The long term objectives of the experiments described in this research proposal are designed to analyze the regulatory effects of lymphokines (IFN-gamma and TNF-alpha) in accelerating or retarding the autoimmune process seen in two animal models of human autoimmune diseases - - nephritis in the (NZBxNZW)F1 mouse, and type I diabetes in the non obese diabetic (NOD) mouse. A series of experiments will probe the possibility of using both with TNF-alpha to achieve more effective prevention/therapy of these two autoimmune diseases. Detailed studies will establish dose, timing, and other characteristics to optimize this therapy and study toxicity sufficiently well to permit a decision as to whether such therapy might be tried in patients. TNF-alpha is most effective in those autoimmune diseases in the mouse in which TNF-alpha production in response to specific stimuli (lipopolysacharride, IFN-gamma) is low in comparison to other mouse strains. Therefore a search will be made for linkage between MHC haplotype and production of low or high levels of TNF-alpha in both the mouse and in patients. Preliminary results indicate that the majority of individuals with HLA-DR2 are low producers of TNF-alpha, while most individuals with HLA-DR3 and 4 are high producers. If linkage studies indicate a link between TNF-alpha response and MHC genotype, genomic cloning of TNF-alpha genes will be undertaken in both high and low producer mouse strains and patients. Genomic clones will be analyzed by restriction mapping in a search for differences between the 5' flanking sequences, intervening sequences, and 3' flanking sequences of TNF-alpha genes from high and low producer genotypes. The results of these studies should lead to better understanding of a number of characteristics of autoimmune disease and to new approaches to therapy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI028896-01
Application #
3143541
Study Section
Immunological Sciences Study Section (IMS)
Project Start
1990-09-01
Project End
1993-08-31
Budget Start
1990-09-01
Budget End
1991-08-31
Support Year
1
Fiscal Year
1990
Total Cost
Indirect Cost
Name
Stanford University
Department
Type
Schools of Medicine
DUNS #
800771545
City
Stanford
State
CA
Country
United States
Zip Code
94305