Abstract

It is proposed that the DQw3.2 molecules act as peptide binding molecules to trigger T cell activation which leads to destruction of Beta cells in the pancreatic islets. In this current proposal, I will focus on understanding the interaction between DQ molecules and DQ binding peptides. An in vivo binding assay will be established to examine the effect of DQalpha and DQBeta polymorphisms on DQ/peptide interactions. An M13 phage peptide binding assay will also be used to identify the binding motif of DQ binding peptides. This binding motif will be used to predict DQ-restricted T cell epitopes of potential diabetogenic autoantigens. T cell that recognize this DQ/peptide complex will be generated and characterized. My long term goals are to understand the role of DQ molecules in normal and abnormal immune responses, the signal transduction pathway after engagement of DQ/peptide and T cell receptor, and whether DQ molecules have other functional roles which differ from other class II molecules. The understanding of this mechanism will lead to design of novel specific immunotherapeutics for the treatment of autoimmune diseases.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Modified Research Career Development Award (K04)
Project #
5K04DK002319-03
Application #
2331370
Study Section
Allergy and Immunology Study Section (ALY)
Project Start
1995-02-01
Project End
2000-01-31
Budget Start
1997-02-01
Budget End
1998-01-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost

  Institution

Name
Benaroya Research Institute at Virginia Mason
Department
Type
DUNS #
City
Seattle
State
WA
Country
United States
Zip Code
98101

  Publications

Lok, Anna S F; Lai, Ching-Lung; Leung, Nancy et al. (2003) Long-term safety of lamivudine treatment in patients with chronic hepatitis B. Gastroenterology 125:1714-22
Ettinger, R A; Liu, A W; Nepom, G T et al. (2000) Beta 57-Asp plays an essential role in the unique SDS stability of HLA-DQA1*0102/DQB1*0602 alpha beta protein dimer, the class II MHC allele associated with protection from insulin-dependent diabetes mellitus. J Immunol 165:3232-8
Kwok, W W; Liu, A W; Novak, E J et al. (2000) HLA-DQ tetramers identify epitope-specific T cells in peripheral blood of herpes simplex virus type 2-infected individuals: direct detection of immunodominant antigen-responsive cells. J Immunol 164:4244-9
Kwok, W W; Reijonen, H; Falk, B A et al. (1999) Peptide binding affinity and pH variation establish functional thresholds for activation of HLA-DQ-restricted T cell recognition. Hum Immunol 60:619-26
Ettinger, R A; Kwok, W W (1998) A peptide binding motif for HLA-DQA1*0102/DQB1*0602, the class II MHC molecule associated with dominant protection in insulin-dependent diabetes mellitus. J Immunol 160:2365-73
Ettinger, R A; Liu, A W; Nepom, G T et al. (1998) Exceptional stability of the HLA-DQA1*0102/DQB1*0602 alpha beta protein dimer, the class II MHC molecule associated with protection from insulin-dependent diabetes mellitus. J Immunol 161:6439-45
Doherty, D G; Penzotti, J E; Koelle, D M et al. (1998) Structural basis of specificity and degeneracy of T cell recognition: pluriallelic restriction of T cell responses to a peptide antigen involves both specific and promiscuous interactions between the T cell receptor, peptide, and HLA-DR. J Immunol 161:3527-35
Koelle, D M; Johnson, M L; Ekstrom, A N et al. (1997) Preferential presentation of herpes simplex virus T-cell antigen by HLA DQA1*0501/DQB1*0201 in comparison to HLA DQA1*0201/DQB1*0201. Hum Immunol 53:195-205
Kwok, W W; Domeier, M L; Raymond, F C et al. (1996) Allele-specific motifs characterize HLA-DQ interactions with a diabetes-associated peptide derived from glutamic acid decarboxylase. J Immunol 156:2171-7
Kwok, W W; Domeier, M E; Johnson, M L et al. (1996) HLA-DQB1 codon 57 is critical for peptide binding and recognition. J Exp Med 183:1253-8

Showing the most recent 10 out of 11 publications