Τόμος 9 (1995) – Τεύχος 2 & 3 – Άρθρο 19 – Επιθεώρηση Κλινικής Φαρμακολογίας και Φαρμακοκινητικής-Διεθνής Έκδοση – Volume 9 (1995) – Issue 2 & 3 – Article 19 – Epitheorese Klinikes Farmakologias και Farmakokinetikes-International Edition

By | | Brian Kay, Dimitrios Monos, Joan Gorga, Άρθρο επισκόπησης - Review Article, Ελισάβετ Ματσούκα - Elisabeth Matsoukas, Ηλίας Αργύρης - Elias Argyris, Πλήρες Κείμενο στα Αγγλικά - Full Text in English, Σ. Δεράος - S. Deraos

 

Title Employment of random peptide libraries for the identification of peptide motifs and peptides bound to diabetogenic HLA-DQ molecules
Authors Dimitrios Monos1, Elias Argyris1, Joan Gorga2, Brian Kay3, Spyros Deraos4 and Elisabeth Matsoukas4

1. Department of Pathology and Laboratory Medicine, and Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104 U.S.A.

2. Department of Pediatrics, University of Pittsburgh, Pittsburgh, PA 15213 U.S.A.

3. Biology Department, University of North Carolina, Chapel Hill, NC 27514 U.S.A.

4. Department of Chemistry, University of Patras, 26110 Patra, Greece
Citation Monos, D., Argyris, E., Gorga, J., Kay, B., Deraos, S. et al.: Employment of random peptide libraries for the identification of peptide motifs and peptides bound to diabetogenic HLA-DQ molecules, Epitheorese Klin. Farmakol. Farmakokinet. 9(2-3): 125-128 (1995)
Publication Date 1995
Full Text Language English
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Keywords Peptide libraries, HLA-DQ8, diabetes mellitus.
Other Terms review article
Summary Insulin-dependent diabetes mellitus (IDDM) is believed to be the result of the autoimmune destruction of insulin-producing β cells in the pancreatic islets of Langerhans. The disease is associated with mononuclear cell infiltration in the islets, hypoinsulinemia and hyperglycemia. The development of diabetes appears to be multi-factorial and has both genetic and environmental contributions. Predisposition to type I diabetes is genetically determined and recent studies have linked multiple haplotypes of the MHC class II region with either an increased risk or a protective effect. The locus within the MHC that is primarily associated with the disease is the DQ. The protein coded by this locus is involved in antigen presentation and the immune response. Population studies have shown that the relative risk for IDDM is significantly increased when the Dαβ chain is characterized by the absence of Asp at position 57, while the α chain is characterized by the presence of Arg at position 52. Additionally, experiments involving transgene NOD mice have shown that structural modification on the Ι-A molecule, the equivalent of the human DQ molecule, affects insulitis in the NOD mice and presumably the course of the disease. Therefore, independently of other genes that may be involved in the pathophysiology of IDDM, HLA-DQ molecules seem to be implicated directly in this process. To address this issue of the autoantigen(s) that bind the diabetogenic DQ molecules, transfectants expressing selective combinations of DQα and DQβ chains from the DR3, DR4 and DR7 haplotypes have been generated. These transfectants are presently used to purify these molecules and study the peptides that can be associated in the binding deft of these DQ molecules. Thus far the DQβ molecule has been purified and by using phage-displayed random peptide libraries we have been identifying peptides that bind to the DQβ molecule. HLA molecules are characterized by a degree of promiscuity as well as specificity and therefore we are not only searching for individual peptides that bind to the DQβ but rather a motif that will characterize binders to this molecule. Tenths of peptides need to be identified as specific binders to the DQβ before a reliable motif can be derived. We are in the process of identifying these molecules. This motif eventually will help us evaluate and identify candidate autoantigen molecules. To this end we have been trying to develop T-cell clones from diabetic and prediabetic individuals with specificity for β-cells that will enable us to identify this autoantigen(s). Our methodology involves development of hprt – T-cell clones which are then tested in a proliferation assay for specific stimulation. While the search is ongoing, it appears that two such T-cell clones have been identified with specificity for the β-cells. We are now in the process of confirming their specificity by titrating the antigen source and showing their HLA restriction. These T-cell clones eventually will be used as probes to identify the pancreatic antigen that is responsible for their specific stimulation.
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