Master of Science
Microbiology and Immunology
Jevnikar, Anthony M.
Cytotoxic effector cells can target and kill parenchymal cells of the kidney which results in injury and loss of function. Endogenous regulatory systems may exist to attenuate Natural Killer (NK) and other effector cell activation and cytotoxicity in diverse conditions, including ischemia-reperfusion injury associated with kidney transplantation. Understanding these mechanisms will direct new therapeutic strategies. Kidney tubular epithelial cells (TEC), the predominant cell type in kidneys, may negatively regulate NK cell activation by surface expression of C-type lectin-related proteins (Clr). Clr-b and -f were found to be expressed by wild type (WT) TEC. Clr-b was upregulated by TNFα+IFNγ in vitro. Elimination of both Clr-b and Clr-f expression with siRNA resulted in increased NK killing of TEC compared to individual silencing of Clr-b or Clr-f TEC (p<0.01), or WT control TEC (p<0.001). NK cells treated in vitro with soluble Clr-b and Clr-f reduced their capacity to kill Clr-b/-f -/- TEC as compared to untreated NK cells (p<0.05). NK cells therefore are regulated by proteins expressed by TEC and thus may represent an important endogenous regulatory system in the kidney to limit organ injury. As no current drugs exist to specifically target NK cells, Clr-b and Clr-f soluble proteins that bind to NK cells may represent a novel and clinically feasible strategy to protect organs from NK cell-mediated inflammation during ischemia-reperfusion and other kidney injury models.
Fuhrmann, Benjamin B., "Inhibition of NK cell-mediated Cytotoxicity by Tubular Epithelial Cell Expression of Clr Proteins" (2018). Electronic Thesis and Dissertation Repository. 5631.
Available for download on Thursday, February 28, 2019