Abstract
This thesis describes the characterization and identification of CTL-defined leukemia-associated minor histocompatibility antigens (mHAg) for the development of novel cellular immunotherapeutic approaches to successfully treat patients with relapsed hematopoietic malignancies after allogeneic stem cell transplantation (SCT). Previously, a leukemia-associated mHAg, HB-1, was identified. Expression analysis showed restricted HB-1 gene expression in B-ALL and Epstein-Barr virus-transformed B cells. Therefore, additional studies were conducted to provide information regarding its potency as a T cell target for cellular immunotherapy. Experimental data indicated that mHAg HB-1 can induce bi-directional CTL responses. Furthermore, TCR-specificity analysis of HB-1 peptide variant-specific CTL revealed that differential recognition o is the result of TCR discrimination. In addition, the potential use of the HB-1 antigen as an autologous T cell target for immunotherapy was investigated. In vitro CTL induction experiments resulted in the generation of autologous cytotoxic and helper T cell responses against the HB-1 antigen. Furthermore, a novel human mHAg, LRH-1, was molecular identified. The immunogenicity for LRH-1 is due to differential protein expression between recipient and donor as a result of a homozygous frameshift polymorphism in the P2X5 gene. Expression analysis of P2X5 showed selective expression in leukemic and normal CD34+ progenitor cells, lymphoid cells, lymphoid tissues and in tumor cells from all stages of lymphoid development. Furthermore, a clear correlation between the emergence of CTL and complete remission of the CML was demonstrated. mHAg HB-1 and LRH-1 represent potent antigens to induce specific GVL reactivity in a significant number of patients in the setting of mHAg-based immunotherapy. The studies described in this thesis provide novel insights and perspectives in mHAg immunobiology. In the future, this knowledge provides a solid basis for the development of specific cellular immunotherapeutic strategies to successfully treat patients with relapsed hematopoietic malignancies after allogeneic SCT
