal, we will focus on the function of the recently elucidated MIF receptor. Our Specific Aims are: 1. Define the Role of the MIF Receptor Complex (CD74/CD44) in the Adaptive Immune Response. Our working hypothesis is that signaling through the MIF receptor sustains the survival of activated T lymphocytes and regulates the adaptive immune response. 2. Define the Functional Importance of the MIF Signaling Receptor, CD44, and of CD44 Variant Isoforms in the Immunopathology of Rheumatoid Arthritis. The expression of CD44 splice variants in T cells is associated with an enhanced trafficking response;and in stromal cells, with an increase in invasive phenotype. Our working hypothesis is that MIF induces the alternative splicing of CD44, which regulates MIF-dependent responses and contributes to the immunopathogenesis of rheumatoid arthritis. 3. Identify High-potency, Small Molecule Antagonists of the MIF Binding Receptor (CD74). Structure-function studies indicate that MIF's N-terminal region binds to the CD74 component of the MIF receptor. We will evaluate small molecules that were rationally designed to bind to the MIF N-terminal region for their ability to inhibit MIF interaction with CD74 and ameliorate experimentally-induced arthritis. The information to be gained will have broad application because it will provide mechanistic insight into how the MIF receptor complex (CD74/CD44) contributes to the immunopathology of rheumatoid arthritis. The translational impact of these studies is that a more precise definition of MIF-receptor action will accelerate the development of small molecule MIF inhibitors. Such inhibitors may show greatest efficacy in those patients with high-expression MIF alleles and who manifest an MIF-dependent form of inflammatory disease.
Funding Period: 2004-01-23 - 2014-08-31
more information: NIH RePORT
- HLA-DRα1 constructs block CD74 expression and MIF effects in experimental autoimmune encephalomyelitisRoberto Meza-Romero
Neuroimmunology Research, Department of Veterans Affairs Medical Center, Portland, OR 97239
J Immunol 192:4164-73. 2014....
- D-dopachrome tautomerase (D-DT or MIF-2): doubling the MIF cytokine familyMelanie Merk
Center of Integrated Protein Science Munich, Division of Clinical Pharmacology, LMU Munich, Germany
Cytokine 59:10-7. 2012..In this review, we highlight the similarities and differences between MIF and D-DT, which we propose to designate "MIF-2", and discuss the implication of D-DT/MIF-2 expression for MIF-based therapies...
- The cytokine midkine and its receptor RPTPζ regulate B cell survival in a pathway induced by CD74Sivan Cohen
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
J Immunol 188:259-69. 2012..These findings could pave the way toward understanding the mechanisms shaping B cell survival and suggest novel therapeutic strategies based on the blockade of the MK/RPTPζ-dependent survival pathway...
- Dual effect of the macrophage migration inhibitory factor gene on the development and severity of human systemic lupus erythematosusAntoine Sreih
Yale University School of Medicine, New Haven, Connecticut 06520, USA
Arthritis Rheum 63:3942-51. 2011..To study the effect of the innate cytokine macrophage migration inhibitory factor (MIF) on the susceptibility and severity of systemic lupus erythematosus (SLE) in a multinational population of 1,369 Caucasian and African American patients...
- The latency-associated nuclear antigen, a multifunctional protein central to Kaposi's sarcoma-associated herpesvirus latencyMary E Ballestas
Department of Pediatrics, Division of Infectious Diseases, University of Alabama in Birmingham, School of Medicine, Children s Harbor Building, Room 148, 1600 6th Ave South, Birmingham, AL 35233, USA
Future Microbiol 6:1399-413. 2011..In addition to episome maintenance, LANA has transcriptional regulatory effects and affects cell growth. LANA exerts these functions through interactions with different cell proteins...
- Macrophage migration inhibitory factor (MIF) exerts antifibrotic effects in experimental liver fibrosis via CD74Daniel Heinrichs
Medical Department III, Rheinisch Westfälische Technische Hochschule Aachen University, 52074 Aachen, Germany
Proc Natl Acad Sci U S A 108:17444-9. 2011..In conclusion, we describe a previously unexplored antifibrotic function of MIF that is mediated by the CD74/AMPK signaling pathway in HSCs. The results imply MIF and CD74 as targets for treatment of liver diseases...
- Drug repositioning and pharmacophore identification in the discovery of hookworm MIF inhibitorsYoonsang Cho
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520, USA
Chem Biol 18:1089-101. 2011..Structure-activity relationships of a pharmacophore based on furosemide included one analog that binds similarly to the active site, yet does not inhibit the Na-K-Cl symporter (NKCC1) responsible for diuretic activity...
- The D-dopachrome tautomerase (DDT) gene product is a cytokine and functional homolog of macrophage migration inhibitory factor (MIF)Melanie Merk
Department of Internal Medicine, Yale University School of Medicine, New Haven, CT 06520, USA
Proc Natl Acad Sci U S A 108:E577-85. 2011..These data indicate that D-DT is a MIF-like cytokine with an overlapping spectrum of activities that are important for our understanding of MIF-dependent physiology and pathology...
- Benzisothiazolones as modulators of macrophage migration inhibitory factorWilliam L Jorgensen
Department of Chemistry, Yale University, New Haven, CT 06520 8107, USA
Bioorg Med Chem Lett 21:4545-9. 2011..Consistently, both compounds were also found to retard the MIF-dependent phosphorylation of ERK1/2 in human synovial fibroblasts...
- Role of macrophage migration inhibitory factor in the Th2 immune response to epicutaneous sensitizationRituparna Das
Department of Medicine, Yale University School of Medicine, The Anlyan Center Room S525, New Haven, CT 06520 8031, USA
J Clin Immunol 31:666-80. 2011..This defect is most profound when both T cells and antigen-presenting cells are lacking MIF. These data suggest that MIF is crucial both for the sensitization and the elicitation phases of a Th2-type immune response in allergic disease...
- Macrophage migration inhibitory factor regulates neutrophil chemotactic responses in inflammatory arthritis in miceLeilani L Santos
Monash Medical Centre, Clayton, Victoria, Australia
Arthritis Rheum 63:960-70. 2011..The effects of MIF on neutrophil recruitment are unknown. This study was undertaken to investigate the contribution of MIF to the regulation of neutrophil chemotactic responses...
- Macrophage migration inhibitory factor and CD74 regulate macrophage chemotactic responses via MAPK and Rho GTPaseHuapeng Fan
Department of Medicine, Centre for Inflammatory Diseases, Monash University, Monash Medical Centre, Clayton, Victoria 3168, Australia
J Immunol 186:4915-24. 2011..These data demonstrate that MIF and CD74 play previously unappreciated roles in CCL2-induced macrophage adhesion and migration, and they indicate that MIF and CD74 mediate this effect via both common and independent mechanisms...
- A novel allosteric inhibitor of macrophage migration inhibitory factor (MIF)Fengwei Bai
L2 Diagnostics, LLC, New Haven, CT 06511, USA
J Biol Chem 287:30653-63. 2012..The mode of p425 binding reveals a unique way to block the activity of the cytokine for potential therapeutic benefit in MIF-associated diseases...
- Flow cytometric identification of fibrocytes in scleroderma lung diseaseThomas M Russell
Section of Pulmonary and Critical Care Medicine, Department of Medicine, Yale University, New Haven, CT, USA
Methods Mol Biol 900:327-46. 2012..It is hoped that this information will allow further investigation of the role that fibrocytes might play in Scleroderma-related lung disease and perhaps lead to new areas of study in this difficult-to-treat and deadly disease...
- Macrophage migration inhibitory factor: association of -794 CATT5-8 and -173 G>C polymorphisms with TNF-α in systemic lupus erythematosusU De la Cruz-Mosso
Instituto de Investigación en Ciencias Biomédicas Programa de Doctorado en Ciencias Biomédicas, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
Hum Immunol 75:433-9. 2014..In conclusion, MIF gene polymorphisms are associated with SLE susceptibility and with an increase of TNF-α serum levels in a Mexican-Mestizo population. ..
- The role of macrophage migration inhibitory factor in autoimmune liver diseaseDavid N Assis
Department of Medicine, Yale University School of Medicine, New Haven, CT
Hepatology 59:580-91. 2014..Significantly higher levels of CD74 were found in patients with PBC versus AIH and controls...
- Macrophage migration inhibitory factor receptor CD74 mediates alphavirus-induced arthritis and myositis in murine models of alphavirus infectionLara J Herrero
Griffith University, Gold Coast Campus, Southport, Queensland, Australia
Arthritis Rheum 65:2724-36. 2013..The present study was undertaken to characterize the role of CD74, a cell surface receptor of MIF, in both RRV- and CHIKV-induced alphavirus arthritides...
- MIF intersubunit disulfide mutant antagonist supports activation of CD74 by endogenous MIF trimer at physiologic concentrationsChengpeng Fan
Department of Pharmacology, Yale University, New Haven, CT 06510, USA
Proc Natl Acad Sci U S A 110:10994-9. 2013..This conclusion has implications for therapeutic development. ..
- Partial MHC class II constructs inhibit MIF/CD74 binding and downstream effectsGil Benedek
Department of Veterans Affairs Medical Center, Neuroimmunology Research, Portland, OR 97239, USA
Eur J Immunol 43:1309-21. 2013..Thus, binding of partial MHC complexes to CD74 blocks both the accessibility and availability of CD74 for MIF binding and downstream inflammatory activity...
- Macrophage-derived, macrophage migration inhibitory factor (MIF) is necessary to induce disease in the K/BxN serum-induced model of arthritisAnjana Singh
Department of Natural Sciences, Immunology and Cell Biology, University of Applied Sciences, von Liebig Str 20, 53359 Rheinbach, Germany
Rheumatol Int 33:2301-8. 2013....
- Small molecular modulation of macrophage migration inhibitory factor in the hyperoxia-induced mouse model of bronchopulmonary dysplasiaHuanxing Sun
Department of Pediatrics, Yale University, New Haven, CT 06520, USA
Respir Res 14:27. 2013..The role and mechanism of action of MIF in bronchopulmonary dysplasia (BPD) are not known. We hypothesized that increased MIF signaling would ameliorate the pulmonary phenotype of BPD in the mouse lung...
- CD84 is a survival receptor for CLL cellsI Binsky-Ehrenreich
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
Oncogene 33:1006-16. 2014..These findings suggest novel therapeutic strategies based on the blockade of this CD84-dependent survival pathway. ..
- Macrophage migration inhibitory factor (MIF): genetic evidence for participation in early onset and early stage rheumatoid arthritisM A Llamas-Covarrubias
Functional Immunogenetics Group and PhD Program in Biomedical Sciences, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara, Jalisco, Mexico
Cytokine 61:759-65. 2013..In conclusion, the MIF gene and protein are associated with RA in a western Mexican population, with a main contribution onto early onset and early stages of disease...
- Role of macrophage migration inhibitory factor in the regulatory T cell response of tumor-bearing miceSusanna Choi
Research Institute of Immunobiology, Catholic Research Institute of Medical Science, Seoul, Korea 137 040
J Immunol 189:3905-13. 2012..Taken together, our data suggest that MIF promotes tumor growth by increasing Treg generation through the modulation of IL-2 production. Thus, anti-MIF treatment might be useful in enhancing the adaptive immune response to colon cancers...
- MIF, MIF alleles, and prospects for therapeutic intervention in autoimmunityRichard Bucala
Department of Medicine, Section of Rheumatology, Yale University School of Medicine, The Anlyan Center for Biomedcal Research, S521, 300 Cedar Street, New Haven, CT 06520 8031, USA
J Clin Immunol 33:S72-8. 2013....
- A small-molecule macrophage migration inhibitory factor antagonist protects against glomerulonephritis in lupus-prone NZB/NZW F1 and MRL/lpr miceLin Leng
Department of Medicine, Yale University, New Haven, CT 06520, USA
J Immunol 186:527-38. 2011..These data highlight the feasibility of targeting the MIF-MIF receptor interaction by small-molecule antagonism and support the therapeutic value of downregulating MIF-dependent pathways of tissue damage in systemic lupus erythematosus...
- Receptor agonists of macrophage migration inhibitory factorWilliam L Jorgensen
Department of Chemistry, Yale University, New Haven, CT 06520, USA
Bioorg Med Chem Lett 20:7033-6. 2010..The compounds contain a triazole core that is readily assembled via Cu-catalyzed click chemistry. The agonist and antagonist behaviors were confirmed via study of MIF-dependent ERK1/2 phosphorylation in human fibroblasts...
- Human cytomegalovirus paralyzes macrophage motility through down-regulation of chemokine receptors, reorganization of the cytoskeleton, and release of macrophage migration inhibitory factorGiada Frascaroli
Institute for Virology, University of Ulm, Ulm, Germany
J Immunol 182:477-88. 2009..Our findings reveal that HCMV uses different mechanisms to interfere with movement and positioning of macrophages, possibly leading to an impairment of antiviral responses and to an enhancement of the local inflammation...
- Discovery of human macrophage migration inhibitory factor (MIF)-CD74 antagonists via virtual screeningZoe Cournia
Department of Chemistry, Yale University, New Haven, Connecticut 06520 8107, USA
J Med Chem 52:416-24. 2009..Inhibition of MIF tautomerase activity was also established for many of the compounds with IC(50) values as low as 0.5 microM; Michaelis-Menten analysis was performed for two cases and confirmed the competitive inhibition...
- Toll-like receptors in systemic lupus erythematosus; prospects for therapeutic interventionWan Uk Kim
Department of Internal Medicine, School of Medicine, Catholic University of Korea, Seoul, South Korea
Autoimmun Rev 8:204-8. 2009..Pharmacologic modulation of TLR-directed pathways may offer new therapeutic approaches for the treatment of SLE...
- Macrophage migration inhibitory factor contributes to the immune escape of ovarian cancer by down-regulating NKG2DMathias Krockenberger
Department for Obstetrics and Gynecology, University of Wurzburg, Wurzburg, Germany
J Immunol 180:7338-48. 2008..Together with the additional tumorigenic properties of MIF, this finding provides a rationale for novel small-molecule inhibitors of MIF to be used for the treatment of MIF-secreting cancers...
- A role for macrophage migration inhibitory factor in the neonatal respiratory distress syndromeKatharine A Kevill
Department of Pediatrics, Yale University School of Medicine, New Haven, CT 06520, USA
J Immunol 180:601-8. 2008..03). This study demonstrates for the first time a role for MIF in lung maturation, and supports a protective role for MIF in newborn lung disease...
- Macrophage migration inhibitory factor induces B cell survival by activation of a CD74-CD44 receptor complexYael Gore
Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel
J Biol Chem 283:2784-92. 2008..Thus, MIF regulates the adaptive immune response by maintaining the mature B cell population...
- The proinflammatory cytokine macrophage migration inhibitory factor regulates glucose metabolism during systemic inflammationToshiya Atsumi
Graduate School of Medicine, Hokkaido University, Sapporo, Japan
J Immunol 179:5399-406. 2007..Genetic MIF deficiency also promotes adipogenesis, which is in accord with a downstream role for MIF in the action of TNF-alpha. These studies support an important role for MIF in host glucose metabolism during sepsis...
- Macrophage migration inhibitory factor (MIF) gene polymorphisms are associated with increased prostate cancer incidenceK L Meyer-Siegler
Research and Development 151, Bay Pines VA Healthcare System, Bay Pines, FL 33744, USA
Genes Immun 8:646-52. 2007..Individuals with -173G/C, -173C/C and -794 7-CATT MIF genotypes have an increased incidence of CaP and these genotypes may serve as an independent marker for cancer recurrence...
- Null mutation for macrophage migration inhibitory factor (MIF) is associated with less aggressive bladder cancer in miceJohn A Taylor
Division of Urology, University of Connecticut Health Center, Farmington, CT, USA
BMC Cancer 7:135. 2007..We studied the development of bladder cancer in wild type (WT) and MIF knockout (KO) mice given N-butyl-N-(4-hydroxybutyl)-nitrosamine (BBN), a known carcinogen, to determine the role of MIF in bladder cancer initiation and progression...
- Macrophage migration inhibitory factor induces MMP-9 expression in macrophages via the MEK-ERK MAP kinase pathwayXiyong Yu
The Guangdong Provincial Cardiovascular Institute, Guangdong Provincial People s Hospital, Guangzhou 510080, China
J Interferon Cytokine Res 27:103-9. 2007..MIF activates the MEK-ERK MAP kinase pathway to induce MMP-9 expression by murine macrophages. Activation of this pathway is necessary for MMP-9 expression and activation in response to MIF stimulation...
- Macrophage migration inhibitory factor promoter polymorphisms and the clinical expression of sclerodermaSou Pan Wu
Yale University School of Medicine, New Haven, Connecticut 06520 8031, USA
Arthritis Rheum 54:3661-9. 2006..To investigate the potential association between functional polymorphisms in the gene for the innate mediator, macrophage migration inhibitory factor (MIF), and the clinical expression of systemic sclerosis (SSc)...
- CD44 is the signaling component of the macrophage migration inhibitory factor-CD74 receptor complexXuerong Shi
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut 06520, USA
Immunity 25:595-606. 2006..These data establish CD44 as an integral member of the CD74 receptor complex leading to MIF signal transduction...
- A tautomerase-null macrophage migration-inhibitory factor (MIF) gene knock-in mouse model reveals that protein interactions and not enzymatic activity mediate MIF-dependent growth regulationGunter Fingerle-Rowson
Clinic I for Internal Medicine, Hematology and Oncology, University Hospital Cologne, Cologne, Germany
Mol Cell Biol 29:1922-32. 2009..These data provide genetic evidence that MIF's intrinsic tautomerase activity is dispensable for this cytokine's growth-regulatory properties and support a role for the N-terminal region in protein-protein interactions...
- MIF deficiency reduces chronic inflammation in white adipose tissue and impairs the development of insulin resistance, glucose intolerance, and associated atherosclerotic diseaseLars Verschuren
TNO Quality of Life, Biosciences, Leiden, The Netherlands
Circ Res 105:99-107. 2009....
- Activation of the JNK signalling pathway by macrophage migration inhibitory factor (MIF) and dependence on CXCR4 and CD74Hongqi Lue
Institute of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Pauwelsstrasse 30, Aachen, Germany
Cell Signal 23:135-44. 2011..Together, these data show that the CXCR4/CD74/SRC/PI3K axis mediates a rapid and transient activation of the JNK pathway as triggered by the inflammatory cytokine MIF in T cells and fibroblasts...
- A role for the B-cell CD74/macrophage migration inhibitory factor pathway in the immunomodulation of systemic lupus erythematosus by a therapeutic tolerogenic peptideSmadar Lapter
Department of Immunology, The Weizmann Institute of Science, Rehovot, Israel
Immunology 132:87-95. 2011..Treatment with hCDR1 diminished the expression of those molecules to the levels determined for young healthy mice. These results suggest that the CD74/MIF pathway plays an important role in lupus pathology...
- Optimization of N-benzyl-benzoxazol-2-ones as receptor antagonists of macrophage migration inhibitory factor (MIF)Alissa A Hare
Department of Chemistry, Yale University, New Haven, CT 06520 8107, USA
Bioorg Med Chem Lett 20:5811-4. 2010..Additional studies for one of the potent inhibitors demonstrated that it is not a covalent inhibitor of MIF and that it attenuates MIF-dependent ERK1/2 phosphorylation in human synovial fibroblasts...
- c-Met and its ligand hepatocyte growth factor/scatter factor regulate mature B cell survival in a pathway induced by CD74Maya Gordin
Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
J Immunol 185:2020-31. 2010..Thus, the CD74-HGF/c-Met axis defines a novel physiologic survival pathway in mature B cells, resulting in the control of the humoral immune response...
- Increased TLR4 expression and downstream cytokine production in immunosuppressed adults compared to non-immunosuppressed adultsDana W Dunne
Department of Internal Medicine, Yale University School of Medicine, New Haven, Connecticut, United States of America
PLoS ONE 5:e11343. 2010..We studied monocyte Toll-like receptor (TLR) expression and cytokine production in 137 patients with autoimmune diseases who were maintained on immunosuppressive medications and 419 non-immunosuppressed individuals...
- Macrophage migration inhibitory factor (MIF): a promising biomarkerGerrit Grieb
Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA
Drug News Perspect 23:257-64. 2010..In this article, we review the clinical data of MIF and discuss its potential as a biomarker for different disease applications...
- Polymorphisms in the macrophage migration inhibitory factor gene and bone loss in postmenopausal womenMaria Swanberg
Clinical and Molecular Osteoporosis Research Unit, Lund University, Department of Clinical Sciences, Malmo University Hospital, Entrance 21, Floor 4, UMAS, SE 20502 Malmo, Sweden
Bone 47:424-9. 2010..We conclude that MIF promoter polymorphisms have modest effects on bone remodeling and are associated with the rate of bone loss in elderly women...
- TAp63 regulates VLA-4 expression and chronic lymphocytic leukemia cell migration to the bone marrow in a CD74-dependent mannerInbal Binsky
Department of Immunology, Weizmann Institute of Science, Rehovot 76100, Israel
J Immunol 184:4761-9. 2010..These results could form the basis of novel therapeutic strategies aimed at blocking homing of CLL cells in their return to the BM and attenuating their survival...
- A new class of isothiocyanate-based irreversible inhibitors of macrophage migration inhibitory factorHajer Ouertatani-Sakouhi
Laboratory of Molecular Neurobiology and Functional Neuroproteomics, Brain Mind Institute and Institute of Biotechnology and Bioengineering, Ecole Polytechnique Federale de Lausanne EPFL, CH 1015 Lausanne, Switzerland
Biochemistry 48:9858-70. 2009..Together, these findings highlight the role of tertiary structure in modulating the biochemical and biological activities of MIF and present new opportunities for modulating MIF biological activities in vivo...
- A functional heteromeric MIF receptor formed by CD74 and CXCR4Verena Schwartz
Department of Biochemistry and Molecular Cell Biology, RWTH Aachen University, Aachen, Germany
FEBS Lett 583:2749-57. 2009..Thus, CD74 forms functional complexes with CXCR4 that mediate MIF-specific signaling...
- Glucocorticoid-induced MIF expression by human CEM T cellsLin Leng
Yale University School of Medicine, New Haven, CT 06520, USA
Cytokine 48:177-85. 2009..These data support a glucocorticoid-mediated MIF secretion response by T cells that may contribute to the regulation of the adaptive immune response...
- Insight into the biology of macrophage migration inhibitory factor (MIF) revealed by the cloning of its cell surface receptorLin Leng
Department of Medicine, Yale University School of Medicine, The Anlyan Center, S525, 300 Cedar Street, New Haven CT 06520 8056, USA
Cell Res 16:162-8. 2006..The MIF receptor, like MIF, does not fall into any established family of protein mediators, providing both new challenges and opportunities for the structural and functional analysis of MIF signal transduction...
- Center for Narcolepsy and Related Disorders (P50)Emmanuel J Mignot; Fiscal Year: 2013..We also want to understand why the immune system destroys hypocretin neurons in narcolepsy and to prevent/cure it. ..
- INNATE IMMUNE RESPONSE TO MICROBIAL INFECTIONWilliam M Nauseef; Fiscal Year: 2013....
- G protein-coupled receptor kinase 3 regulation of leukocyte function in inflammatTERESA KATHLEEN TARRANT; Fiscal Year: 2013....
- MIF AND THE HOST RESPONSE TO INFECTIONRICHARD J BUCALA; Fiscal Year: 2013..This work also will enable the identification of individuals who are at risk for severe infection and lethal outcome, so that appropriate measures can be taken to better treat their infections. ..
- Role of CX3CR1 in adaptive immunity during autoimmune encephalomyelitisAstrid E Cardona; Fiscal Year: 2013..We will use knock-in mice expressing the human variant as a low affinity model to investigate the role of the I249/M280 in APC activation and T cell polarization in vivo during CNS autoimmunity. ..
- Therapeutic Application of Small Molecule MIF Inhibitors in Rheumatoid ArthritisYoonsang Cho; Fiscal Year: 2013..Outcomes of this proposed research will allow us to better understand MIF action to its receptors and also will provide potential drug leads for the treatment of inflammatory diseases. ..
- Signaling in Inflammation, Stress, and TumorigenesisGEORGE ROBERT STARK; Fiscal Year: 2013..abstract_text> ..
- Pacific NorthWest Regional Center of Excellence (PNWRCE)Jay A Nelson; Fiscal Year: 2013..pseudomallei host pathogen response during both the septicemic as well as the intracellular phases of the disease. ..
- Northeast Biodefense CenterW Ian Lipkin; Fiscal Year: 2013..As a Center based in a School of Public Health and a State Department of Health, the NBC has a firm commitment to and practical understanding of Emergency Preparedness. ..
- Molecular Analyses and Interventions for Biodefense and Emerging PathogensOlaf Schneewind; Fiscal Year: 2013..Research and training at the GLRCE is governed by a mechanism involving ongoing review of scientific excellence and translational goals, inter-institutional advisory boards and external scientific advisory bodies. ..
- Therapeutic Opportunities for Pediatric AstrocytomaRosalind A Segal; Fiscal Year: 2013..The three projects interact with one another and are further unified by economies of scale enabled by an Innovative Neuropathology (INP) core. ..
- Autoimmunity Center of Excellence (ACE) at StanfordCHARLES GARRISON FATHMAN; Fiscal Year: 2013..The Stanford ACE proposes clinical research projects that encompass three different autoimmune diseases (SSc, psoriatic arthritis and SJIA), and proposes to study the MoA of therapeutics for preventing or treating different Al diseases. ..
- Developing Small MIF Inhibitors for Rheumatoid ArthritisChristian Grant; Fiscal Year: 2013..Dose finding studies and PK profiling will first be performed with a preference for oral dosing. An optimized dose and route of administration will then be chosen to test the therapeutic efficacy of two lead compounds in the RA models ..
- Blood Stem Cell Transplantation as ImmunotherapySamuel Strober; Fiscal Year: 2013..The results are also expected to reduce the risk of graft versus host disease in patients given hematopoietic cell transplants to treat leukemia and lymphoma. (End of Abstract) ..
- CSHL CANCER CENTER SUPPORT GRANTBRUCE W STILLMAN; Fiscal Year: 2013....