Allogeneic stem cell transplantation (alloSCT) is a curative treatment for a variety of hematologic diseases. The mechanism of curation by an alloSCT is the induction of an immune response of donor... Show moreAllogeneic stem cell transplantation (alloSCT) is a curative treatment for a variety of hematologic diseases. The mechanism of curation by an alloSCT is the induction of an immune response of donor T cells attacking patients hematopoiesis, including the malignant hematopoietic cells. This is called the graft-versus-leukemia (GVL) reactivity. However, donor T cells can also be directed against healthy tissue cells of the recipient, causing graft-versus-host disease (GVHD). In this thesis we focused on targeting HLA class II by donor CD4 T cells to induce GVL without GVHD, because under non-inflammatory conditions, HLA class II is mainly expressed on hematopoietic cells and not on other tissue cells. We showed that CD4 T cells from HLA-identical sibling donors can induce conversion from mixed to full donor chimerism with GVL reactivity, but without GVHD, by targeting HLA class II restricted minor histocompatibility antigens. We also analyzed the immunopeptidome of different HLA-DP alleles. HLA-DP peptide binding motifs showed a clear association with the HLA-DP allele specific sequences of the binding groove. Functional hierarchies among HLA-DP alleles were unravelled, providing new molecular insights into HLA-DP classification. Permissiveness of mismatches between donor and recipient is not a black and white phenomenon, but rather gradual based on similarities and differences in the peptidomes. Show less
Alemtuzumab (ALM) is a cytotoxic monoclonal antibody that is used as a therapeutic agent in a variety of clinical settings. The target antigen for ALM is CD52, which is highly expressed on the... Show moreAlemtuzumab (ALM) is a cytotoxic monoclonal antibody that is used as a therapeutic agent in a variety of clinical settings. The target antigen for ALM is CD52, which is highly expressed on the membrane of mature lymphocytes, but not or only marginally on hematopoietic stem cells, red blood cells, and non-hematopoietic tissues. As such, ALM can be administered for the purpose of lymphocyte depletion with no or only minimal toxicity to other tissues. In this thesis, the mechanism of action of ALM was investigated in the context of two clinical settings, i.e. T-cell depletion before allogeneic stem cell transplantation (alloSCT) and depletion of malignant cells in B lymphoblastic leukemia (B-ALL). Show less
