Abstract

The proteasome is a multi-subunit multi-catalytic protease complex present in the cytosol that is proposed to mediate cytosolic antigen processing to produce peptides for MHC class I presentation. LMP2 and 7 are regulated subunits that are present in a subset of proteasomes. They appear to alter proteasome activity to enhance cytosolic MHC I antigen (Ag) processing. They are constitutively expressed in some cell types, and expression is regulated by cytokines in other cell types. The investigators hypothesize that disruption of the MHC I Ag processing pathway in tumor cells results in escape from immune surveillance. The studies described in this application will evaluate the contribution of proteasomes, LMP2 and 7, in MHC I Ag processing and presentation to the immune system for generating antitumor immunity.
Aim 1 will analyze the effects of novel dipeptide aldehyde proteasome inhibitors on conventional MHC I Ag processing.
Aim 2 will use these inhibitors to assess the contribution of proteasomes to alternative mechanisms for processing of exogenous Ags.
Aim 3 will test the hypothesis that LMP expression may be altered in tumor cells, resulting in tumor cell escape from immune surveillance. These studies should suggest mechanisms to enhance immune responses to tumors and facilitate immunotherapy of cancer.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA070149-02
Application #
2443242
Study Section
Experimental Immunology Study Section (EI)
Project Start
1996-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Case Western Reserve University
Department
Pathology
Type
Schools of Medicine
DUNS #
077758407
City
Cleveland
State
OH
Country
United States
Zip Code
44106

  Publications

Bagheri, Nayer; Pepple, Douglas A; Hassan, Medhat O et al. (2005) Development of immune-complex glomerulonephritis in athymic mice: T cells are not required for the genesis of glomerular injury. Lab Invest 85:354-63
Johnsen, A K; France, J; Nagy, N et al. (2001) Systemic deficits in transporter for antigen presentation (TAP)-1 or proteasome subunit LMP2 have little or no effect on tumor incidence. Int J Cancer 91:366-72
Ramachandra, L; Song, R; Harding, C V (1999) Phagosomes are fully competent antigen-processing organelles that mediate the formation of peptide:class II MHC complexes. J Immunol 162:3263-72
Song, R; Porgador, A; Harding, C V (1999) Peptide-receptive class I major histocompatibility complex molecules on TAP-deficient and wild-type cells and their roles in the processing of exogenous antigens. Immunology 97:316-24
Johnsen, A K; Templeton, D J; Sy, M et al. (1999) Deficiency of transporter for antigen presentation (TAP) in tumor cells allows evasion of immune surveillance and increases tumorigenesis. J Immunol 163:4224-31
Ramachandra, L; Chu, R S; Askew, D et al. (1999) Phagocytic antigen processing and effects of microbial products on antigen processing and T-cell responses. Immunol Rev 168:217-39
De Silva, A D; Boesteanu, A; Song, R et al. (1999) Thermolabile H-2Kb molecules expressed by transporter associated with antigen processing-deficient RMA-S cells are occupied by low-affinity peptides. J Immunol 163:4413-20
Matousek, M P; Nedrud, J G; Cieplak Jr, W et al. (1998) Inhibition of class II major histocompatibility complex antigen processing by Escherichia coli heat-labile enterotoxin requires an enzymatically active A subunit. Infect Immun 66:3480-4
Johnsen, A; France, J; Sy, M S et al. (1998) Down-regulation of the transporter for antigen presentation, proteasome subunits, and class I major histocompatibility complex in tumor cell lines. Cancer Res 58:3660-7
Ramachandra, L; Sramkoski, R M; Canaday, D H et al. (1998) Flow analysis of MHC molecules and other membrane proteins in isolated phagosomes. J Immunol Methods 213:53-71

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