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
Allogeneic stem cell transplantation (alloSCT) can be a curative treatment for hematological malignancies. However, the desired anti-tumor or Graft-versus-Leukemia (GvL) effect is often... Show moreAllogeneic stem cell transplantation (alloSCT) can be a curative treatment for hematological malignancies. However, the desired anti-tumor or Graft-versus-Leukemia (GvL) effect is often accompanied by undesired side effects, a complication known as Graft-versus-Host Disease (GvHD). GvL and GvHD are both caused by donor-derived T-cells recognizing alloantigens on patient cells. The main challenge for treatment of hematological malignancies with alloSCT is to evoke effective GvL reactivity, while limiting the risk of severe GvHD. In HLA-matched alloSCT, alloantigens recognized by donor T-cells are polymorphic peptides presented by HLA surface molecules on patient cells, the so-called minor histocompatibility antigens (MiHA). MiHA with hematopoiesis-restricted expression are relevant targets for immunotherapy, since donor T-cells for these MiHA will attack the malignant cells of the patient, while sparing healthy hematopoietic cells of donor origin. This thesis focused on efficient characterization of MiHA with potential therapeutic relevance, including MiHA that are encoded or produced by alternative transcripts, by analysis of in vivo immune responses after alloSCT. This analysis is relevant to provide insight into the immunobiology of GvL and GvHD after alloSCT and to identify MiHA with restricted expression on hematopoietic cells as potential targets for T-cell therapy to stimulate GvL reactivity after alloSCT without GvHD. Show less
This thesis emphasizes the presence of minor H antigen specific immune responses directly after birth, which will be present throughout life. The presence of minor H antigen mismatched... Show moreThis thesis emphasizes the presence of minor H antigen specific immune responses directly after birth, which will be present throughout life. The presence of minor H antigen mismatched microchimeric cells obtained through pregnancy from a mother or a child play a crucial role in this. Subsequent immunization against minor H antigens can lead to both cytotoxic and tolerogenic responses. Furthermore HA-1 specific T cells can share the same TCR Vbeta, yet being functionally different. The here performed studies enhances our understanding of immune reactions after HSCT and if applicable after renal transplantation, especially regarding the birth order effect and the assumed less favourable role of women as transplant donors. Show less
Zouwen, B. van der; Kruisselbrink, A.B.; Falkenburg, J.H.F.; Jedema, I. 2014
