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You searched for +publisher:"University of Iowa" +contributor:("Griffith, Thomas S."). Showing records 1 – 2 of 2 total matches.

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University of Iowa

1. Brincks, Erik L. Roles for TRAIL in the immune response to influenza virus infection.

Degree: PhD, Immunology, 2010, University of Iowa

The increasing threat of epidemic and pandemic influenza underscore the need to better-understand the immune response to influenza virus infections and to better understand the factors that contribute to the clearance of virus without complications of immunopathology. A hallmark of the adaptive immune response to primary influenza virus infections is the induction of influenza-specific CD8+ T cell responses. These T cells target and kill influenza-infected epithelial cells in the airway, thereby clearing the virus and allowing recovery of the infected host. Recent reports demonstrated that CD8+ T cells express TNF-related apoptosis-inducing ligand (TRAIL) after influenza virus infection. While roles for perforin/granzyme and Fas:FasL interactions in clearing influenza virus infections had been established, little was known about the role of TRAIL in the CD8+ T cell responses to influenza virus infection. We hypothesized that influenza-specific CD8+ T cells would express TRAIL after influenza infection and could utilize TRAIL to induce the apoptosis of virally-infected cells. We discovered that CD8+ T cells do express TRAIL after influenza infection, and that this expression occurs in an influenza-specific fashion. Further, we demonstrated that these influenza-specific CD8+ T cells utilize this TRAIL to kill virally infected cells and protect the host from death, while T cells lacking TRAIL were unable to kill targets as efficiently and provided reduced protection. These data supported our hypothesis that CD8+ T cells utilize TRAIL to kill infected cells. Unexpectedly, when we increased the initial viral inoculum, the pulmonary cytotoxicity of T cells in TRAIL-/- mice was increased compared to those in TRAIL+/+ mice. Investigation of this phenomenon revealed that changes in cytotoxicity correlated not with changes in effector molecule expression on the T cells, but with increased recruitment of T cells to the lung. T cell recruitment to the lungs of TRAIL-/- mice was dependent on CCR5 and CXCR3, and likely the result of aberrant expression of MIG and MIP-1α in the lungs. Together, these data suggest that TRAIL expression contributes not only to T cell cytotoxicity, but also to the regulation of chemokine expression and associated cell recruitment after influenza virus infections. To confirm the relevance of our animal model to the study of human disease, we examined the potential role for TRAIL in the human immune response to infection. We determined that in vitro influenza infection stimulates upregulation of functional TRAIL on the surface of CD3+, CD14+, CD19+, and CD56+ PBMC populations. This expression was not caused by infection of the cells, but by interferon produced as a result of the infection. Infected (TRAIL-expressing) PBMCs killed influenza-infected lung epithelial cells, revealing that influenza infection sensitizes epithelial… Advisors/Committee Members: Griffith, Thomas S. (supervisor).

Subjects/Keywords: CD8 T cell; immunity; influenza; TRAIL; Immunology of Infectious Disease

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Brincks, E. L. (2010). Roles for TRAIL in the immune response to influenza virus infection. (Doctoral Dissertation). University of Iowa. Retrieved from https://ir.uiowa.edu/etd/467

Chicago Manual of Style (16th Edition):

Brincks, Erik L. “Roles for TRAIL in the immune response to influenza virus infection.” 2010. Doctoral Dissertation, University of Iowa. Accessed February 16, 2019. https://ir.uiowa.edu/etd/467.

MLA Handbook (7th Edition):

Brincks, Erik L. “Roles for TRAIL in the immune response to influenza virus infection.” 2010. Web. 16 Feb 2019.

Vancouver:

Brincks EL. Roles for TRAIL in the immune response to influenza virus infection. [Internet] [Doctoral dissertation]. University of Iowa; 2010. [cited 2019 Feb 16]. Available from: https://ir.uiowa.edu/etd/467.

Council of Science Editors:

Brincks EL. Roles for TRAIL in the immune response to influenza virus infection. [Doctoral Dissertation]. University of Iowa; 2010. Available from: https://ir.uiowa.edu/etd/467


University of Iowa

2. Gurung, Prajwal. Regulation of immune responses by apoptotic cells.

Degree: PhD, Immunology, 2011, University of Iowa

Billions of cells die everyday as a result of normal tissue turnover, infection, trauma or injury. These dead cells are taken up, processed and presented to T cells by antigen presenting cells resulting in tolerance or immunity. Apoptotic cells induce tolerance; however, the precise mechanisms are still unknown. Previous studies have shown that direct infusion of apoptotic cells induce tolerance mediated by TRAIL-expressing CD8+ T cells. We hypothesized that immunologic tolerance induced by apoptotic cells is dependent on the activation status of apoptotic cells and mediated by direct killing of target cells by TRAIL-expressing CD8+ T cells. Three different experimental systems were used to elucidate the mechanisms by which apoptotic cells regulate immune responses. Using a classical system of tolerance induction, we examined the immunological consequence of intravenous (i.v.) delivery of ex vivo-generated naïve or activated apoptotic cells. Naïve apoptotic cells induced tolerance when injected i.v.; however, previously activated apoptotic cells induced immunity. Further analysis revealed a key role for CD154 in the tolerogenic or immunogenic nature of the naïve or activated apoptotic cells, respectively, as tolerance resulted after i.v. injection of either naïve or activated apoptotic CD154-/- cells, while co-injection of an agonistic anti-CD40 mAb with naïve apoptotic T cells induced robust immunity. The infusion of large numbers of apoptotic cells has limited physiological relevance, so the investigation of the influence of apoptotic cells on the immune system turned to another experimental tolerance model where soluble peptide antigen is injected systemically to induce the peripheral deletion of a population of antigen-specific T cells. Using this system, we investigated how apoptotic cells generated in vivo leads to T cell tolerance. Following adoptive transfer of OT-II cells, wild-type mice injected with soluble OVA323-339 became unresponsive to subsequent CFA/OVA immunization. Interestingly, Trail-/- or Dr5-/- mice developed robust immunity; even though all strains displayed peripheral deletion of OVA-specific T cells. Subsequent investigation found the mechanism of action of the CD8+ T cells was TRAIL-mediated deletion of the OVA-responsive T cells in a TCR-specific manner. The experimental systems used above have some clinical relevance but are still not physiologic. To study the impact of apoptotic cells in a physiologic setting, we took advantage of the medical condition sepsis, which is accompanied by massive apoptosis of multiple immune cell populations. Thus, the final set of experiments in this thesis examined the tolerance induced during sepsis using a clinically-relevant cecal-ligation and puncture (CLP) model that included a secondary bacterial infection. CLP-treated WT mice had a reduced ability to control the secondary bacterial infection, which was paralleled by suppressed T cell responses, compared to sham-treated WT mice. In contrast, CLP- and sham-treated Trail-/-… Advisors/Committee Members: Griffith, Thomas S. (supervisor).

Subjects/Keywords: Apoptosis; CD8+ T regulatory cells; Sepsis; Tolerance; Immunology of Infectious Disease

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APA · Chicago · MLA · Vancouver · CSE | Export to Zotero / EndNote / Reference Manager

APA (6th Edition):

Gurung, P. (2011). Regulation of immune responses by apoptotic cells. (Doctoral Dissertation). University of Iowa. Retrieved from https://ir.uiowa.edu/etd/974

Chicago Manual of Style (16th Edition):

Gurung, Prajwal. “Regulation of immune responses by apoptotic cells.” 2011. Doctoral Dissertation, University of Iowa. Accessed February 16, 2019. https://ir.uiowa.edu/etd/974.

MLA Handbook (7th Edition):

Gurung, Prajwal. “Regulation of immune responses by apoptotic cells.” 2011. Web. 16 Feb 2019.

Vancouver:

Gurung P. Regulation of immune responses by apoptotic cells. [Internet] [Doctoral dissertation]. University of Iowa; 2011. [cited 2019 Feb 16]. Available from: https://ir.uiowa.edu/etd/974.

Council of Science Editors:

Gurung P. Regulation of immune responses by apoptotic cells. [Doctoral Dissertation]. University of Iowa; 2011. Available from: https://ir.uiowa.edu/etd/974

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