Browsing by Subject "Immune suppression"

Now showing 1 - 3 of 3
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    Differentially Expressed Gene Transcripts Using RNA Sequencing from the Blood of Immunosuppressed Kidney Allograft Recipients
    (2016-02-29) Dorr, Casey; Wu, Baolin; Guan, Weihua; Muthusamy, Amutha; Sanghavi, Kinjal; Schladt, David; Maltzman, Jonathan; Scherer, Steven; Brott, Marcia; Matas, Arthur; Jacobson, Pamala; Oetting, William; Israni, Ajay; isran001@umn.edu; Israni, Ajay
    This is the FPKM and clinical covariate data from a paper in PLOS One. These data will be useful for future researchers to study gene expression patterns over time before and after immunosuppression and kidney transplantation. We removed subject names and any other identifiers in order to de-identify the subjects.
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    Impaired CD4 T Cell-Mediated Immunity After Sepsis
    (2020-08) Sjaastad, Frances
    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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    Re-aligning patient prognosis: the role of collagen in establishing an immunosuppressive microenvironment and facilitating cancer cell dissemination in pancreatic ductal adenocarcinoma
    (2021-10) Callaway, Mackenzie
    Pancreatic ductal adenocarcinoma (PDA) is an aggressive cancer with particularly poor clinical outcomes, in part, because of a dramatically altered stromal environment and striking immune dysfunction. Physical properties within tumors— such as aligned fiber architectures—are fundamental to cancer progression and invasion, and negatively correlate with survival in cancers like those of the breast. However, the influence of aligned architectures in PDA remains unexplored. Here, we elucidate the role extracellular matrix alignment has in establishing an immunosuppressive, metastasis-conducive tumor microenvironment in early, preinvasive PDA, as well as in precursory pancreatic inflammation. Using both mouse and human samples, we demonstrate an inextricable link between collagen, alignment, and 1) immunosuppressive macrophage localization, phenotype, and function (Chapter 2); 2) epithelial cell extrusion and subsequent invasion from intact ductal structures (Chapter 3). The contribution of alignment in both driving macrophage polarization and tumor cell dissemination could be attributed to altered focal adhesion dynamics, as targeting FAK in vivo resulted in a concomitant decrease in aligned collagen architectures, disseminated tumor cells, metastatic burden, and elongated, immunosuppressive macrophages. In Chapter 4, we explore the interplay between macrophages, collagen, and cancer cell extrusion using novel 3D microtissue co-cultures and human biopsies to reveal contributions of macrophages to dissemination in vitro and in vivo. Importantly, we show aligned collagen signatures and immunosuppressive macrophages are abundantly prevalent in pancreatitis, a known risk factor for PDA, suggesting that pancreatic precursory disease may create stromal memory that is later conducive to early immunosuppression and dissemination of PDA. This work highlights the opportunity to utilize FAK inhibitors to target stromal immunity and architectures and supports a model in which collagen architecture drives the early involution of an immunosuppressive, malignant microenvironment. Further, this thesis underscores the importance of targeting stromal matrices in precursor inflammation, limit cancer progression, and “reprogram” stromal immunity.