In the context of HLA-DP-mismatched allogeneic stem cell transplantation, mismatched HLA-DP alleles can provoke profound allo-HLA-DP-specific immune responses from the donor T-cell repertoire... Show moreIn the context of HLA-DP-mismatched allogeneic stem cell transplantation, mismatched HLA-DP alleles can provoke profound allo-HLA-DP-specific immune responses from the donor T-cell repertoire leading to graft-versus-leukemia effect and/or graft-versus-host disease in the patient. The magnitude of allo-HLA-DP-specific immune responses has been shown to depend on the specific HLA-DP disparity between donor and patient and the immunogenicity of the mismatched HLA-DP allele(s). HLA-DP peptidome clustering (DPC) was developed to classify the HLA-DP molecules based on similarities and differences in their peptide-binding motifs. To investigate a possible categorization of HLA-DP molecules based on overlap of presented peptides, we identified and compared the peptidomes of the thirteen most frequently expressed HLA-DP molecules. Our categorization based on shared peptides was in line with the DPC classification. We found that the HLA-DP molecules within the previously defined groups DPC-1 or DPC-3 shared the largest numbers of presented peptides. However, the HLA-DP molecules in DPC-2 segregated into two subgroups based on the overlap in presented peptides. Besides overlap in presented peptides within the DPC groups, a substantial number of peptides was also found to be shared between HLA-DP molecules from different DPC groups, especially for groups DPC-1 and -2. The functional relevance of these findings was illustrated by demonstration of cross-reactivity of allo-HLA-DP-reactive T-cell clones not only against HLA-DP molecules within one DPC group, but also across different DPC groups. The promiscuity of peptides presented in various HLA-DP molecules and the cross-reactivity against different HLA-DP molecules demonstrate that these molecules cannot be strictly categorized in immunogenicity groups. Show less
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
Laghmouchi, A.; Hoogstraten, C.; Falkenburg, J.H.F.; Jedema, I. 2020
Allogeneic (allo) stem cell transplantation is applied to patients suffering from hematologic malignancies to replace the diseased hematopoietic system with cells derived from a donor stem cell... Show moreAllogeneic (allo) stem cell transplantation is applied to patients suffering from hematologic malignancies to replace the diseased hematopoietic system with cells derived from a donor stem cell graft. The majority of 10/10matched unrelated donors are HLA-DP-mismatched, and this may result in varying degrees of the graft-versusleukemia (GVL) effect with or without the occurrence of graft-versus-host disease (GVHD). Allo-HLA-reactive T cells are commonly present in the donor T cell repertoire, and thus a very profound alloreactive immune response can be provoked in the HLA-DP-mismatched setting. The magnitude and the diversity of the allo-HLA-DP-specific immune response likely dictates the balance between the occurrence of GVL and/or GVHD after transplantation. To understand the nature of the allo-HLA-DP-specific immune response provoked under different stimulatory conditions, immune responses were induced from both the naive and memory T cell compartments using either HLA-DP-mismatched professional antigen-presenting cells (APCs) (monocyte-derived dendritic cells [allo-DCs]) or HLA-DP-mismatched nonprofessional APCs (skin-derived fibroblasts [allo-fibroblasts]) as stimulator cells. In this study, we observed that allo-HLA-DP-reactive T cells could be provoked from both the naive and memory compartments by both types of APCs. However, the magnitude of the allo-HLA-DP-specific immune response was greater when stimulation was performed with allo-DCs. Moreover, we found that the frequency of allo-HLA-DPreactive T cells was greater in the naive T cell compartment compared with the memory T cell compartment, but we observed a comparable lineage specificity of these allo-HLA-DP-specific reactivities. Overall, the data from this study illustrate that the presence of professional APCs of recipient origin will mostly dictate the magnitude of the allo-HLA-DP-specific immune response derived from both the naive and memory T cell compartments, but does not exclusively mediate the induction of these immune responses. (C) 2020 American Society for Transplantation and Cellular Therapy. Published by Elsevier Inc. Show less
Clinical studies demonstrated that HLA-DPB1 mismatched stem cell transplantation (SCT) is associated with a decreased risk of disease relapse and an increased risk of graft versus host disease ... Show moreClinical studies demonstrated that HLA-DPB1 mismatched stem cell transplantation (SCT) is associated with a decreased risk of disease relapse and an increased risk of graft versus host disease (GVHD) compared to HLA-DPB1 matched SCT. In T-cell depleted SCT, mismatching of HLA-DPB1 was not associated with an increased risk of severe GVHD, whereas a significant decreased risk of disease relapse was still observed. In this thesis we showed that HLA-DPB1 mismatched allo-SCT followed by donor lymphocyte infusion (DLI) late after transplantation can result in selective graft versus leukemia (GVL) reactivity. Although several studies have suggested that some HLA-DPB1-mismatches were less immunogenic, we demonstrated that all HLA-DPB1-mismatches as defined by allele typing are immunogenic and resulted in vitro in high frequency immune responses. Finally, in a cohort of 24 patients transplanted for various hematological ma lignancies with a 10 out 10 matched HLA-DPB1 mismatched SCT followed by DLI, HLA-DP specific immune responses were frequently found. The presence of HLA-DP specific CD4+ T cells correlated with clinical immune responses including both selective GVL-reactivity and GVHD. It is likely that in each individual local environmental circumstances possibly in combination with the induction of other immune responses may finally determine the balance between GVHD and GVL-reactivity HLA-DP HLA-class II mismatch alloreactivity hematopoietic stem cell transplantation donor lymphocyte infusion graft versus host disease graft versus leukemia reactivity immunotherapy Show less
