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Andrew Tager, MD
Assistant Physician, Pulmonary Unit, Massachusetts General Hospital
Principal Investigator, Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital
Assistant Professor of Medicine, Harvard Medical School
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Lysophosphatidic Acid in the Pathogenesis of Pulmonary Fibrosis
Diseases characterized by pulmonary fibrosis cause high morbidity and mortality, and are largely refractory to currently available pharmacologic therapies. The development of effective therapies in these diseases will require improved understanding of the biologic processes involved in fibrogenesis per se, and more complete identification of the molecular mediators driving these processes. We have recently found that the bioactive lipid lysophosphatidic acid (LPA) is a critically important mediator of fibrogenesis in the bleomycin mouse model of pulmonary fibrosis. LPA is induced by lung injury in the bleomycin model, and mice deficient for one of LPA's G protein-coupled receptors, LPA1, are dramatically protected from fibrosis and mortality produced by bleomycin injury. We are investigating the mechanisms by which the LPA-LPA1 pathway contributes to lung fibrosis in the bleomycin model, and determining the relevance of this novel pathway to human fibrotic lung diseases, including idiopathic pulmonary fibrosis (IPF) and fibroproliferative phase acute respiratory distress syndrome (ARDS). The LPA1 receptor is expressed by multiple cell types, including fibroblasts, endothelial cells, and epithelial cells, enabling LPA to mediate diverse biologic effects. We hypothesize that the LPA-LPA1 pathway plays a central role in the development of pulmonary fibrosis by mediating multiple biologic processes critically involved in the lung's fibrogenic response to injury, including the development of vascular leak, the recruitment of fibroblasts, and the activation of TGF-beta. We hypothesize that the attenuation of all three of these interconnected fibrogenic processes in the absence of LPA1 accounts for the dramatic degree of protection from bleomycin-induced fibrosis that LPA1-deficient mice demonstrate, and are currently investigating the roles of the LPA-LPA1 pathway in each of these three processes.
Humanized Mouse Model of HIV Infection
Despite great effort, an ideal animal model in which to study HIV pathogenesis and test vaccine efficacy remains elusive. Non-human primates susceptible to HIV infection do not typically develop immunodeficiency, and although simian immunodeficiency virus (SIV) infection of rhesus macaques has provided critical insights into retroviral pathogenesis, inherent differences between SIV and HIV as well as financial considerations have limited the general applicability of this system. Mouse models have been extremely useful in investigations of many areas of immunology, but the ability of mice to provide a model of HIV infection has been limited. Recently, we and others have developed a markedly improved humanized mouse model of HIV by transplanting human CD34+ stem cells and autologous human thymic grafts into immunodeficient mice.
In this model, we have achieved robust repopulation of mouse lymphoid tissues with human immune cells, and have generated robust anti-HIV cellular and humoral immune responses in these humanized mice. We believe this improved humanized mouse model will allow us to study questions regarding the biology of HIV-1 not readily approachable through human studies. For example, in collaboration with CIID investigator, Thorsten Mempel, we are studying the migratory behavior of both HIV itself and of human T cells and dendritic cells in the lymph nodes of our humanized mice using multiphoton intravital microscopy (MV-IVM). We are also using this model to investigate the role of the PD-1 pathway, a member of the B7-CD28 family of cell surface receptors that negatively regulates T cell activity, in HIV infection in vivo. We are testing the hypothesis that inhibiting the PD-1 pathway will reinvigorate "exhausted" CD8+ T cells in vivo and lead to better control of HIV replication.
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