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Killer Immunoglobulin-Like Receptor-Ligand Interactions Predict Clinical Outcomes following Unrelated Donor Transplantations.

ABSTRACT: Killer immunoglobulin-like receptor (KIR) and KIR ligand (KIRL) interactions play an important role in natural killer (NK) cell-mediated graft-versus-leukemia effect following hematopoietic cell transplantation (HCT). However, there is considerable heterogeneity in the KIR gene and KIRL content in individuals, making it difficult to estimate the full clinical impact of NK cell reconstitution following HCT. Here we present a novel adaptive mathematical model designed to quantify these interactions to better assess the influence of NK cell-mediated alloreactivity on transplant outcomes. Ninety-eight HLA- matched unrelated donor (URD) HCT recipients were studied retrospectively. The KIR-KIRL interactions were quantified using a system of matrix equations. Unit values were ascribed to each KIR-KIRL interaction, and the directionality of interactions was denoted by either a positive (activating) or negative (inhibition) symbol; these interactions were then summed. The absolute values of both the missing KIRL and inhibitory KIR-KIRL interactions were significantly associated with overall survival and relapse. These score components were initially used to develop a weighted score (w-KIR score) and subsequently a simplified, nonweighted KIR-KIRL interaction score (IM-KIR score). Increased w-KIR score and IM-KIR score were predictive of all-cause mortality and relapse (w-KIR score: hazard ratio [HR], .37 [P = .001] and .44 [P = .044], respectively; IM-KIR score: HR, .5 [P = .049] and .44 [P = .002], respectively). IM-KIR score was also associated with NK cell reconstitution post-HCT. KIR-KIRL interactions as reflected by the w-KIR and IM-KIR scores influence both relapse risk and survival in recipients of HLA-matched URD HCT with hematologic malignancies.

SUBMITTER: Krieger E

PROVIDER: S-EPMC7190417 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Natural killer (NK) cell determinants predict relapse-free survival after allogeneic hematopoietic cell transplantation (HCT) for acute myelogenous leukemia, and previous studies have shown a beneficial graft-versus-leukemia effect in patients with juvenile myelomonocytic leukemia (JMML). However, whether NK cell determinants predict protection against relapse for JMML patients undergoing HCT is unknown. Therefore, we investigated NK cell-related donor and recipient immunogenetics as determinants of HCT outcomes in patients with JMML. Patients with JMML (age 0 to <19 years) who underwent a first allogeneic HCT from an unrelated donor between 2000 and 2017 and had available donor samples from the Center for International Blood and Marrow Transplant Research Repository were included. Donor killer immunoglobulin receptor (KIR) typing was performed on pre-HCT samples. The primary endpoint was disease-free survival (DFS); secondary endpoints included relapse, grade II-IV acute graft versus-host-disease (aGVHD), chronic GVHD (cGVHD), GVHD-free relapse-free survival, transplantation-related mortality, and overall survival (OS). Donor KIR models tested included KIR genotype (AA versus Bx), B content (0-1 versus ≥2), centromeric and telomeric region score (AA versus AB versus BB), B content score (best, better, or neutral), composite score (2 versus 3 versus 4), activating KIR content, and the presence of KIR2DS4. Ligand-ligand and KIR-ligand mismatch effects on outcomes were analyzed in HLA-mismatched donors (≤7/8; n = 74) only. Univariate analyses were performed for primary and secondary outcomes of interest, with a P value <.05 considered significant. One hundred sixty-five patients (113 males), with a median follow-up of 85 months (range, 6 to 216 months) met the study criteria. Of these, 111 underwent an unrelated donor HCT and 54 underwent a UCB HCT. Almost all (n = 161; 98%) received a myeloablative conditioning regimen. After exclusion of recipients of reduced-intensity/nonmyeloablative conditioning regimens and ex vivo T cell-depleted grafts (n = 8), there were 42 AA donors and 115 Bx donors, respectively. Three-year DFS, OS, relapse, and GRFS for the entire cohort were 58% (95% confidence interval [CI], 50% to 66%), 67% (95% CI, 59% to 74%), 26% (95% CI, 19% to 33%), and 27% (95% CI, 19% to 35%), respectively. The cumulative incidence of grade II-IV aGVHD at 100 days was 36% (95% CI, 27% to 44%), and that of cGVHD at 1 year was 23% (95% CI, 17% to 30%). There were no differences between AA donors and Bx donors for any recipient survival outcomes. The risk of grade II-IV aGVHD was lower in patients with donors with a B content score of ≥2 (hazard ratio [HR], 0.46; 95% CI, 0.26 to 0.83; P = .01), an activating KIR content score of >3 (HR, 0.52; 95% CI, 0.29 to 0.95; P = .032), centromeric A/B score (HR, 0.57; 95% CI, 033 to 0.98; P = .041), and telomeric A/B score (HR, 0.58; 95% CI, 0.34 to 1.00; P = .048). To our knowledge, this is the first study analyzing the association of NK cell determinants and outcomes in JMML HCT recipients. This study identifies potential benefits of donor KIR-B genotypes in reducing aGVHD. Our findings warrant further study of the role of NK cells in enhancing the graft-versus-leukemia effect via recognition of JMML blasts.

Project description:To analyze the outcomes of living-donor liver transplantation (LDLT) using left-lobe (LL) or right-lobe (RL) small-for-size (SFS) grafts.Prospectively collected data of adult patients who underwent LDLT at our hospital in the period from January 2003 to December 2013 were reviewed. The patients were divided into the RL-LDLT group and the LL-LDLT group. The two groups were compared in terms of short- and long-term outcomes, including incidence of postoperative complication, graft function, graft survival, and patient survival. A SFS graft was defined as a graft with a ratio of graft weight (GW) to recipient standard liver volume (RSLV) (GW/RSLV) of < 50%. The Urata formula was used to estimate RSLV.Totally 218 patients were included for analysis, with 199 patients in the RL-LDLT group and 19 patients in the LL-LDLT group. The two groups were similar in terms of age (median, 53 years in the RL-LDLT group and 52 years in the LL-LDLT group, P = 0.997) but had significantly different ratios of men to women (165:34 in the RL-LDLT group and 8:11 in the LL-LDLT group, P < 0.0001). The two groups were also significantly different in GW (P < 0.0001), GW/RSLV (P < 0.0001), and graft cold ischemic time (P = 0.007). When it comes to postoperative complication, the groups were comparable (P = 0.105). Five patients died in hospital, 4 (2%) in the RL-LDLT group and 1 (5.3%) in the LL-LDLT group (P = 0.918). There were 38 graft losses, 33 (16.6%) in the RL-LDLT group and 5 (26.3%) in the LL-LDLT group (P = 0.452). The 5-year graft survival rate was significantly better in the RL-LDLT group (95.2% vs 89.5%, P = 0.049). The two groups had similar 5-year patient survival rates (RL-LDLT: 86.8%, LL-LDLT: 89.5%, P = 0.476).The use of SFS graft in LDLT requires careful tailor-made surgical planning and meticulous operation. LL-LDLT can be a good alternative to RL-LDLT with similar recipient outcomes but a lower donor risk. Further research into different patient conditions is needed in order to validate the use of LL graft.

Project description:Glioblastoma (GBM) is the most aggressive brain malignancy in adults, where survival is approximately 14.6?months. Novel therapies are urgently needed and immunotherapy has hailed a new dawn for treatment of solid tumors. Natural killer (NK) cells may be amenable therapeutic effectors against heterogeneous GBM, since they also do not require co-stimulation and antigen specificity. However, it is unclear how culture media routinely used in pre-clinical studies affect GBM cell responses to NK-mediated cytotoxicity. We hypothesized that the culture medium would affect GBM cell phenotype, proliferation, and responses to NK cytotoxicity. We investigated in paired analyses n?=?6 patient-derived primary GBM cells propagated in stem cell or serum-containing medium for morphology, proliferation, as well as susceptibility to NK cytolysis and related this to expression of surface and intracellular lineage markers, as well as ligands for NK cell activating and inhibitory receptors. We genotyped the GBM cells for human leukocyte antigen (HLA) as well as the killer immunoglobulin-like receptors (KIR) of the n?=?6 allogeneic NK cells used as effector cells. Culture in serum-containing medium induced a switch in GBM cell morphology from suspension neuropsheres to adherent epithelial-mesenchymal-like phenotypes, which was partially reversible. The differentiated cells diminished expression of nestin, CD133 (prominin-1), and A2B5 putative glioma stem-cell markers, attenuated growth, diminished expression of ligands for activating NK cell receptors, while upregulating class I HLA ligands for NK cell inhibitory receptors. When maintained in serum-containing medium, fewer GBM cells expressed intercellular cell adhesion molecule-1 (ICAM-1) and were less susceptible to lysis by NK cells expressing ?L?2 integrin receptor (LFA-1), mediated through combination of inhibitory KIR-HLA ligand mismatch and diminished activation receptor-ligand interactions compared to cells maintained in stem cell media. We conclude that development of preclinical immunotherapy strategies against GBM should not use cells propagated in serum-containing media to avoid misinterpretation of potential therapeutic responses.

Project description:ObjectiveOne of the main problems of lung transplantation is the shortage of organs as well as reduced survival rates. In the absence of an international standardized model for lung donor-recipient allocation, we set out to develop such a model based on the characteristics of past experiences with lung donors and recipients with the aim of improving the outcomes of the entire transplantation process.MethodsThis was a retrospective analysis of 404 lung transplants carried out at the Reina Sofía University Hospital (Córdoba, Spain) over 23 years. We analyzed various clinical variables obtained via our experience of clinical practice in the donation and transplantation process. These were used to create various classification models, including classical statistical methods and also incorporating newer machine-learning approaches.ResultsThe proposed model represents a powerful tool for donor-recipient matching, which in this current work, exceeded the capacity of classical statistical methods. The variables that predicted an increase in the probability of survival were: higher pre-transplant and post-transplant functional vital capacity (FVC), lower pre-transplant carbon dioxide (PCO2) pressure, lower donor mechanical ventilation, and shorter ischemia time. The variables that negatively influenced transplant survival were low forced expiratory volume in the first second (FEV1) pre-transplant, lower arterial oxygen pressure (PaO2)/fraction of inspired oxygen (FiO2) ratio, bilobar transplant, elderly recipient and donor, donor-recipient graft disproportion requiring a surgical reduction (Tailor), type of combined transplant, need for cardiopulmonary bypass during the surgery, death of the donor due to head trauma, hospitalization status before surgery, and female and male recipient donor sex.ConclusionsThese results show the difficulty of the problem which required the introduction of other variables into the analysis. The combination of classical statistical methods and machine learning can support decision-making about the compatibility between donors and recipients. This helps to facilitate reliable prediction and to optimize the grafts for transplantation, thereby improving the transplanted patient survival rate.

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Killer Immunoglobulin-Like Receptor-Ligand Interactions Predict Clinical Outcomes following Unrelated Donor Transplantations.

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