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.
| Clouthier, D E; Comerford, S A; Hammer, R E (1997) Hepatic fibrosis, glomerulosclerosis, and a lipodystrophy-like syndrome in PEPCK-TGF-beta1 transgenic mice. J Clin Invest 100:2697-713 |
| Aldrich, C J; DeCloux, A; Woods, A S et al. (1994) Identification of a Tap-dependent leader peptide recognized by alloreactive T cells specific for a class Ib antigen. Cell 79:649-58 |
| Lowen, L C; Aldrich, C J; Forman, J (1993) Analysis of T cell receptors specific for recognition of class IB antigens. J Immunol 151:6155-65 |
| Aldrich, C J; Waltrip, R; Hermel, E et al. (1992) T cell recognition of QA-1b antigens on cells lacking a functional Tap-2 transporter. J Immunol 149:3773-7 |
| 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 |
