182,707 research outputs found
Natural killer cell evolution: cellular and molecular studies on Xenopus
Full text linkThe presence of natural killer cells at lower evolutionary levels was investigated in the amphibian Xenopus laevis. Chromium release microcytotoxicity assays revealed that fresh splenocytes from early-thymectomised Xenopus displayed significant spontaneous cytotoxicity against allogeneic B(_3)B(_7) thymic tumor cell targets, unlike those from control Xenopus, suggesting that 'NK-like' activity is greater in thymectomised (T cell-deficient) animals. Addition of Concanavalin A- derived active supernatants to splenocytes from a thymectomised animal caused a significant increase in cytolytic activity, but had no effect on cells from a control animal. This finding of enhanced cytotoxicity was indicative of lymphokine-activated killing in Xenopus, and supported the concept that tumour cell lysis was mediated by NK - like cells. Attempts were made to enrich the splenocytes for natural killer cells through the selective depletion of other lymphocyte subsets, using the techniques of 'panning’ and 'magnetic bead' separation following monoclonal antibody labelling of cells. On comparison of the two techniques, it was found that both were able to deplete a splenocyte culture of B cells to the same extent, but that magnetic sorting produced far superior results for depletion of T cells. Optimum conditions for magnetic sorting were determined, and used to generate 'purified' populations which were tested for their cytolytic activity. Such preliminary investigations suggested that natural killer like activity in Xenopus is likely to be mediated by a 'non-T / non-B' lymphoid subset. Finally, preliminary work was undertaken into the development of 'phage display' technology for the generation of single chain Fy antibody fragments (ultimately against NK cell surface antigens). PGR amplification of the V(_H) and Kappa chains was attempted on RNA extracted (using various methods) from Carboxypeptidase Y-injected-, B(_3)B(_7)-injected-, and unimmunised mice. Following RNA extraction under optimum conditions. Kappa chains were successfully amplified from experimental spleens, but the heavy chains still require more development
Population dynamics and distribution of northern Norwegian killer whales in relation to wintering herring
No full textThe northern Norwegian killer whale (Orcinus orca) is an important predator but little is known about its population dynamics, particular in response to changes in its main prey, the highly dynamic Norwegian spring spawning (NSS) herring (Clupea harengus). The main aims of this thesis were to estimate killer whale population parameters, to explore the future viability of the population, and to explore the response of this predator to changes in distribution and abundance of its main prey over the last 25 years. Population size was estimated as ~ 700 individuals, taking heterogeneity of capture probabilities into account and correcting for unmarked animals. Apparent survival rates of 0.974 (SE = 0.006) for adult males and 0.984 (SE = 0.006) for adult females were estimated accounting for temporary emigration, transience and trap-dependency. Temporary emigration was greater for males than females. Calving intervals ranged from 3 to 14 years (mean = 5.06); equivalent to 0.197 calves per mature female per year. Future viability of the killer whale population was evaluated under various plausible scenarios. The baseline scenario using the best available information predicted a viable population and indicated that the population may be increasing size. Analysis of data on naval sonar activity, killer whale sightings and herring abundance showed that naval sonar activity appeared to have a negative effect on killer whale presence during a period of low prey availability. A time lag of four years was found between the first sign of NSS herring changing its distribution and reduced killer whale presence inside the fjord system. Analysis of energy budgets showed that killer whales spent more time travelling/foraging in 2005/06 than the 1990s. The fjord system was inferred to be a preferred habitat for killer whales when there was a higher density of NSS herring in this area compared to offshore area
Matched sizes of activating and inhibitory receptor/ligand pairs are required for optimal signal integration by human Natural Killer cells
Full text linkIt has been suggested that receptor-ligand complexes segregate or co-localise within immune synapses according to their size, and this is important for receptor signaling. Here, we set out to test the importance of receptor-ligand complex dimensions for immune surveillance of target cells by human Natural Killer (NK) cells. NK cell activation is regulated by integrating signals from activating receptors, such as NKG2D, and inhibitory receptors, such as KIR2DL1. Elongating the NKG2D ligand MICA reduced its ability to trigger NK cell activation. Conversely, elongation of KIR2DL1 ligand HLA-C reduced its ability to inhibit NK cells. Whereas normal-sized HLA-C was most effective at inhibiting activation by normal-length MICA, only elongated HLA-C could inhibit activation by elongated MICA. Moreover, HLA-C and MICA that were matched in size co-localised, whereas HLA-C and MICA that were different in size were segregated. These results demonstrate that receptor-ligand dimensions are important in NK cell recognition, and suggest that optimal integration of activating and inhibitory receptor signals requires the receptor-ligand complexes to have similar dimensions
Competing conservation objectives for predators and prey : estimating killer whale prey requirements for Chinook salmon
No full textEcosystem-based management (EBM) of marine resources attempts to conserve interacting species. In contrast to single-species fisheries management, EBM aims to identify and resolve conflicting objectives for different species. Such a conflict may be emerging in the northeastern Pacific for southern resident killer whales (Orcinus orca) and their primary prey, Chinook salmon (Oncorhynchus tshawytscha). Both species have at-risk conservation status and transboundary (Canada–US) ranges. We modeled individual killer whale prey requirements from feeding and growth records of captive killer whales and morphometric data from historic live-capture fishery and whaling records worldwide. The models, combined with caloric value of salmon, and demographic and diet data for wild killer whales, allow us to predict salmon quantities needed to maintain and recover this killer whale population, which numbered 87 individuals in 2009. Our analyses provide new information on cost of lactation and new parameter estimates for other killer whale populations globally. Prey requirements of southern resident killer whales are difficult to reconcile with fisheries and conservation objectives for Chinook salmon, because the number of fish required is large relative to annual returns and fishery catches. For instance, a U.S. recovery goal (2.3% annual population growth of killer whales over 28 years) implies a 75% increase in energetic requirements. Reducing salmon fisheries may serve as a temporary mitigation measure to allow time for management actions to improve salmon productivity to take effect. As ecosystem-based fishery management becomes more prevalent, trade-offs between conservation objectives for predators and prey will become increasingly necessary. Our approach offers scenarios to compare relative influence of various sources of uncertainty on the resulting consumption estimates to prioritise future research efforts, and a general approach for assessing the extent of conflict between conservation objectives for threatened or protected wildlife where the interaction between affected species can be quantified.Peer reviewe
IL28B, HLA-C, and KIR variants additively predict response to therapy in chronic Hepatitis C virus infection in a European cohort: A cross-sectional study
Full text linkBackground
To date, drug response genes have not proved as useful in clinical practice as was anticipated at the start of the genomic era. An exception is in the treatment of chronic hepatitis C virus (HCV) genotype 1 infection with pegylated interferon-alpha and ribavirin (PegIFN/R). Viral clearance is achieved in 40%–50% of patients. Interleukin 28B (IL28B) genotype predicts treatment-induced and spontaneous clearance. To improve the predictive value of this genotype, we studied the combined effect of variants of IL28B with human leukocyte antigen C (HLA-C), and its ligands the killer immunoglobulin-like receptors (KIR), which have previously been implicated in HCV viral control.
Methods and Findings
We genotyped chronic hepatitis C (CHC) genotype 1 patients with PegIFN/R treatment-induced clearance (n = 417) and treatment failure (n = 493), and 234 individuals with spontaneous clearance, for HLA-C C1 versus C2, presence of inhibitory and activating KIR genes, and two IL28B SNPs, rs8099917 and rs12979860. All individuals were Europeans or of European descent. IL28B SNP rs8099917 “G” was associated with absence of treatment-induced clearance (odds ratio [OR] 2.19, p = 1.27×10−8, 1.67–2.88) and absence of spontaneous clearance (OR 3.83, p = 1.71×10−14, 2.67–5.48) of HCV, as was rs12979860, with slightly lower ORs. The HLA-C C2C2 genotype was also over-represented in patients who failed treatment (OR 1.52, p = 0.024, 1.05–2.20), but was not associated with spontaneous clearance. Prediction of treatment failure improved from 66% with IL28B to 80% using both genes in this cohort (OR 3.78, p = 8.83×10−6, 2.03–7.04). There was evidence that KIR2DL3 and KIR2DS2 carriage also altered HCV treatment response in combination with HLA-C and IL28B.
Conclusions
Genotyping for IL28B, HLA-C, and KIR genes improves prediction of HCV treatment response. These findings support a role for natural killer (NK) cell activation in PegIFN/R treatment-induced clearance, partially mediated by IL28B
Efficient lysis of rhabdomyosarcoma cells by cytokine-induced killer cells : implications for adoptive immunotherapy after allogeneic stem cell transplantation
No full textBackground: Rhabdomyosarcoma is the most common soft tissue sarcoma in childhood and has a poor prognosis. Here we assessed the capability of ex vivo expanded cytokine-induced killer cells to lyse both alveolar and embryonic rhabdomyosarcoma cell lines and investigated the mechanisms involved.
Design and Methods: Peripheral blood mononuclear cells from six healthy donors were used to generate and expand cytokine-induced killer cells. The phenotype and composition of these cells were determined by multiparameter flow cytometry, while their cytotoxic effect against rhabdomyosarcoma cells was evaluated by a europium release assay.
Results: Cytokine-induced killer cells efficiently lysed cells from both rhabdomyosarcoma cell lines. Antibody-mediated masking of either NKG2D molecule on cytokine-induced killer cells or its ligands on rhabdomyosarcoma cells (major histocompatibility antigen related chain A and B and UL16 binding protein 2) diminished this effect by 50%, suggesting a major role for the NKG2D molecule in rhabdomyosarcoma cell killing. No effect was observed after blocking CD11a, CD3 or TCRαβ molecules on cytokine-induced killer cells or CD1d on rhabdomyosar-coma cells. Remarkably, cytokine-induced killer cells used tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) to activate caspase-3, as the main caspase responsible for the execution of apoptosis. Accordingly, blocking TRAIL receptors on embryonic rhabdomyosarcoma cell lines significantly reduced the anti-tumor effect of cytokine-induced killer cells. About 50% of T cells within the cytokine-induced killer population had an effector memory phenotype, 20% had a naïve phenotype and approximately 30% of the cells had a central memory phenotype. In addition, cytokine-induced killer cells expressed low levels of activation-induced markers CD69 and CD137 and demonstrated a low alloreactive potential.
Conclusions: Our data suggest that cytokine-induced killer cells may be used as a novel adoptive immunotherapy for the treatment of patients with rhabdomyosarcoma after allogeneic stem cell transplantation
Activation of natural killer cells during microbial infections.
Full text linkNatural killer (NK) cells are large granular lymphocytes that express a diverse array of germline encoded inhibitory and activating receptors for MHC Class I and Class I-like molecules, classical co-stimulatory ligands, and cytokines. The ability of NK cells to be very rapidly activated by inflammatory cytokines, to secrete effector cytokines, and to kill infected or stressed host cells, suggests that they may be among the very early responders during infection. Recent studies have also identified a small number of pathogen-derived ligands that can bind to NK cell surface receptors and directly induce their activation. Here we review recent studies that have begun to elucidate the various pathways by which viral, bacterial, and parasite pathogens activate NK cells. We also consider two emerging themes of NK cell-pathogen interactions, namely their contribution to adaptive immune responses and their potential to take on regulatory and immunomodulatory functions
Changes in dive behaviour during naval sonar exposure in killer whales, long-finned pilot whales, and sperm whales.
Full text linkAnthropogenic underwater sound in the environment might potentially affect the behavior of marine mammals enough to have an impact on their reproduction and survival. Diving behavior of four killer whales (Orcinus orca), seven long-finned pilot whales (Globicephala melas), and four sperm whales (Physeter macrocephalus) was studied during controlled exposures to naval sonar [low frequency active sonar (LFAS): 1–2 kHz and mid frequency active sonar (MFAS): 6–7 kHz] during three field seasons (2006–2009). Diving behavior was monitored before, during and after sonar exposure using an archival tag placed on the animal with suction cups. The tag recorded the animal's vertical movement, and additional data on horizontal movement and vocalizations were used to determine behavioral modes. Killer whales that were conducting deep dives at sonar onset changed abruptly to shallow diving (ShD) during LFAS, while killer whales conducting deep dives at the onset of MFAS did not alter dive mode. When in ShD mode at sonar onset, killer whales did not change their diving behavior. Pilot and sperm whales performed normal deep dives (NDD) during MFAS exposure. During LFAS exposures, long-finned pilot whales mostly performed fewer deep dives and some sperm whales performed shallower and shorter dives. Acoustic recording data presented previously indicates that deep diving (DD) is associated with feeding. Therefore, the observed changes in dive behavior of the three species could potentially reduce the foraging efficiency of the affected animals.Peer reviewe
Functional design and use of acoustic signals produced by killer whales (Orcinus orca)
No full textThis study aimed to investigate possible functions of the sounds produced by
herring-eating killer whales in the Northeast Atlantic.
In this study, I investigated the whistle repertoire of killer whales, which had
previously only been studied in British Columbia, where it appeared to be restricted to
the audible range. However, I show that high frequency whistles (> 17 kHz) were
detected in Northeast Atlantic populations but not in Northeast Pacific populations.
These results indicated substantial intraspecific variation in whistle production in
killer whales. Little variation was observed in high frequency whistles recorded from
three different sites in the Northeast Atlantic, suggesting this signal has a similar
function across locations.
The estimated active space of high frequency whistles and burst-pulse calls
suggested that these are short-range signals used for within-group communication.
Source levels of burst-pulse calls were lower than what was previously described in
British Columbia, which possibly reflected the fact that these sounds do not need to
propagate far because distances between group members are generally short. Calls,
high frequency whistles and herding calls produced at different depths did not appear
to suffer effects due to increased pressure, such as changing frequency or duration
characteristics.
Feeding appeared to take place below 10 m of depth, as suggested by the
localisation of depth of production of feeding-related sounds. These depths were
consistent with those at which tailslaps were produced in Dtags attached to individual
whales. Feeding periods were characterised by deep diving, increased sound
production and highly non-directional movement. These findings suggested that killer
whales in a herring spawning ground use a feeding strategy different from carousel
feeding used in herring overwintering grounds.
These findings showed that Northeast Atlantic killer whales have a different sound
repertoire to other populations, and suggested that they may employ different feeding
strategies depending on prey behaviour
Identification of the ancestral killer immunoglobulin-like receptor gene in primates
No full textBackground: Killer Immunoglobulin-like Receptors (KIR) are essential immuno- surveillance molecules. They are expressed on natural killer and T cells, and interact with human leukocyte antigens. KIR genes are highly polymorphic and contribute vital variability to our immune system. Numerous KIR genes, belonging to five distinct lineages, have been identified in all primates examined thus far and shown to be rapidly evolving. Since few KIR remain orthologous between species, with only one of them, KIR2DL4, shown to be common to human, apes and monkeys, the evolution of the KIR gene family in primates remains unclear.Results: Using comparative analyses, we have identified the ancestral KIR lineage ( provisionally named KIR3DL0) in primates. We show KIR3DL0 to be highly conserved with the identification of orthologues in human ( Homo sapiens), common chimpanzee ( Pan troglodytes), gorilla ( Gorilla gorilla), rhesus monkey ( Macaca mulatta) and common marmoset ( Callithrix jacchus). We predict KIR3DL0 to encode a functional molecule in all primates by demonstrating expression in human, chimpanzee and rhesus monkey. Using the rhesus monkey as a model, we further show the expression profile to be typical of KIR by quantitative measurement of KIR3DL0 from an enriched population of natural killer cells.Conclusion: One reason why KIR3DL0 may have escaped discovery for so long is that, in human, it maps in between two related leukocyte immunoglobulin-like receptor clusters outside the known KIR gene cluster on Chromosome 19. Based on genomic, cDNA, expression and phylogenetic data, we report a novel lineage of immunoglobulin receptors belonging to the KIR family, which is highly conserved throughout 50 million years of primate evolution
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