We have utilized the QlOd/Ld major histocompatibility complex (MHC) class I hybrid gene containing 414bp of QlO promotor to produce QlO/L transgenic mice. Two lines have been established which express the QlO/L mRNA and protein on hepatocytes in liver but not on kidney, spleen, thymus, or brain. These mice appear to be tolerant in vivo to this antigen since histologically their livers appear normal and there is no elevation of liver enzymes detected in serum. In this proposal we will determine whether these animals are tolerant in vivo to this antigen by determining whether they have anti-QlO reactive cytotoxic T lymphocyte (CTL) precursors. We will also ascertain the immunogenicity of hepatocytes as well as their susceptibility to CTL mediated lysis. Since our preliminary evidence indicates that the transgenic mice have CTL capable of recognizing QlO/L in vitro, we will challenge these animals in vivo using several different protocols to see if we can alter the apparent in vivo tolerance. The QlO/L molecule is not upregulated by interferon. Therefore, we will mutate a portion of the promoter region to correct this defect and produce additional transgenic mice to see if interferon responsiveness alters the recognition of QlO/L hepatocytes in vivo. These experiments will provide new information regarding the extent of self tolerance to antigens expressed on parenchymal and not bone marrow derived cells. Our studies will also give fundamental insights into how exposure to antigens in an immunogenic form may lead to changes in in vivo tolerance leading to autoimmune disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI028332-04
Application #
3142770
Study Section
Immunobiology Study Section (IMB)
Project Start
1989-09-01
Project End
1994-07-31
Budget Start
1992-09-01
Budget End
1993-07-31
Support Year
4
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Texas Sw Medical Center Dallas
Department
Type
Schools of Medicine
DUNS #
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Wieties, K; Hammer, R E; Jones-Youngblood, S et al. (1990) Peripheral tolerance in mice expressing a liver-specific class I molecule: inactivation/deletion of a T-cell subpopulation. Proc Natl Acad Sci U S A 87:6604-8