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Waldman, James
The efforts of the Waldman laboratory are directed toward several issues of biomedical significance including (i) elucidation of mechanisms by which cytomegalovirus (CMV) evades host immune responses, (ii) identification of antiviral mechanisms of novel antiviral agents, (iii) resolution of etiologic interactions of endothelial-reactive autoantibodies in several disease processes, and (iv) elucidation of mechanisms of pathobiological responses to environmental airborne nano-particulate exposure. 1. Mechanisms of CMV-mediated inhibition of MHC class II: CMV, a member of the herpes group, remains a significant cause of serious complications under conditions of immune compromise (AIDS patients, organ transplant recipients). Like many pathogens, CMV has evolved several strategies to evade recognition and clearance by the host immune system, including inhibition of MHC class II expression. Previous work by the Waldman lab and collaborators has demonstrated CMV-mediated disruption of the IFNγ-inducible JAK/STAT signaling pathway required for IFNγ-mediated MHC class II expression. The current series of studies are directed toward elucidation of mechanisms by which CMV disrupts the transport of constitutively expressed MHC class II complexes to the cell surface in infected host cells and, using cosmid constructs spanning the entire CMV genome, the identification of viral gene product(s) responsible for this disruption. 2. Antiviral drug discovery and development: Despite substantial progress, antiviral chemotherapy remains less than ideal, marginally beneficial, or completely ineffective against many viral pathogens. Many of the currently prescribed medications produce toxic side effects. In addition, many of these agents act by similar or nearly identical mechanisms resulting in the emergence of multi-drug-resistant viral variants. The Waldman lab has previously demonstrated that leflunomide, an experimental immunosuppressive agent currently in Phase I clinical trials in organ transplant recipients, exerts potent antiviral activity against CMV in vitro and in vivo, and HSV1 in vitro. In contrast to anti-herpesvirus drugs currently in use, leflunomide does not inhibit viral DNA synthesis, but rather appears to act at the level of virion assembly by inhibiting nucleocapsid tegumentation. Likely as a consequence of this unique mechanism, leflunomide is equally effective against multi-drug-resistant CMV isolates. Current studies are directed toward identification of specific antiviral mechanisms, focusing particularly on leflunomide-mediated inhibition of viral structural protein phosphphorylation and consequent disruption of viral protein-protein interactions required for late-stage assembly of the complete infectious virion. Dr. Waldman’s team has also shown effectiveness of leflunomide against polyomavirus, a source of infrequent but serious complications in renal transplant recipients, and respiratory syncytial virus, a cause of severe, often life-threatening neonatal respiratory disease. Studies directed toward elucidation of antiviral mechanisms against these two very different viruses are also in progress. 3. Etiologic interactions of endothelial-reactive autoantibodies in idiopathic pulmonary fibrosis and lung allograft dysfunction: The Waldman group has recently demonstrated the presence of circulating endothelial-reactive autoantibodies in patients with idiopathic pulmonary fibrosis and lung transplant recipients experiencing graft dysfunction in the absence or paucity of cellular infiltrates, and in the absence of anti-donor MHC antibodies. These antibodies appear to be reactive with a number of protein components of endothelial cells including vimentin and α-actin, and unlike antibodies in sera of healthy individuals, they are internalized and dispersed within the cytoplasm of live cultured endothelial cells where they bind to their respective targets. Current studies are underway to determine the mechanisms by which patient serum antibodies gain entrance into endothelial cells and subsequently escape vesicles and disperse in the cytoplasm. 4. Pathobiological responses to environmental airborne nano-particulate exposure: Epidemiological studies have demonstrated an association between airborne particulate matter (coal fly ash emitted by coal-burning power plants, diesel exhaust particulates) and cardiopulmonary disease. This association appears strongest for particulates ≤ 2.5 μm in size. Pathophysiologic interactions underlying this association, however, remain ill-defined. Current regulations limiting industrial emissions are based solely on particulate size; however physicochemical properties of such particulates vary dramatically. For example, whereas coal fly ash consists primarily of a complex mixture of crystalline inorganics, the particulate component of diesel exhaust contains high levels of organic products of incomplete combustion, such as polycyclic aromatic hydrocarbons. The Waldman lab is a leading component of an interdisciplinary alliance composed of investigators in the Departments of Pathology, Chemistry, Molecular Virology, Immunology and Medical Genetics, Veterinary Biosciences, and the Center for Automotive Research, whose mission is to (i) synthesize simplified model carbon and quantum dot-based particulates of constant size, down into the nm range, and of homogeneous chemical composition, (ii) identify specific physicochemical properties that determine bioactivity of particulates (pure carbon, presence of surface Fenton-reactive iron, surface charge, surface benzo-a-pyrene, etc.), (iii) define biophysical mechanisms by which particulates, especially those in the nm size range, are internalized and distributed within living cells, tissues, and organ systems, and (iv) elucidate pathobiological responses to particulate exposure as a function of particulate size and physicochemical properties. Selected publications Waldman WJ, Knight DA, Huang EH (1998): An in vitro model of T cell activation by autologous CMV-infected human adult endothelial cells: Contribution of CMV-enhanced endothelial ICAM-1. Journal of Immunology 160: 3143-3151. Waldman WJ, Knight DA, Lurain NS, Miller DM, Sedmak DD, Williams JW, Chong AS-F (1999): Novel mechanism of inhibition of CMV by the experimental immunosuppressive agent leflunomide. Transplantation 68: 814-825. Waldman WJ, Magro CM, Knight DA (2003): The endothelium as a mediator of CMV-associated immunopathology. Monographs in Virology 24: 1-9. Kristovich R, Knight DA, Long JF, Williams MV, Dutta PK, Waldman WJ (2004): Macrophage-mediated endothelial inflammatory responses to airborne particulates: Impact of particulate physicochemical properties. Chemical Research in Toxicology 17: 1303-1312. Knight DA, Magro CM, Adams PW, Orosz CG, Ross P, Pope-Harman A, Waldman WJ: Acute pulmonary microvascular injury associated with endothelial-reactive, non-MHC antibodies in lung transplant recipients. American Journal of Pathology: submitted. Laboratory personnel Contact 4160 Graves Links |
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W. James Waldman, Ph.D. is an Associate Professor in the Department of Pathology, with cross-appointments in the Department of Molecular Virology, Immunology and Medical Genetics, and the Radiologic Technology Division of the School of Allied Medical Professions. He is also Director of Pathology Graduate Studies, a faculty member of the Integrated Biomedical Sciences Graduate Program, and an investigator of the Environmental Molecular Sciences Institute. He joined the faculty in 1993.