Kidney ischemia reperfusion injury (IRI) is a major cause of acute renal failure (ARF) in both native and allograft kidney. We and others have demonstrated an important modulatory role for T cells in experimental kidney ARF. The next stage is to understand the mechanisms underlying the role for T cells in renal IRI. We hypothesize that T cells modulate renal IRI by trafficking into ischemic kidney, becoming activated through antigen specific interactions through the T cell receptor (TCR)-major histocompatibility complex (MHC), and produce inflammatory mediators that work in concert with other specific lymphocytes.
Specific Aim 1 : We hypothesize that the TCR-MHC complex mediates T cell participation in renal IRI through antigen specific responses. We have preliminary data that TCR receptors, as well as MHC class II directly influence outcome of renal IRI. We will use an established mouse model of renal IRI and mice with specific knockouts, and evaluate renal, molecular and cellular responses. We will also perform T cell adoptive transfer studies and use bone marrow chimeras. We will use CD4 TCR transgenic mice to probe the role of antigen specificity and T cell activation in IRI.
Specific Aim 2 : We hypothesize that early T cell trafficking, activation and production of cytokines mediates subsequent injury following renal IRI. We will use our new developed lymphocyte isolation technique to evaluate trafficking of T cells into postischemic kidney. We will compare T cell trafficking with that of other leukocytes, and characterize the renal T cells ex vivo in terms of activation status and production of proinflammatory cytokines at the protein and mRNA level. Adoptive transfer techniques will be used to directly test the functional role of these T cell cytokines.
Specific Aim 3 : We hypothesize that T cells interact with NKT and B cells for full expression of renal injury after IRI. We will use mice deficient in NKT and B cell function, and perform adoptive transfer studies. We will perform complementary experiments with agonists, blockers and depleting agents in wild type mice using new developed tools that previously limited these studies. This is a novel direction that will lead to new insights into the very early cellular steps that initiate postischemic kidney inflammation. The long term goal will be to identify the antigens and molecular pathways that fuel the injury processes in renal IRI, and develop targeted immune therapies for ARF. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
2R01DK054770-06A1
Application #
7048009
Study Section
Pathobiology of Kidney Disease Study Section (PBKD)
Program Officer
Rys-Sikora, Krystyna E
Project Start
2000-08-15
Project End
2010-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
6
Fiscal Year
2006
Total Cost
$334,833
Indirect Cost
Name
Johns Hopkins University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
001910777
City
Baltimore
State
MD
Country
United States
Zip Code
21218
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Gandolfo, Maria Teresa; Jang, Hye Ryoun; Bagnasco, Serena M et al. (2010) Mycophenolate mofetil modifies kidney tubular injury and Foxp3+ regulatory T cell trafficking during recovery from experimental ischemia-reperfusion. Transpl Immunol 23:45-52
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Jang, Hye Ryoun; Gandolfo, Maria Teresa; Ko, Gang Jee et al. (2010) B cells limit repair after ischemic acute kidney injury. J Am Soc Nephrol 21:654-65
Liu, Manchang; Grigoryev, Dmitry N; Crow, Michael T et al. (2009) Transcription factor Nrf2 is protective during ischemic and nephrotoxic acute kidney injury in mice. Kidney Int 76:277-85
Hassoun, Heitham T; Lie, Mihaela L; Grigoryev, Dmitry N et al. (2009) Kidney ischemia-reperfusion injury induces caspase-dependent pulmonary apoptosis. Am J Physiol Renal Physiol 297:F125-37
Linfert, Douglas; Chowdhry, Tayseer; Rabb, Hamid (2009) Lymphocytes and ischemia-reperfusion injury. Transplant Rev (Orlando) 23:1-10
Huang, Edmund; Samaniego-Picota, Millie; McCune, Thomas et al. (2009) DNA testing for live kidney donors at risk for autosomal dominant polycystic kidney disease. Transplantation 87:133-7
Li, Xiang; Hassoun, Heitham T; Santora, Rachel et al. (2009) Organ crosstalk: the role of the kidney. Curr Opin Crit Care 15:481-7

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