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High-probability grants
According to our matching algorithm, Julie A. Urban is the likely recipient of the following grants.
| Years |
Recipients |
Code |
Title / Keywords |
Matching
score |
| 2008 — 2009 |
Urban, Julie Anne |
F32Activity Code Description:
To provide postdoctoral research training to individuals to broaden their scientific background and extend their potential for research in specified health-related areas. |
Helper and Suppressor Roles of Cd8+ T Cells @ University of Pittsburgh At Pittsburgh
[unreadable] DESCRIPTION (provided by applicant): The clearance of antigen-carrying dendritic cells (Ag-carrying DC) by effector CD8+ T cells has been postulated as a mechanism for limiting cytotoxic T lymphocyte (CTL) responses. However, in situations of prolonged Ag exposure, such as chronic infection or cancer, DC elimination by chronically-activated CD8+ T cells may lead to immune suppression. Our preliminary observations indicate that the addition of a tumor-irrelevant (LCMV-gp33) peptide to tumor-lysate loaded DC can increase the efficacy of cancer vaccines administered in therapeutic settings in the presence of pre-existing tumor-specific immunity. Such beneficial effects of rely on the presence of memory-type LCMV-gp33-specific CD8+ T cells; whereas effector-typeLCMV-gp33-specific CD8+ T cells abolished the efficacy of the vaccine. These data suggest that the sequential phases of CD8+ T cell activation are associated with different immunoregulatory activities of CD8+ T cells. Therefore, we propose to delineate the mechanisms underlying the suppressive and helper functions of effector and memory-stage CD8+ T cells, respectively. Additionally, we will examine how these immunoregulatory functions can be, respectively, avoided or exploited for improved cancer immuno-therapies. The work outlined within this proposal will follow three specific aims- (1) To determine the mechanism of immunosuppression by effector CD8+ T cells; (2) to determine the mechanism of helper activity of memory CD8+ T cells; and (3) compare the impact of CD8+ help versus suppression on the survival of vaccine-carrying DC in preventative vs. therapeutic settings. We will use small molecule inhibitors, blocking antibodies and transgenic mice in in vitro assays examining killing of DC by effector-stage CD8+ T cells and the induction of DC maturation and IL-12 secretion by memory-stage CD8+ T cells. Using a DC migration assay in vivo, we will use transgenic mice to determine the pathways involved in helper and suppressor functions in pre-immunized mice carrying memory or effector stage responses, respectively. Lastly, these experiments will also be performed in tumor-bearing mice to delineate the pathways that effect DC-based immunotherapies. Relevance: Therapeutic DC-based vaccines are typically administered in the periphery, where the tumor-specific effector cells predominate and can kill the vaccine. By determining the mechanisms underlying CD8+ T cell immunoregulatory functions, we can design vaccines that are resistant to the suppressive functions and are more capable of receiving the memory cell-derived help, prospectively allowing us to design effective therapeutic vaccines for cancer patients. [unreadable] [unreadable] [unreadable]
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0.942 |