Impaired CD4 T Cell-Mediated Immunity After Sepsis
2020-08
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Impaired CD4 T Cell-Mediated Immunity After Sepsis
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2020-08
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It is estimated that 1.7 million Americans suffer from sepsis every year. While improvements in intensive care over the last 30 years have reduced mortality from the initial septic event from 80% to 10-20%, sepsis survivors suffer from a functional impairment of the immune system resulting in increased susceptibility to secondary infection that can last for years. In fact, approximately 70% of sepsis related deaths are due to secondary infection that occurs after the initial septic event as result of immunosuppression. While our understanding of sepsis has grown and improved over the last several decades, there are currently no approved targeted therapies for treatment of the dysregulated host response to the initial infection or the subsequent sepsis induced immune suppression. An improvement of our understanding of the mechanisms responsible for the dysregulated host response to infection and the immunosuppression observed after sepsis will be critical for developing effective therapies and improving the survival and quality of life for septic patients. Previous research has found that despite the transient nature of the CD4 T cell compartment depletion, recovery is uneven when looking at naïve antigen specific populations. Furthermore, it is unknown what impact this uneven recovery has on immunization responses, including CD4 T cell-dependent B cell responses, and how recovery occurs in memory populations of antigen specific CD4 T cells. In the following studies, we have investigated the hypothesis that alterations in the number and function of antigen specific populations of CD4 T cells after sublethal CLP-induced sepsis are responsible for the suppressed immunity that leads to increased mortality from secondary infection in sepsis survivors. Additionally, we have investigated inflammatory responses and CD4 T cell compartment depletion in an immune experienced mouse using various models of sepsis. Through these efforts we have uncovered evidence of innate immune training in the cohoused immune experienced mouse which heightens inflammatory responses and reduces survival following sepsis onset. Our rationale for these studies is that once we understand how immune experience influences inflammatory responses and cells within the adaptive immune system are affected during sepsis, we will be able to develop new and innovative therapeutic approaches to restore immune cell numbers and function in sepsis survivors.
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University of Minnesota Ph.D. dissertation. August 2020. Major: Microbiology, Immunology and Cancer Biology. Advisor: Thomas Griffith. 1 computer file (PDF); viii, 149 pages.
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Sjaastad, Frances. (2020). Impaired CD4 T Cell-Mediated Immunity After Sepsis. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/216828.
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