NON-H-2 HISTOCOMPATIBILITY GENES &ENCODED ANTIGENS

  • Wettstein, Peter J (PI)

Project: Research project

Project Details

Description

Histocompatibility (H) antigens encoded by genes mapping outside
of the major histocompatibility complex comprise a formidable
barrier to successful tissue transplantation. Although the family
of non-H-2 H antigens in the mouse has served as an important
model system for studying the regulation of the T cell response,
virtually nothing is known of the origins and functions of these
antigens. This continuing program has been aimed at elucidating
the mechanisms of responses to multiple and single H antigens.
We have recently discovered that H antigens are generated by
germline integration of retroviruses and tumor viruses. The
proposed research plan is a multi-faceted approach to
understanding the mechanisms and regulation of the T cell
response to H antigens and the identification of members of this
important family. The first experiments are aimed at revealing
the basis for the preferential, in vitro T cell response to
immunodominant antigens and its relevance to T cell responses in
vivo. Potential roles for (1) preferential presentation of dominant
antigens by H-2K/D molecules, (2) differences in affinity and
number of IL-2 receptors on T cells specific for dominant and
dominated antigens, and (2) different classes of dominant antigens
for helper and cytolytic T cells will be investigated. The T cell
response to single H antigens will be analyzed to determine (1) the
role of discrete regions of H-2K molecules in H antigen
presentation and determination of Ir gene status, (2) the effects
of T cell receptor V genes used by H antigen-specific T cells on
antigen specificity and H-2 restriction, and (3) the relationship
between the mechanisms of in vivo and in vitro T cell responses.
These studies will be complemented by the cloning and
identification of non-H-2 H genes. The observation that the SV40
T-antigen is seen as an H antigen in transgenic mice will be
extended by determining the effects of different promoters and
flanking regions on its expression as an H antigen. The
association between a new mammary tumor virus and a mutant H
antigen will be confirmed by cloning this retrovirus to assess its
ability to encode this H antigen. The relationship between coat
color and H gene mutations will be extended to confirm that coat
color mutant reversions lead to the loss of H antigens. Finally,
retroviral vectors will be employed as insertional mutagens to
inactivate a single H gene; the cloning of the integrated
retrovirus will facilitate the first cloning of an H gene from a
cosmid library.
StatusFinished
Effective start/end date8/1/797/31/04

Funding

  • National Institutes of Health: $316,782.00
  • National Institutes of Health: $156,985.00
  • National Institutes of Health
  • National Institutes of Health: $307,555.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health: $326,285.00
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health
  • National Institutes of Health

ASJC

  • Medicine(all)
  • Immunology and Microbiology(all)

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