HA-1 and the SMCY-derived peptide FIDSYICQV (H-Y) are immunodominant minor histocompatibility antigens after bone marrow transplantation.

BACKGROUND: Allogeneic bone marrow donors can be incompatible at different levels. Even HLA-identical pairs will be still incompatible for numerous minor histocompatibility antigens (mHag). Nevertheless, some incompatibilities are found to be associated with an increased risk of graft-versus-host disease (GVHD), which could be related to the way the immune system recognizes these antigens. METHODS: We determined the specificity of cytotoxic T-cell clones isolated during acute GVHD or during bone marrow graft rejection in patients (n=14) transplanted with marrow from donors who were histoincompatible for different minor and/or major histocompatibility antigens. RESULTS: We found a clear hierarchy among the different types of histoincompatibilities. In three combinations mismatched for a class I allele, all 27 clones isolated during GVHD were specific for the incompatible HLA molecule. In the 11 class I-identical combinations, 14 different mHags were recognized. The mHag HA-1, known to have a significant impact on the development of GVHD, was recognized in the two HA-1-incompatible combinations. In one of these combinations, which was sex mismatched, all 56 clones analyzed were directed against HA-1, demonstrating the dominance of this mHag. In the four HA-1-compatible, sex-mismatched combinations, the anti-H-Y response was directed against one immunodominant epitope rather than against multiple Y-chromosome-encoded epitopes. All male specific cytotoxic T lymphocytes (n=15) recognized the same high-performance liquid chromatography-purified peptide fraction presented by T2 cells. Moreover, all cytotoxic T lymphocytes tested (n=6) were specific for the SMCY-derived peptide FIDSYICQV, originally described as being the H-Y epitope recognized in the context of HLA-A*0201. CONCLUSIONS: Some histocompatibility antigens are recognized in an immunodominant fashion and will therefore be recognized in the majority of mismatched combinations. Only for such antigens, correlations between mismatches and the occurrence of GVHD or graft rejections will be found.

Post-transcriptional down-regulation of expression of transcription factor NF1 by Ha-ras oncogene.

NF1 is a family of polypeptides that binds to discrete DNA motifs and plays varying roles in the regulation of gene expression. These polypeptides are also thought to mediate the expression of differentiation-specific markers such as adipocyte and mammary cell type-specific genes. The expression of a number of cellular differentiation-specific markers is down-regulated during neoplastic transformation. We therefore investigated whether oncogenic transformation interferes with the action of NF1. Stable transfection of activated Ha-ras into a number of murine cells correlated with a down-regulation of the expression of the NF1 genes NF1/CTF and NF1/X. The down-regulation was not at the transcriptional level but at the level of stability of the NF1 mRNAs. The level of the DNA binding activity of the NF1 proteins was also reduced in Ha-v-ras-transformed cells, and the expression of a gene that depends on this family of transcription factors was specifically repressed. These results demonstrate that an activated Ha-ras-induced pathway destabilizes the half-life of mRNAs encoding specific members in the NF1 family of transcription factors, which leads to a decrease in NF1-dependent gene expression.