HLA class II restricted minor histocompatibility antigens - identification, processing and biology

Abstract

Allogeneic stem cell transplantation is a potentially curative treatment for many hematological malignancies. The beneficial Graft-versus-Leukemia (GvL) effect is thereby mediated by donor-derived T-cells recognizing the malignant cells of the patient as foreign. However, the same T-cells might also target healthy non-hematopoietic cells of the patient such as skin, liver and gut causing a detrimental and sometimes lethal side effect, referred to as Graft-versus-Host disease (GvHD). In HLA-matched stem cell transplantation donor-derived T-cells recognize polymorphic peptides presented in self-HLA, so called minor histocompatibility antigens (MiHA). One strategy to induce GvL effect without GvHD is to exploit CD4+ T-cells, as HLA class II molecules are normally predominantly expressed on the hematopoietic system. However, under inflammatory conditions HLA class II might be up-regulated on non-hematopoietic tissues. Furthermore, until recently the identification of HLA class II restricted MiHAs was hampered by technical limitations. In this thesis we identified four new HLA class II restricted MiHA and characterized their intracellular processing and presentation in HLA class II. Furthermore we analyzed the possibility to separate GvL effect and GvHD based on differential intracellular processing of different antigen