We are interested in delineating mechanisms of cytotoxic lymphocyte activation, differentiation and effector function. In our laboratory we have developing strategies for targeting therapeutic agents to the enzymes expressed in the specialized cytolytic granules contained within these cells. These agents have proven useful both in elucidating the role of specific enzymes in cytotoxic lymphocyte function and in defining the contribution of cytotoxic lymphocyte effector function to organ allograft rejection, the development of organ specific inflammatory lesions during graft versus host disease and the role of cytotoxic lymphocytes in antiviral immune responses.
Much of our recent research effort has focused on delineating mechanisms employed by cytotoxic lymphocytes in clearing virally infected cells from the liver. Findings from these studies indicate that Fas / Fas Ligand interactions play more prominent roles in killing of hepatocyte targets by cytotoxic T cells than in killing of target cells of non-hepatic origin. This appears to relate to the cytokine regulated expression within virally infected hepatocytes of serpins that block the cytolytic granule exocytosis pathway of CTL mediated killing.
RESEARCH INTERESTS
Antiviral immune responses
Cytotoxic lymphocyte function
Transplantation immunology
RECENT PUBLICATIONS
Miller BC, Eckman EA, Sambamurti K, Dobbs N, Chow KM, Eckman CB, Hersh LB and Thiele DL, "Amyloid-beta peptide levels in brain are inversely correlated with insulysin activity levels in vivo" Proc Natl Acad Sci U S A, 100:6221-6226, 2003
Barrie MB, HW Stout, MS Abougergi, BC Miller and DL Thiele, "Anti-viral cytokines induce hepatic expression of the granzyme B inhibitors proteinase inhibitor 9 and serine proteinase inhibitor 6" J Immunol, 172:6453-6459, 2004
Kam CM, M Gotz, G Koot, M McGuire, D Thiele, D Hudig and JC Powers, "Design and evaluation of inhibitors for dipeptidyl peptidase I (Cathepsin C)" Arch. Biochem. Biophy., 427:123-134, 2004
Abougergi MC, SJ Gidner, DK Spady, BC Miller and DL Thiele, "Fas and TNFR1 but not cytolytic granule dependent mechanisms mediate clearance of liver adenovirus infection" Hepatology, 41:97-102, 2004
Stout-Delgado HW, Y Getachew, TE Rogers, BC Miller and DL Thiele, "The role of serpinB9 / serine protease inhibitor 6 in preventing granzyme B dependent hepatotoxicity" Hepatology, 45:In Press, 2007
SIGNIFICANT PUBLICATIONS
Thiele DL, Eigenbrodt ML, Bryde SE, Eigenbrodt EH and Lipsky PE, "Intestinal graft versus-host disease is initiated by donor T cells distinct from classic cytotoxic T lymphocytes" J. Clin. Invest., 84:1947-1956, 1989
Thiele DL and Lipsky PE, "The action of leucyl-leucine methyl ester on cytotoxic lymphocytes requires uptake by a novel dipeptide-specific facilitated transport system and dipeptidyl peptidase I mediated conversion to membranolytic products" J. Exp. Med., 172:183-194, 1990
Thiele DL and Lipsky PE, "Regulation of cellular function by products of lysosomal enzyme activity: Elimination of human natural killer cells by a dipeptide methyl ester generated from L-leucine methyl ester by monocytes or polymorphonuclear leukocytes" Proc. Natl. Acad. Sci. USA, 82:2468-2472, 1985
McGuire MJ, Lipsky PE and Thiele DL, "Generation of active myeloid and lymphoid granule serine proteases requires processing by the granule thiol protease dipeptidyl peptidase I" J. Biol. Chem., 268:2458-2467, 1993
Thiele DL, McGuire MJ and Lipsky PE, "A selective inhibitor of dipeptidyl peptidase I impairs generation of CD8(+) T cell cytotoxic effector function" J. Immunol., 158:5200-5210, 1997
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