Selecting the Optimal Unrelated Hematopoietic Stem Cell Transplant Donor for Relapse Prevention in Acute Myeloid Leukemia

Introduction/Background Hematopoietic cell transplantation (HCT) provides a cure for patients with acute myeloid leukemia. Natural killer cells (NK) play an important role in graft versus leukemia (GVL) effect after HCT, through killer immunoglobulin-like receptor (KIR) interaction with HLA ligands. This study is undertaken to validate our previously published mathematical model accounting for the KIR-KIRL interactions in a post HCT setting. Methods Retrospective data were obtained from the Center for International Blood and Marrow Transplant Registry for 2317 donor recipient pairs (DRP) who underwent 7/8 or 8/8 HLA allelic matched unrelated donor (URD) HCT for AML. KIR-HLA interaction scores were calculated by summing interaction values as previously described (Krieger et. Al BBMT 2019). Results Relapse risk was significantly reduced with donor-recipient pairs (DRP) with the higher inhibitory KIR-KIRL interaction and missing KIRL scores, Cox prop hazard, HR=0.86 (P=0.01) & HR=0.84 (P=0.02) respectively. The inhibitory KIR-KIRL interaction score components were then summed to give an IM-KIR score; IM KIR score =5 was also associated with a lower relapse risk, HR 0.8 (P=0.003). Subset analysis of 8/8 HLA matched patients showed further relapse reduction HR 0.75 (P=0.001); those patients with IM-KIR=5 donors who received ATG for in vivo T cell depletion (N=730) showed a 39% relapse reduction (HR 0.61, P=0.001) with a trend toward improved RFS, HR 0.84 (p=0.11). The use of ATG was shown to modify the effect of IM KIR score in interaction analysis (p=0.049), suggesting higher NK cell magnitude of KIR-KIRL interaction compensates for the general increase of relapse who receive in vivo T cell depletion. Conclusion This large international study confirms that unrelated DRPs with high iKIR and mKIR scores, as well as a combined IM-KIR scores confer significant relapse protection after MUD HCT, indicating that donors with a higher iKIR content may be considered optimal for URD HCT recipients with AML

Impact of killer-immunoglobulin-like receptor and human leukocyte antigen genotypes on the efficacy of immunotherapy in acute myeloid leukemia

Interactions between killer-immunoglobulin-like receptors (KIRs) and their HLA class I ligands are instrumental in natural killer (NK) cell regulation and protect normal tissue from NK cell attack. Human KIR haplotypes comprise genes encoding mainly inhibitory receptors (KIR A) or activating and inhibitory receptors (KIR B). A substantial fraction of humans lack ligands for inhibitory KIRs (iKIRs), that is, a 'missing ligand' genotype. KIR B/x and missing ligand genotypes may thus give rise to potentially autoreactive, unlicensed NK cells. Little is known regarding the impact of such genotypes in untransplanted acute myeloid leukemia (AML). For this study, NK cell phenotypes and KIR/HLA genotypes were determined in 81 AML patients who received immunotherapy with histamine dihydrochloride and low-dose IL-2 for relapse prevention (NCT01347996). We observed that presence of unlicensed NK cells impacted favorably on clinical outcome, in particular among patients harboring functional NK cells reflected by high expression of the natural cytotoxicity receptor (NCR) NKp46. Genotype analyses suggested that the clinical benefit of high NCR expression was restricted to patients with a missing ligand genotype and/or a KIR B/x genotype. These data imply that functional NK cells are significant anti-leukemic effector cells in patients with KIR/HLA genotypes that favor NK cell autoreactivity

Regulation of T cell lymphokine production by killer cell inhibitory receptor recognition of self HLA class I alleles.

The killer cell inhibitory receptors (KIRs) are surface glycoproteins expressed by natural killer (NK) and T cells that specifically recognize defined groups of polymorphic human histocompatibility leukocyte antigen (HLA) class I molecules. Interactions between KIRs on NK or T cells and major histocompatibility complex (MHC) class I molecules on potential target cells inhibit cell-mediated cytotoxicity, presumably by delivering a negative signal preventing lymphocyte activation. In this study we examined whether KIRs also regulate cytokine production induced in response to T cell receptor-dependent T cell activation. CD4+ and CD8+ T cell clones were stimulated by bacterial superantigens in the presence or absence of monoclonal antibodies (mAbs) against the KIR NKB1 or MHC class I molecules, and production of tumor necrosis factor alpha and interferon gamma was evaluated. When bacterial superantigen was presented by an autologous antigen-presenting cell (APC) to a KIR+ T cell clone, cytokine production was always enhanced in the presence of anti-MHC class I mAb. Similarly, anti-KIR mAb also augmented cytokine production, provided that the APC expressed a HLA class I allele recognized by the KIR. These results suggest that recognition of autologous MHC class I molecules by KIR+ T cells provides a regulatory mechanism acting to modulate the potency of their responses to antigenic challenge

Phosphotyrosines in the killer cell inhibitory receptor motif of NKB1 are required for negative signaling and for association with protein tyrosine phosphatase 1C.

NKB1 is one member of a growing family of killer cell inhibitory receptors (KIR). It is expressed on natural killer (NK) cells and T cells, and has been shown to inhibit cytolytic functions of these cells upon interacting with its ligand, HLA-B (Bw4). We demonstrate here that the cytoplasmic region of NKB1 is capable of inhibiting T cell activation in Jurkat cells. The tyrosine phosphorylation of the NKB1 KIR consensus motif, YxxL(x)26 YxxL, induces an association with the protein tyrosine phosphatase 1C (PTP1C). Importantly, mutation of both tyrosines in the motif abolished the inhibitory functions of NKB1 and abrogated PTP1C association. Mutational analysis of the individual tyrosines suggest that the membrane proximal tyrosine may play a crucial role in mediating the inhibitory signal. These results demonstrate that KIR can not only inhibit cytolytic activity, but can also negatively regulate T cell receptor activation events that lead to downstream gene activation, and further supports a model that implicates PTP1C as a mediator in the KIR inhibitory signal

A study involving the completion of quasi 2-normed space

The fundamental aim of this paper is to introduce and investigate a new property of quasi 2-normed space based on a question given by C. Park (2006) [2] for the completion quasi 2-normed space. Finally, we also find an answer for a question Park's.Comment: 7 page

The effect of different compost applications in organic production of lettuce (Lactuca sativa L.)

It is well-known that compost and manure applications to all kinds of soils if these organic materials are mature and composted under favorable conditions result in improved soil fertility and crop production in terms of yield and quality, but because manure is expensive in our region and the application of in-farm production compost for organic lands and farms of Turkey is limited, there is a great and urgent need for demonstrate compost using advantages to soil fertility, plant yield-quality and food safety (Kir 2006). Vegetables account for only approximately 2% of total organic production in Turkey, but there is great potential for growth of organic production for both export and domestic consumption of organic products in our country. Lettuce (Lactuca sativa L.) is one of the most important species for testing effects of compost applications because of its sensitivity related with phyto-toxic effects of compost (Fuchs et al. 2008) and very important to find out productivity and sustainable production levels in crop production. It is obtained from the results at the end of the first two-year trials, respectively of the three year-planned research under organic management (framework of regulations of EU and Turkey) that (1) the artificial organic materials sourced from farms can be composted and applied to lettuce production to get a great profit in terms of environment and economic aspects of organic lettuce production significantly, (2) promising improvement of industry of compost production can be expected, (3) Organic lettuce can be consumed as microbiologically safe, (4) high quality lettuce production can be attained by using compost

Evidence that neuronal G-protein-gated inwardly rectifying K+ channels are activated by Gβγ subunits and function as heteromultimers

Guanine nucleotide-binding proteins (G proteins) activate K+ conductances in cardiac atrial cells to slow heart rate and in neurons to decrease excitability. cDNAs encoding three isoforms of a G-protein-coupled, inwardly rectifying K+ channel (GIRK) have recently been cloned from cardiac (GIRK1/Kir 3.1) and brain cDNA libraries (GIRK2/Kir 3.2 and GIRK3/Kir 3.3). Here we report that GIRK2 but not GIRK3 can be activated by G protein subunits Gβ1 and G2 in Xenopus oocytes. Furthermore, when either GIRK3 or GIRK2 was coexpressed with GIRK1 and activated either by muscarinic receptors or by Gβ subunits, G-protein-mediated inward currents were increased by 5- to 40-fold. The single-channel conductance for GIRK1 plus GIRK2 coexpression was intermediate between those for GIRK1 alone and for GIRK2 alone, and voltage-jump kinetics for the coexpressed channels displayed new kinetic properties. On the other hand, coexpression of GIRK3 with GIRK2 suppressed the GIRK2 alone response. These studies suggest that formation of heteromultimers involving the several GIRKs is an important mechanism for generating diversity in expression level and function of neurotransmitter-coupled, inward rectifier K+ channels

Killer cell immunoglobulin-like receptor (KIR) genes and their HLA-C ligands in a Ugandan population.

Killer cell immunoglobulin-like receptor (KIR) genes are expressed by natural killer cells and encoded by a family of genes exhibiting considerable haplotypic and allelic variation. HLA-C molecules, the dominant ligands for KIR, are present in all individuals and are discriminated by two KIR epitopes, C1 and C2. We studied the frequencies of KIR genes and HLA-C1 and C2 groups in a large cohort (n = 492) from Kampala, Uganda, East Africa and compared our findings with published data from other populations in sub-Saharan Africa (SSA) and several European populations. We find considerably more KIR diversity and weaker linkage disequilibrium in SSA compared to the European populations and describe several novel KIR genotypes. C1 and C2 frequencies were similar to other SSA populations with a higher frequency of the C2 epitope (54.9 %) compared to Europe (average 39.7 %). Analysis of this large cohort from Uganda in the context of other African populations reveals variations in KIR and HLA-C1 and C2 that are consistent with migrations within Africa and potential selection pressures on these genes. Our results will help understand how KIR/HLA-C interactions contribute to resistance to pathogens and reproductive success