The human minor histocompatibility antigen HA-1 : its processing, presentation and recognition

Abstract

The minor histocompatibility (mH) antigen HA-1 is expressed by cells of hematopoietic origin only. The sequences of the immunogenic CTL epitope VLHDDLLEA (HA-1H) and the VLRDDLLEA (HA-1R) counterpart differ by one aminoacid. Selectively infusing HA-1H specific donor cytotoxic T cells may mediate a strong GvL effect with a low risk for GvHD. However, this HA-1H specific immunotherapy is currently feasible only for HLA-A2 HA-1HH or HA-1HR patients who relapsed following an SCT from an HLA-A2 HA-1RR donor. In addition, the therapy is not guaranteed for all of these patients. For instance, the anonymous umbilical cord blood (UCB) donors cannot be traced again for use of DLI or adoptive immunotherapy following transplantation. Moreover, the success rate of HA-1H specific HLA2 restricted CTL induction is donor dependent. This thesis describes the following important features, which may lead to extension of the patient population that may benefit from HA-1 specific immunotherapy: - The instable natural presentation of HA-1R in HLA-A2. - A novel HLA-B60 restricted HA-1H epitope. - Hematopoietic-specific CTLs from UCB directed against HA-1H in the context of HLA-A2. - HA-1 specific TCR transfer directing non- HA-1 TCR expressing adult and UCB CD8+ T cells to hematopoietic-specific cytolytic activity.