Expression Profiling of Major Histocompatibility and Natural Killer Complex Genes Reveals Candidates for Controlling Risk of Graft versus Host Disease

Novota, Peter; Zinöcker, Severin; Norden, Jean; Wang, Xiao Nong; Sviland, Lisbet; Opitz, Lennart; Salinas-Riester, Gabriela; Rolstad, Bent; Dickinson, Anne M.; Walter, Lutz; Dressel, Ralf

doi:10.1371/journal.pone.0016582

Cited by 14 publications

(13 citation statements)

References 74 publications

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“…2). Also, the Ly49s3R gene was not differentially regulated in skin explant or GVHD skin samples derived from the same rat model in a recent microarray study [32].…”

Section: Discussionmentioning

confidence: 84%

“…Animal models have the advantage that unlike human alloHCT patients who receive immunosuppressive treatment, such as steroids and cell-targeted antibodies, experimental GVHD is not influenced by such treatment and thus, better reflects the native disease. We have shown previously that the rat is an adequate experimental model, which resembles the pathology of human skin GVHR [29] and has the potential to identify genes that may predict GVHR and disease [29,32]. The present study was outlined to characterize processes related to the pathophysiology of aGVHD and to discover disease-associated markers.…”

Section: Discussionmentioning

confidence: 99%

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Kinetics of lymphocyte reconstitution after allogeneic bone marrow transplantation: markers of graft-versus-host disease

Zinöcker

Sviland

Dressel

et al. 2011

Journal of Leukocyte Biology

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GVHD causes extensive morbidity and mortality in patients who receive alloHCT. Predictive and reliable markers for GVHD are currently lacking but required to improve the safety and accessibility of alloHCT. We present an experimental rat model of myeloablative total body irradiation and fully mismatched major and minor histoincompatible, T cell-depleted BMT, followed by delayed infusion of donor lymphocytes. This treatment, in contrast to marrow transplantation alone, resulted in severe aGVHD and 100% lethality within 2-6 weeks. We investigated the reconstitution kinetics and phenotypes of donor leukocyte subpopulations as well as the histopathology of selected organs that may correlate with GVHD, with the goal to find potential disease-related markers. We observed histological changes mainly confined to the skin, with degenerative changes in the basal layer. LNs and spleen showed deranged architecture with markedly increased accumulation of lymphocytes, whereas the gut, liver, and lungs appeared normal. Of the lymphocyte markers tested, donor-derived CD62L(+) T cells were markedly decreased in animals suffering from GVHD. Furthermore, we observed peripheral depletion of CD4(+)CD25(hi)FoxP3(+) T(reg), which was in contrast to controls. The relative frequency of these lymphocyte subpopulations in blood may therefore serve as accessible cellular markers of aGVHD. We propose that the animal model presented is instructive for the identification of clinically relevant markers of GVHD, which could improve disease diagnosis and management in alloHCT.

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“…2). Also, the Ly49s3R gene was not differentially regulated in skin explant or GVHD skin samples derived from the same rat model in a recent microarray study [32].…”

Section: Discussionmentioning

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Kinetics of lymphocyte reconstitution after allogeneic bone marrow transplantation: markers of graft-versus-host disease

Zinöcker

Sviland

Dressel

et al. 2011

Journal of Leukocyte Biology

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“…In an expression profiling study with special emphasis on MHC and NK gene complex (NKC) genes, 11 MHC, 6 NKC, and 168 genes in other genomic regions were identified to be regulated during GvHR in rat skin explants (Novota et al, 2011). For MHC and NKC genes, the results were verified by real time PCR experiments on samples from other skin explant assays using different strain combinations, on skin with cutaneous GvHD from transplanted rats, and on samples from human skin explant assays.…”

Section: The Rat Skin Explant Assaymentioning

confidence: 99%

“…For MHC and NKC genes, the results were verified by real time PCR experiments on samples from other skin explant assays using different strain combinations, on skin with cutaneous GvHD from transplanted rats, and on samples from human skin explant assays. The genes that were confirmed to be regulated also in human skin explant samples with GvHR included TAP1 , PSMB8 , C2 , UBD , and OLR1 (Novota et al, 2011). These genes have known polymorphisms in humans and are therefore potential candidates for diagnostic biomarkers in the clinic.…”

Section: The Rat Skin Explant Assaymentioning

confidence: 99%

Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

Zinöcker¹,

Dressel²,

Wang³

et al. 2012

Front. Immun.

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Allogeneic hematopoietic cell transplantation (alloHCT) extends the lives of thousands of patients who would otherwise succumb to hematopoietic malignancies such as leukemias and lymphomas, aplastic anemia, and disorders of the immune system. In alloHCT, different immune cell types mediate beneficial graft-versus-tumor (GvT) effects, regulate detrimental graft-versus-host disease (GvHD), and are required for protection against infections. Today, the “good” (GvT effector cells and memory cells conferring protection) cannot be easily separated from the “bad” (GvHD-causing cells), and alloHCT remains a hazardous medical modality. The transplantation of hematopoietic stem cells into an immunosuppressed patient creates a delicate environment for the reconstitution of donor blood and immune cells in co-existence with host cells. Immunological reconstitution determines to a large extent the immune status of the allo-transplanted host against infections and the recurrence of cancer, and is critical for long-term protection and survival after clinical alloHCT. Animal models continue to be extremely valuable experimental tools that widen our understanding of, for example, the dynamics of post-transplant hematopoiesis and the complexity of immune reconstitution with multiple ways of interaction between host and donor cells. In this review, we discuss the rat as an experimental model of HCT between allogeneic individuals. We summarize our findings on lymphocyte reconstitution in transplanted rats and illustrate the disease pathology of this particular model. We also introduce the rat skin explant assay, a feasible alternative to in vivo transplantation studies. The skin explant assay can be used to elucidate the biology of graft-versus-host reactions, which are known to have a major impact on immune reconstitution, and to perform genome-wide gene expression studies using controlled combinations of minor and major histocompatibility between the donor and the recipient.

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“…TAP1 and TAP2 are transporters associated with antigen processing 1 and 2, responsible for translocating peptides into the endoplasmic reticulum before loading on MHC class I molecules. In a rat skin explant model, an increase in expression of Tap1 as well as Psbm8 and Ubd mRNA during graft-versus-host reaction was observed (103). UBD, also known as FAT10, is involved in the proteasomal degradation of cytosolic proteins by providing a ubiquitin-independent signal (149).…”

Section: Mirna and Mrna Expression Profiling In Hsctmentioning

confidence: 99%

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes

Gam

Shah²,

Crossland

et al. 2017

Front. Immunol.

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The outcome of hematopoietic stem cell transplantation (HSCT) is controlled by genetic factors among which the leukocyte antigen human leukocyte antigen (HLA) matching is most important. In addition, minor histocompatibility antigens and non-HLA gene polymorphisms in genes controlling immune responses are known to contribute to the risks associated with HSCT. Besides single-nucleotide polymorphisms (SNPs) in protein coding genes, SNPs in regulatory elements such as microRNAs (miRNAs) contribute to these genetic risks. However, genetic risks require for their realization the expression of the respective gene or miRNA. Thus, gene and miRNA expression studies may help to identify genes and SNPs that indeed affect the outcome of HSCT. In this review, we summarize gene expression profiling studies that were performed in recent years in both patients and animal models to identify genes regulated during HSCT. We discuss SNP–mRNA–miRNA regulatory networks and their contribution to the risks associated with HSCT in specific examples, including forkheadbox protein 3 and regulatory T cells, the role of the miR-155 and miR-146a regulatory network for graft-versus-host disease, and the function of MICA and its receptor NKG2D for the outcome of HSCT. These examples demonstrate how SNPs affect expression or function of proteins that modulate the alloimmune response and influence the outcome of HSCT. Specific miRNAs targeting these genes and directly affecting expression of mRNAs are identified. It might be valuable in the future to determine SNPs and to analyze miRNA and mRNA expression in parallel in cohorts of HSCT patients to further elucidate genetic risks of HSCT.

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Expression Profiling of Major Histocompatibility and Natural Killer Complex Genes Reveals Candidates for Controlling Risk of Graft versus Host Disease

Cited by 14 publications

References 74 publications

Kinetics of lymphocyte reconstitution after allogeneic bone marrow transplantation: markers of graft-versus-host disease

Kinetics of lymphocyte reconstitution after allogeneic bone marrow transplantation: markers of graft-versus-host disease

Immune Reconstitution and Graft-Versus-Host Reactions in Rat Models of Allogeneic Hematopoietic Cell Transplantation

Genetic Association of Hematopoietic Stem Cell Transplantation Outcome beyond Histocompatibility Genes

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