Studies with erythrocytes and artificial lipid bilayers in many laboratories have yielded the fundamental features of membrane attack mechanisms by complement (C). Consequently, our research during the last few years has been devoted to understanding the mechanism(s) of C-mediated cell death in metabolically active nucleated cells (NC). We have found that cytolysis of NC requires multiple C5b-9 channels, due to the defense mechanism of the cell to survive limited C attack by eliminating the potentially lytic C channels. In addition, the channels, when present in sublytic numbers, cause a transient increase in cellular Ca2+ and exert a variety of biological effects such as activation of phospholipases, lipid methyltransferases, and neutral proteases in the cell. Our program is aimed at studying the mechanisms by which C5b-9 mediates cell death, stimulates the cell to repair limited injury, and modulates cellular functions that are relevant to the pathophysiology of the target cells in inflammation and immunity. Specifically, we want to determine the C-induced biochemical signals that stimulate the repair process. We will also investigate whether cell death elicited by the remaining channels is entirely dependent on colloid-osmotic deregulation, and if applicable which metabolic pathways are involved in the process of cell death. In addition, we will examine whether metabolic stimulation of repair processes similar to those produced by C5b-9 also occur in targets following limited attack by channel-forming proteins derived from CTL or NK-cells. We will continue to study the structure and functional aspects of C8-binding protein, and its role in nucleated cell killing and stimulation by homologous C5b- 9. These studies, collectively, will significantly increase our knowledge on the biological activities of complement channels and other channel forming immune effectors on NC targets.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI019622-07
Application #
3128951
Study Section
Experimental Immunology Study Section (EI)
Project Start
1983-01-01
Project End
1992-12-31
Budget Start
1989-01-01
Budget End
1989-12-31
Support Year
7
Fiscal Year
1989
Total Cost
Indirect Cost
Name
University of Maryland Baltimore
Department
Type
Schools of Medicine
DUNS #
003255213
City
Baltimore
State
MD
Country
United States
Zip Code
21201
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Niculescu, F; Rus, H; Shin, S et al. (1993) Generation of diacylglycerol and ceramide during homologous complement activation. J Immunol 150:214-24
Rus, H G; Kim, L M; Niculescu, F I et al. (1992) Induction of C3 expression in astrocytes is regulated by cytokines and Newcastle disease virus. J Immunol 148:928-33
Lee, S C; Collins, M; Vanguri, P et al. (1992) Glutamate differentially inhibits the expression of class II MHC antigens on astrocytes and microglia. J Immunol 148:3391-7
Papadimitriou, J C; Carney, D F; Shin, M L (1991) Inhibitors of membrane lipid metabolism enhance complement-mediated nucleated cell killing through distinct mechanisms. Mol Immunol 28:803-9

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