The gene which confers the greatest susceptibility for IDDM in both man and NOD mice is the MHC class II allele. Both the human and murine IDDM-associated MHC class II genes contain two unique amino acid polymorphisms at codons beta-56 and beta-57. Transgenic NOD mice which co-express an I-Ag7 Abeta molecule in which either position 56 or 57 has been mutated do not develop IDDM. The protection conferred by co-expression of an IDDM-resistant MHC II transgene appears to involve the induction of regulatory responses by bone marrow derived cells (BMDC). We will test the hypotheses that: 1) the gene-therapy directed expression of a mutant I-Ag7 Abeta gene can prevent the initiation, as well as the progression, of autoimmune disease in NOD mice and; 2) the mechanism of protection involves the induction of regulatory responses. We will focus on genetically engineering BMDC and APC in vitro to express an I-Ag7 Abeta gene with substituted amino acids at positions 56 and/or 57. By genetically engineering the BMDC in vitro we should be able to achieve high levels of mutant I-Ag7 Abeta expression and avoid any possibility of introducing genetic alterations in gametes. Based on a number of considerations, we will initially focus on using chimeric RNA/DNA oligonucleotides to direct the site-specific mutagenesis of the I-Ag7 Abeta beta-56 or beta-57 codons in the genomic DNA of BMDC and APC. Other modalities of expressing a modified I-Ag7 Abeta gene will be tested if this strategy proves to be ineffective. The expression of an IDDM-resistant MHC class II gene has potential clinical for application, as this approach may be less invasive than other treatments that broadly interfere with immune system function. Furthermore, it may also be applicable to other autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, which are also associated with specific MHC class II alleles.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21DK060211-02
Application #
6523687
Study Section
Special Emphasis Panel (ZDK1-GRB-3 (M1))
Program Officer
Akolkar, Beena
Project Start
2001-09-01
Project End
2003-08-31
Budget Start
2002-09-01
Budget End
2003-08-31
Support Year
2
Fiscal Year
2002
Total Cost
$152,500
Indirect Cost
Name
University of California Los Angeles
Department
Anesthesiology
Type
Schools of Medicine
DUNS #
119132785
City
Los Angeles
State
CA
Country
United States
Zip Code
90095
Washburn, L R; Dang, H; Tian, J et al. (2007) The postnatal maternal environment influences diabetes development in nonobese diabetic mice. J Autoimmun 28:19-23