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The Okusa laboratory is currently interested in understanding the immunological mechanisms of acute kidney injury and chronic kidney disease and translating this knowledge to novel therapies.

Contact Information:

Mark D. Okusa, M.D.
John C. Buchanan Distinguished Professor of Internal Medicine
Division Chief, Division of Nephrology
Box 800133, UVA Health System
Charlottesville, VA, 22908
434.924.2187 | Fax 434.924.5848
Email mdo7y@virginia.edu
Express mail: 1 Lane Rd, Room 5807 OHW
University of Virginia, Charlottesville, VA 22908

Immune Activation in Ischemic Acute Kidney Injury

Following ischemia-reperfusion injury (IRI), appearance in the kidneys of neutrophils and macrophages-components of the innate immune system-provides clear support for an antigen-independent mechanism of tissue damage (1). The innate immune system has evolved as a host defense mechanism that recognizes microbial products. Toll-like receptors and a limited number of other receptors respond to highly conserved structures leading to an immediate and generic response(2, 3). Once activated, an inflammatory and immune response leads to sequestration of leukocytes in inflamed sites, complement activation and eradication of pathogens through cytokines, complement/membrane attack complex and natural killer cells.

Although effective in eradicating pathogens, a consequence of such a stereotypical, generalized response is secondary tissue injury. Neutrophils, phagocytic macrophages lymphocytes, natural killer (NK) cells and NKT cells probably participate in the early phase of IRI. Although classically thought to be activated by antigen-presenting cells, there is evidence that activation of NKT and T cells via an antigen-independent mechanism occurs through production of pro-inflammatory cytokines such as interferon gamma (IFN-γ) interleukin-12 (IL-12), IL-6, IL-1b and tumor necrosis factor alpha, chemokines and reactive oxygen intermediates released following exposure of cells to necrotic issue (1, 4). Glycolipids presented on the CD1d molecules activate NKT cells (5). Thus endogenous factors released during tissue damage directly activate T cells (1, 4) and NKT cells (5).

Late phase IRI is likely to involve antigen-dependent activation of T cells. Toll-like receptors or the receptors for inflammatory mediators trigger a phenotypic switch of dendritic cells from an immature cell type (characterized by high phagocytic capacity, and low levels of expression of class II major histocompatibility complex [MHC II] and co-stimulatory proteins) to a mature cell type (characterized by low phagocytic capacity, and high surface expression of MCH II and co-stimulatory molecules).  Inflammatory cytokines and chemokines also activate infiltrated macrophages or macrophage-derived dendritic cells with up-regulated class II and co-stimulatory molecules (6, 7). Activated macrophages, resident and macrophage-derived dendritic cells migrate to the kidney draining lymph node to facilitate T, B cell activation and differentiation (8, 9). Activated T, B cells and memory T, B cells can then participate in the late phase of IRI. So, macrophages and dendritic cells serve as a crucial interface between the innate and adaptive immune systems.

References
1.    Rabb, H. 2002. The T cell as a bridge between innate and adaptive immune systems: implications for the kidney. Kidney Int 61:1935-1946.
2.    Anders, H. J., B. Banas, and D. Schlondorff. 2004. Signaling danger: toll-like receptors and their potential roles in kidney disease. J Am Soc Nephrol 15:854-867.
3.    Janeway, C. A., Jr., and R. Medzhitov. 2002. Innate immune recognition. Annu Rev Immunol 20:197-216.
4.    Lappas, C. M., J. M. Rieger, and J. Linden. 2005. A2A adenosine receptor induction inhibits IFN-gamma production in murine CD4+ T cells. J Immunol 174:1073-1080.
5.    Mattner, J., K. L. Debord, N. Ismail, R. D. Goff, C. Cantu, 3rd, D. Zhou, P. Saint-Mezard, V. Wang, Y. Gao, N. Yin, K. Hoebe, O. Schneewind, D. Walker, B. Beutler, L. Teyton, P. B. Savage, and A. Bendelac. 2005. Exogenous and endogenous glycolipid antigens activate NKT cells during microbial infections. Nature 434:525-529.
6.    Geissmann, F., S. Jung, and D. R. Littman. 2003. Blood monocytes consist of two principal subsets with distinct migratory properties. Immunity 19:71-82.
7.    Qu, C., E. W. Edwards, F. Tacke, V. Angeli, J. Llodra, G. Sanchez-Schmitz, A. Garin, N. S. Haque, W. Peters, N. van Rooijen, C. Sanchez-Torres, J. Bromberg, I. F. Charo, S. Jung, S. A. Lira, and G. J. Randolph. 2004. Role of CCR8 and other chemokine pathways in the migration of monocyte-derived dendritic cells to lymph nodes. J Exp Med 200:1231-1241.
8.    Banchereau, J., F. Briere, C. Caux, J. Davoust, S. Lebecque, Y. J. Liu, B. Pulendran, and K. Palucka. 2000. Immunobiology of dendritic cells. Annu Rev Immunol 18:767-811.
9.    Mellman, I., and R. M. Steinman. 2001. Dendritic cells: specialized and regulated antigen processing machines. Cell 106:255-258.

Current Projects

Leukocyte trafficking in acute renal failure. This project focuses on the role of immune cell activation in the pathogenesis of acute renal failure. We study T lymphocytes, natural killer T cells, antigen presenting cells including macrophages and dendritic cells to determine their role in the innate and adaptive immune response to ischemia-reperfusion injury.

Lysophosphatidic acid  (LPA) and sphingosine 1 phosphate (S1P) in acute renal failure. LPA is produced following ischemia-reperfusion injury and has heterogenous effects.  On one hand they are vital for cell survival; however, in other instances they can induce cell death. We believe that the heterogeneous response to LPA in kidney is due to effects on LPA receptor subtypes (LPA1, LPA2 and LPA3). Sphingolipid metabolites are important signaling molecules in health and diseases. S1P, found in high concentrations in human serum is formed by action of of sphingosine kinase (SPHK) in response to a variety of stimuli and can regulate diverse biological processes such as cell growth and proliferation, angiogenesis and inhibition of apoptosis. S1P was once considered to be simply breakdown product of ceramide, the backbone of most sphingolipids. The importance of this lipid mediator as an important signaling molecule and recent discovery of their role as a ligand of specific S1P receptors (S1P1 to S1P5) led to make progress in understanding the complex role of this lipid mediator in diverse physiological and pathological conditions.  Our studies focus on the role of S1P metabolism and their cognate receptors in acute renal failure.

Adenosine and renal injury. In this project we are investigating the role of adenosine 2a receptors in mitigating the inflammation that participates in the pathogenesis of diabetic kidney disease. In particular a novel area of study is the immunobiology of podocytes which are glomerular epithelial cells that functions as a critical element in maintaining the glomerular permeability barrier and injury to these cells leads to certain disorders including diabetic nephropathy. Our studies examine the mechanisms by which adenosine 2a agonists reduce proteinuria and renal injury.

We use a number of different in vivo models that include genetically deficient mice, chimeric mice, tissue specific gene knockout mice and transgenic mice. Cell culture, molecular biology, pharmacology as well as immunological methods that use Elispot, flow cytometry are routinely employed.