Cytotoxic T lymphocytes (CTL) provide an important component of the host response against virally induced tumors, viruses themselves and some types of graft rejection. Using a tumor allograft model, we have been studying the mechanism by which such immune cells recognize and destroy antigen-bearing cells. We have identified unique responses within the cells being attacked which separates this form of immune damage from attack by antibody and complement (Ab + C'). Part of the current proposal is to test the hypothesis that the target itself actively participates in its own destruction after receiving a signal from the CTL. We have observed that the target response has many similarities to mitosis and therefore hypothesized that similar metabolic machinery may be involved. The current proposal seeks to extend these studies by attempting to modulate the target response using procedures which modify mitotic events in other systems. In addition, we will attempt to identify the CTL component(s) responsible for triggering the interaction. Finally, we will explore the hypothesis that some of these """"""""mitotic"""""""" signalling events may be non-lethal and be expressed in a variety of T cell subsets. Such non-lethal signalling could be responsible for initiating damage associated with delayed type hypersensitivity reactions and produce new forms of lesions not previously associated with T cells. Some of this damage could contribute to unknown etiologies of a variety of autoimmune phenomena. Finally, we will explore potential membrane substrates of protein kinase C for their involvement in CTL function and signal transduction pathways. We have preliminary evidence for the identification of a unique peptide which is phosphorylated in response to perturbation of the T cell antigen receptor.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA028533-12
Application #
3168191
Study Section
Immunobiology Study Section (IMB)
Project Start
1980-06-01
Project End
1993-05-31
Budget Start
1991-06-01
Budget End
1992-05-31
Support Year
12
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Washington University
Department
Type
Schools of Medicine
DUNS #
062761671
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
Sabelko-Downes, K A; Russell, J H (2000) The role of fas ligand in vivo as a cause and regulator of pathogenesis. Curr Opin Immunol 12:330-5
Sabelko-Downes, K A; Gimenez, M T; Suvannavejh, G C et al. (2000) Genetic control of pathogenic mechanisms in autoimmune demyelinating disease. J Neuroimmunol 110:168-76
Sabelko-Downes, K A; Russell, J H; Cross, A H (1999) Role of Fas--FasL interactions in the pathogenesis and regulation of autoimmune demyelinating disease. J Neuroimmunol 100:42-52
Sabelko-Downes, K A; Cross, A H; Russell, J H (1999) Dual role for Fas ligand in the initiation of and recovery from experimental allergic encephalomyelitis. J Exp Med 189:1195-205
Thilenius, A R; Sabelko-Downes, K A; Russell, J H (1999) The role of the antigen-presenting cell in Fas-mediated direct and bystander killing: potential in vivo function of Fas in experimental allergic encephalomyelitis. J Immunol 162:643-50
Sabelko, K A; Kelly, K A; Nahm, M H et al. (1997) Fas and Fas ligand enhance the pathogenesis of experimental allergic encephalomyelitis, but are not essential for immune privilege in the central nervous system. J Immunol 159:3096-9
Rogers, A M; Thilenius, A R; Russell, J H (1997) Cyclosporine-insensitive partial signaling and multiple roles of Ca2+ in Fas ligand-induced lysis. J Immunol 159:3140-7
Cook, J R; Wormstall, E M; Hornell, T et al. (1997) Quantitation of the cell surface level of Ld resulting in positive versus negative selection of the 2C transgenic T cell receptor in vivo. Immunity 7:233-41
Wang, R; Ciardelli, T L; Russell, J H (1997) Partial signaling by cytokines: cytokine regulation of cell cycle and Fas-dependent, activation-induced death in CD4+ subsets. Cell Immunol 182:152-60
Wang, R; Rogers, A M; Ratliff, T L et al. (1996) CD95-dependent bystander lysis caused by CD4+ T helper 1 effectors. J Immunol 157:2961-8

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