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Michal Olszewski, D.V.M., Ph.D.
Immune modulation by TNFα antagonists during C. neoformans
Cryptococcus neoformans is an opportunistic pathogen that is capable of establishing a chronic pulmonary infection in immunocompromised hosts, including AIDS patients, transplant recipients, and recently, patients being treated with TNFα antagonist therapies. An early TNFα response is critical to the establishment of a protective cell mediated immune response. Previous work with C. neoformans infection during anti-TNFα treatment has shown that a single dose of anti-TNFα antibody at the time of infection is sufficient to skew the immune response from a protective Th1 response, which results in fungal clearance, to a non-protective Th2 response, which results in a chronic infection. The mechanism by which this occurs is unknown. My thesis project will examine the effects of TNFα antagonists on dendritic cells in the context of C. neoformans infection, including early changes in maturation and activation, epigenetic regulation and immune training, changes in DC trafficking to lymph nodes, and DC-T cell interactions in the lung and lymph node. I hypothesize that anti-TNFα antibodies exert their effects both through blocking TNFα signaling to receptors and through “reverse signaling” through transmembrane TNFα resulting in epigenetic changes. To accomplish this, I plan to utilize both in vivo, and in vitro techniques including infection of WT and modified mice, protein and mRNA analysis, live animal imaging studies, mathematical modeling of cytokine network during infection, and possibly, analysis of epigenetic changes through ChIP assays and ChIPseq. I plan to analyze the effects of a-TNF on DC in vitro and use adoptive transfer experiments to link the effects of a-TNF with the specific cell susbest(s).
Farnand AW, Eastman AJ, Herrero R, Hanson JF, Mongovin S, Altemeier WA, Matute-Bello G. Fas Activation in Alveolar Epithelial Cells Induces KC (CXCL1) Release by a MyD88-dependent Mechanism. Am J Respir Cell Mol Biol. 2011 Jan 21.
Jayadev S, Case A, Eastman AJ, Nguyen H, Pollak J, Wiley JC, Möller T, Morrison RS, Garden GA. Presenilin 2 is the predominant γ-secretase in microglia and modulates cytokine release. PLoS One. 2010 Dec 29 ;5(12):e15743.
Lozon TI, Eastman AJ, Matute-Bello G, Chen P, Hallstrand TS, Altemeier WA. PKR-dependent CHOP induction limits hyperoxia-induced lung injury. Am J Physiol Lung Cell Mol Physiol. 2011 Mar ;300(3):L422-9. Epub 2010 Dec 24.
Alison J. Eastman, Lisa M. Rogers, Katie L. Mason, David M. Aronoff. In vitro innate immune response to spores of the intrauterine pathogen Clostridium sordellii. Autumn Immunology Conference, Chicago, IL, November 2012.
Alison Eastman, David Aronoff. Innate immune response to spores of intrauterine pathogen Clostridium sordellii in vivo and in vitro. Anita Payne Symposium, Ann Arbor, MI, November 2012.
Alison Eastman, Michal Olszewski. Assessing the role of TNFα in Cryptococcus neoformans infection in the mouse model. Midwestern Neglected Infectious Disease Conference, Notre Dame, IN, August 2013
Alison J. Eastman, Michal Olszewski. Immune polarization during TNFα blockade in Cryptococcus neoformans infection. Autumn Immunology Conference, Chicago, IL, November 2013.
Eastman AJ, Carolan J, Davis M, Malachowski A, Kunkel S, Kryczek I, Olszewski MA. TNF-alpha-induced stability of DC1 programming is required for maintenance of protective Th1/Th17 immune response against Cryptococcus neoformans. 9th International Conference on Cryptococcus and Cryptococcosis,
Amsterdam, Netherlands, May 2014
Rackham Predoctoral Fellowship, University of Michigan, 2014-15
Rackham Conference Travel Grant, University of Michigan, 2012
Benard Maas Fellowship, University of Michigan, 2011