Cell mediated cytotoxicity has been shown to be a major component of the immune responses directed against allogeneic tissues. Leu-Leu-OMe treatment of human or murine leukocytes has been observed to deplete natural killer cells, cytotoxic T lymphocytes (CTL), CTL precursors and cells of myeloid origin, while T helper cells, B cells and cells of non-bone marrow origin remain functionally intact. Moreover, Leu- Leu-OMe treatment of donor cells prevents development of lethal graft-versus-host disease in a semi-allogeneic MHC disparate murine model of bone marrow transplantation. The selective killing of cytotoxic lymphocytes and myeloid cells by this agent has been shown to be dependent upon the, presence of high levels of dipeptidyl peptidase I (DPPI) within the specialized granules of these cells. The overall goals of this project are to make use of new information on the biochemistry of Leu-Leu-OMe and DPPI to probe a number of aspects of the physiology of cytotoxic cells, the biology of their granules and the role of these cells in graft versus host disease and allograft rejection.
The specific aims are: (1) Assess the role of DPPI generated membranolytic (Leu-Leu)n-OMe products in inducing apoptosis within DPPI- enriched cells; (2) Test the proposition the DPPI plays an obligate role in post-translational processing of murine granzymes A and B; (3) test the hypothesis that inhibition of DPPI activity during CTL activation impairs effector functions dependent upon granule serine protease activity; and (4) delineate the role of DPPI enriched cells and the specific role of DPPI enzymatic activity in the evolution of in vivo alloimmune responses.
|Kam, Chih-Min; Gotz, Marion G; Koot, Gretchen et al. (2004) Design and evaluation of inhibitors for dipeptidyl peptidase I (Cathepsin C). Arch Biochem Biophys 427:123-34|
|Brown, Geri R; Lee, Edward L; Thiele, Dwain L (2003) TNF enhances CD4+ T cell alloproliferation, IFN-gamma responses, and intestinal graft-versus-host disease by IL-12-independent mechanisms. J Immunol 170:5082-8|
|Brown, Geri R; Lee, Ed; Thiele, Dwain L (2002) TNF-TNFR2 interactions are critical for the development of intestinal graft-versus-host disease in MHC class II-disparate (C57BL/6J-->C57BL/6J x bm12)F1 mice. J Immunol 168:3065-71|
|Brown, G R; Thiele, D L (2000) T-cell activation and differentiation are regulated by TNF during murine DBA/2-->B6D2F1 intestinal graft-versus-host disease. J Clin Immunol 20:379-88|
|Mabee, C L; Thiele, D L (2000) Mechanisms of autoimmune liver disease. Clin Liver Dis 4:431-45, vii|
|Brown, G R; Thiele, D L (2000) Enhancement of MHC class I-stimulated alloresponses by TNF/TNF receptor (TNFR)1 interactions and of MHC class II-stimulated alloresponses by TNF/TNFR2 interactions. Eur J Immunol 30:2900-7|
|Brown, G R; Lindberg, G; Meddings, J et al. (1999) Tumor necrosis factor inhibitor ameliorates murine intestinal graft-versus-host disease. Gastroenterology 116:593-601|
|Mabee, C L; McGuire, M J; Thiele, D L (1998) Dipeptidyl peptidase I and granzyme A are coordinately expressed during CD8+ T cell development and differentiation. J Immunol 160:5880-5|
|Thiele, D L; Lipsky, P E (1992) Spectrum of toxicities of amino acid methyl esters for myeloid cells is determined by distinct metabolic pathways. Blood 79:964-71|