Grant: $616,000 - National Institutes of Health - Sep. 24, 2009
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Award Description: During liver damage due to ischemia and reperfusion, the host pro-inflammatory effector memory, rather than naïve, CD4 T cells, promote local innate immune activation without de novo Ag-specific stimulation via the CD154-CD40 T cell costimulation pathway.
Project Description: To study the role of T cells in innate immunity-driven liver damage. We plan to: (1). Determine the specific CD4 T cell subset and its function in liver IRI. We expect that effector, rather than naïve, CD4 T cell subset function in IRI via CD154 signaling. We will reconstitute T cell-deficient nude mice with distinct CD4 subset -enriched or -depleted splenocytes, andf then assess their ability to trigger IR-induced liver damage. To determine whether Th1 and Th2 type effector CD4 T cells have comparable effects in liver IRI, we will employ purified CD4 T cell subsets from groups of Stat4- vs. Stat 6- KO mice. (2) Determine that the previously activated (effector memory; EM) but not naïve, T cells function in an Ag-non-specific fashion to trigger liver IRI. We will use OT II mice in which all T cells are in naïve state due to their minimal cross-reactivity to self Ags. The susceptibility to liver IRI will be tested in groups of naïve or OVA-immunized OT II mice. Naive or activated OT II CD4 T cells will be adoptively transferred into nude mice to recreate IRI in OLTs from syngeneic nude donors. We will also employ cell culture systems to determine whether and how Ag-non-specific stimulation triggers CD4 T cells to express CD154. These interlocked experimental series will provide the final clue as to how Ag-specific T cells regulate tissue inflammation in the absence of specific Ag stimulation during liver IR. The successful execution of the experimental series will provide novel cellular and molecular evidence on the dynamic interplay between innate and adaptive immunity in the disease process, and address the long-elusive question as to how T cells become activated and function in liver pro-inflammatory immune response/tissue injury in the absence of exogenous Ag stimulation. The anticipated results should advance our understanding of the mechanism of liver IRI, and provide rationale for much needed novel therapies to prevent or ameliorate IRI in patients.
Jobs Summary: N/A (Total jobs reported: 0)
Project Status: Not Started
This award's data was last updated on Sep. 24, 2009. Help expand these official descriptions using the wiki below.