Impact of KIR2DS1 and KIR3DL1 donor gene content on outcome after allogeneic hematopoietic cell transplantation for patients with myeloid neoplasia

Improved donor selection based on immune-genetic markers may improve outcome after allogeneic hematopoietic cell transplantation (alloHCT). Until now, information on the degree of HLA-compatibility, donor age, donor sex and ABO blood group is considered for donor selection. A recent series of publications suggests that harnessing natural killer (NK) cell reactivity could further improve outcome after alloHCT. Especially, the presence of KIR2DS1 genes in the donor genome and advantageous combinations of KIR3DL1 donor content and HLA-Bw4 ligands in the patient have been associated with a reduced risk of relapse. This study aims at a validation of these recently reported findings.

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Retrospective Study on Immunosurveillance by NK- and T-cells of leukemogenesis in AML

The immunologic control of nascent leukemia is incompletely understood. T-cells can recognize intracellular antigens, presented by HLA-class I molecules, which derive from mutated oncoproteins. Tumor cells can downregulate HLA-class I molecules from the cell surface and thereby evade T-cell recognition. In this situation, Natural Killer (NK) cells can take over immune control. Via Killer-Immunoglobulin-like Receptors (KIR) these cells receive inhibitory signals when they encounter self HLA-class-I molecules. If this signal is missing, NK-cells may kill the target cells. With this study we want to test the hypothesis, that T-cell mediated immune surveillance depends on the individual HLA-repertoire. In analogy, NK-cell mediated immune control may depend on the individual KIR-repertoire. These hypotheses shall be tested by comparing the HLA- and KIR-repertoire of patients with AML to the repertoire of the corresponding general population. The study design represents a case-control study. Existing samples from patients with AML will be typed for HLA- and KIR-genes and the results will be compared to reference values. This retrospective study does not require the collection of new samples or of medical data. Results of this study may give insights to the role of T- and NK-cell mediated leukemia control and may instruct donor selection for future adoptive cellular therapies.

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Retrospective Study on the impact of KIR2DS1 and KIR3DL1 donor gene content on outcome after allogeneic hematopoietic cell transplantation for patients with myeloid dysplastic syndromes

Relapse and subsequent death are the major reasons for failure of allogeneic hematopoietic cell transplantation. Natural Killer (NK) cells might contribute to Graft versus Leukemia (GvL) effects. Their degranulation depends on the net effect of activating versus inhibiting signals. Killer cell immunoglobulin-like receptor (KIR) genes are encoded on Chromosome 19 and are inherited independently from the major histocompatibility (MHC) complex. KIR genotype information has been associated with transplant outcomes in the framework of a Receptor-Ligand model aiming at maximization of activation and minimization of inhibition (KIR2DS1 and KIR3DL1; Venstrom, NEJM, 2012 & Boudreau, JCO, 2017) and by grouping donors according to presence or absence of haplotype B motifs which contain more activating KIRs (Cooley, Blood, 2010). Here we report results of a large confirmatory study.

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