T cell modulation of renal ischemia reperfusion injury.

Johns Hopkins University, Baltimore MD

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Abstract

[unreadable] DESCRIPTION (provided by applicant): Kidney ischemia reperfusion injury (IRI) is a major cause of acute renal failure (ARF) in both the native and allograft kidney. We and others have demonstrated an important modulatory role for T cells in experimental kidney ARF as well as in IRI of other organs. Despite strong evidence for this concept, there is minimal information on the mechanisms underlying the role for T cells in renal IRI. The Aims of this project are to elucidate the mechanisms by which T cells modulate kidney IRI. Our focus will be on integrative in vivo mechanisms, thus the studies proposed will be performed in an established murine model of ARF. Specific Aim 1: To investigate if the major molecules that constitute the first signal for conventional T cell responses, "Signal 1," play a role in the T cell's participation in renal IRI. We will use an established mouse model of renal IRI and mice with specific knockouts, and then evaluate kidney function, structure, molecular and cellular responses. We will perform T cell adoptive transfer studies and develop bone marrow chimeras. Specific Aim 2: To investigate if the function of the T cell in renal IRI is due to the direct infiltration of T cells into the kidney or if T cell function and infiltration can be disassociated. We will evaluate the early trafficking of T cells into post ischemic kidney and phenotype these T cells using immunohistochemistry and a leukocyte isolation and purification technique. We will compare T cell trafficking with trafficking of other leukocytes, and correlate these findings with functional, structural and molecular endpoints for injury. We will perform serum and T cell transfer studies to evaluate if infiltration into kidney which is essential to mediate the T cell's role. Specific Aim 3: To investigate if the T cell is modulating kidney IRI by interactions with other lymphocytes. We will use mice deficient in B cells and specialized T cells, and perform adoptive transfer studies using soluble and cellular factors. This is a novel direction that should lead to new insights into the very early cellular steps that initiate post ischemic inflammation. The long term goal will be to identify the antigens and molecular pathways that fuel the injury processes in ARF and develop targeted therapies. [unreadable] [unreadable] [unreadable]