Research Project
3172721
The aim of this project is to understand the genetic and functional aspects of immune responses to a major transplantation antigen. The mechanism and implications of Ir gene control of response to these antigens will be studied in depth. We are concerned with the problem of how the same molecule can function as a ~major' antigen for effector modalities of the response and as a ~minor' or self-restricted antigen for helper modalities. We will investigate the relationship between reactions to slightly modified, major transplantation antigens and typical ~altered self' MHC-restricted reactions in terms of the distribution of specific reactivity in the normal T-cell repertoire. Such slight structural modifications accompany intra-MHC recombination in rats. In view of the importance of immune responses to MHC molecules in clinical transplantation, we will analyze the implications of Ir gene control of transplantation reactions using rat kidney allografts. We have shown that the antibody response to a major transplantation antigen is subject not only to Ir gene control, but also to specific suppression and a remarkable form of regulation in which the response to individual epitopes on the molecules appears to be dominated by a single isotype. We intend to analyze and extend these observations to understand specific regulation in general. We have shown that the structural modification in Class I proteins that accompanies intra-MHC recombination is due to a dominant transacting function that maps into the B or D regions of RT1. The B and D regions are known to code for the Class II major histocompatibility antigens. We are able to detect the structural modification of Class I glycoproteins both by the specificity of cytotoxic T cells and by monoclonal antibodies. The structural change is very small but immunodominant for T cells. We have shown that the part of the Class I molecule affected by the change is conformationally flexible. Studies during the past year have been dominated by our cloning of the whole MHC of two rat strains into cosmid vectors. Class I and Class II genes have been expressed in mouse L cells, and the sequences coding for rat alpha and beta chains of Ia molecules identified. Several nonclassical Class I molecules have been found. These are presently being correlated with the molecules expressed by the rat MHC C-region. It is now clear that the C region encodes the antigen systems formerly known as CT but not previously mapped. (AG)
