William Karpus, PhD
Marie A. Fleming Research Professor of Pathology and Microbiology-Immunology
Director, Integrated Graduate Program in the Life Sciences
Feinberg School of Medicine
Associate Director, Clinical Flow Cytometry
Northwestern Memorial Hospital
Research Interests:
The central theme of Dr. Karpus' research program is the role of chemokines and chemokine receptors in the regulation of autoimmune disease, chronic viral diseases, mucosal immunity and tolerance to gut pathogens. The three major research projects are listed below.
1. The laboratory of Dr. William Karpus studies the pathogenesis and regulation of experimental autoimmune encephalomyelitis (EAE), an animal model of human multiple sclerosis (MS). EAE follows a relapsing-remitting course of paralysis and is characterized by lymphocyte and monocyte infiltrates of the central nervous system (CNS) with areas of demyelination. It is clear that similarities exist in both clinical course and histopathology between relapsing forms of EAE and MS and this allows us to develop new therapeutic strategies for human disease. As a result of this autoimmunity, T lymphocytes migrate from the peripheral lymphoid tissue and blood to the brain and spinal cord. This is a central feature in the pathogenesis of both MS and EAE. A number of factors, including cell-associated integrins and soluble chemokines, regulate the migration or trafficking of T cells to tissue sites. We have identified a number of chemokines and chemokine receptors responsible for paralytic disease induction and progression. Current projects include: a. Chemokine regulation of dendritic cell trafficking in EAE development, remission and relapse. b. Chemokine regulation of T cell effector function. c. Chemokine regulation of T cell trafficking during remission and disease relapses. d. Targeting of chemokines for novel therapeutic intervention. e. Epitope spreading and lymphocyte trafficking.
2. Theiler’s murine encephalomyelitis virus (TMEV) chronically infects mice and induces a progressive paralytic disease resembling MS. In contrast to EAE, the disease course is chronic progressive and un-remitting. However, lymphocytes and monocytes infiltrate the brain and spinal cord and induce demyelination. We have identified chemokines, MCP-1 in particular, responsible for the induction of paralytic disease. Current projects include: a. Chemokine receptor regulation of chronic disease progression. b. Chemokine regulation of resultant autoimmune responses. c. Chemokine regulation of viral persistence.
3. There is a growing body of evidence that indicates aberrant chemokine receptor expression by both human B cell and T cell lymphomas and leukemias. Similarly, chemokine ligand expression has been noted in human B cell, T cell, and Hodgkin’s lymphoma. These findings raise the possibility that chemokines and their receptors may be involved in lymphoma cell movement between lymphoid as well as non-lymphoid sites. The idea that chemokines and their receptors functionally direct the migration of lymphoma cells to lymphoid and extra-lymphoid tissues has not been formally tested either clinically or preclinically. Using a mouse model of B cell lymphoma we propose to test the hypothesis that chemokine expression in lymphoid and non-lymphoid tissue regulates the migration of lymphoma cells expressing specific chemokine receptors to those particular tissues.
Selected Publications:
Dogan, R. N., Elhofy, A. and Karpus, W. J. (2008). Production of CCL2 by central nervous system cells regulates development of murine experimental autoimmune encephalomyelitis through the recruitment of TNF- and iNOS-expressing macrophages and myeloid dendritic cells. J Immunol 180, 7376-84.
Karpus, W. J., Reynolds, N., Behanna, H. A., Van Eldik, L. J. and Watterson, D. M. (2008). Inhibition of experimental autoimmune encephalomyelitis by a novel small molecular weight proinflammatory cytokine suppressing drug. J Neuroimmunol 203, 73-8.
Thompson, W. L., Karpus, W. J. and Van Eldik, L. J. (2008). MCP-1-deficient mice show reduced neuroinflammatory responses and increased peripheral inflammatory responses to peripheral endotoxin insult. J Neuroinflammation 5, 35.
Bennett, J. L., Elhofy, A., Charo, I., Miller, S. D., Dal Canto, M. C. and Karpus, W. J. (2007). CCR2 regulates development of Theiler's murine encephalomyelitis virus-induced demyelinating disease. Viral Immunol 20, 19-33.
Karpus, W. J., Kennedy, K. J., Fife, B. T., Bennett, J. L., Dal Canto, M. C., Kunkel, S. L. and Lukacs, N. W. (2006). Anti-CCL2 treatment inhibits Theiler's murine encephalomyelitis virus-induced demyelinating disease. J Neurovirol 12, 251-61.
