| 1. |
- Forslund, Elin, et al.
(författare)
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Microchip-Based Single-Cell Imaging Reveals That CD56(dim) CD57(-)KIR(-)NKG2A(+) NK Cells Have More Dynamic Migration Associated with Increased Target Cell Conjugation and Probability of Killing Compared to CD56(dim)CD57(-)KIR(-)NKG2A(-) NK Cells
- 2015
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Ingår i: Journal of Immunology. - : The American Association of Immunologists. - 0022-1767 .- 1550-6606. ; 195:7, s. 3374-3381
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Tidskriftsartikel (refereegranskat)abstract
- NK cells are functionally educated by self-MHC specific receptors, including the inhibitory killer cell Ig-like receptors (KIRs) and the lectin-like CD94/NKG2A heterodimer. Little is known about how NK cell education influences qualitative aspects of cytotoxicity such as migration behavior and efficacy of activation and killing at the single-cell level. In this study, we have compared the behavior of FACS-sorted CD56(dim)CD57(-)KIR(-)NKG2A(+) (NKG2A(+)) and CD56(dim)CD57(-)KIR(-)NKG2A(+) (lacking inhibitory receptors; IR-) human NK cells by quantifying migration, cytotoxicity, and contact dynamics using microchip-based live cell imaging. NKG2A(+) NK cells displayed a more dynamic migration behavior and made more contacts with target cells than IR-NK cells. NKG2A(+) NK cells also more frequently killed the target cells once a conjugate had been formed. NK cells with serial killing capacity were primarily found among NKG2A(+) NK cells. Conjugates involving IR- NK cells were generally more short-lived and IR- NK cells did not become activated to the same extent as NKG2A(+) NK cells when in contact with target cells, as evident by their reduced spreading response. In contrast, NKG2A(+) and IR- NK cells showed similar dynamics in terms of duration of conjugation periods and NK cell spreading response in conjugates that led to killing. Taken together, these observations suggest that the high killing capacity of NKG2A(+) NK cells is linked to processes regulating events in the recognition phase of NK-target cell contact rather than events after cytotoxicity has been triggered.
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| 2. |
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| 3. |
- Haroun-Izquierdo, Alvaro, et al.
(författare)
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Adaptive single-KIR(+)NKG2C(+) NK cells expanded from select superdonors show potent missing-self reactivity and efficiently control HLA-mismatched acute myeloid leukemia
- 2022
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Ingår i: Journal for ImmunoTherapy of Cancer. - : BMJ. - 2051-1426. ; 10:11, s. e005577-
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundNatural killer (NK) cells hold great promise as a source for allogeneic cell therapy against hematological malignancies, including acute myeloid leukemia (AML). Current treatments are hampered by variability in NK cell subset responses, a limitation which could be circumvented by specific expansion of highly potent single killer immunoglobulin-like receptor (KIR)(+)NKG2C(+) adaptive NK cells to maximize missing-self reactivity.MethodsWe developed a GMP-compliant protocol to expand adaptive NK cells from cryopreserved cells derived from select third-party superdonors, that is, donors harboring large adaptive NK cell subsets with desired KIR specificities at baseline. We studied the adaptive state of the cell product (ADAPT-NK) by flow cytometry and mass cytometry as well as cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq). We investigated the functional responses of ADAPT-NK cells against a wide range of tumor target cell lines and primary AML samples using flow cytometry and IncuCyte as well as in a mouse model of AML.ResultsADAPT-NK cells were >90% pure with a homogeneous expression of a single self-HLA specific KIR and expanded a median of 470-fold. The ADAPT-NK cells largely retained their adaptive transcriptional signature with activation of effector programs without signs of exhaustion. ADAPT-NK cells showed high degranulation capacity and efficient killing of HLA-C/KIR mismatched tumor cell lines as well as primary leukemic blasts from AML patients. Finally, the expanded adaptive NK cells had preserved robust antibody-dependent cellular cytotoxicity potential and combination of ADAPT-NK cells with an anti-CD16/IL-15/anti-CD33 tri-specific engager led to near-complete killing of resistant CD45(dim) blast subtypes.ConclusionsThese preclinical data demonstrate the feasibility of off-the-shelf therapy with a non-engineered, yet highly specific, NK cell population with full missing-self recognition capability.
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| 4. |
- Philippon, Camille, et al.
(författare)
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Allelic variation of KIR and HLA tunes the cytolytic payload and determines functional hierarchy of NK cell repertoires
- 2023
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Ingår i: Blood Advances. - : American Society of Hematology. - 2473-9529 .- 2473-9537. ; 7:16, s. 4492-4504
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Tidskriftsartikel (refereegranskat)abstract
- The functionality of natural killer (NK) cells is tuned during education and is associated with remodeling of the lysosomal compartment. We hypothesized that genetic variation in killer cell immunoglobulin-like receptor (KIR) and HLA, which is known to influence the functional strength of NK cells, fine-tunes the payload of effector molecules stored in secretory lysosomes. To address this possibility, we performed a high-resolution analysis of KIR and HLA class I genes in 365 blood donors and linked genotypes to granzyme B loading and functional phenotypes. We found that granzyme B levels varied across individuals but were stable over time in each individual and genetically determined by allelic variation in HLA class I genes. A broad mapping of surface receptors and lysosomal effector molecules revealed that DNAM-1 and granzyme B levels served as robust metric of the functional state in NK cells. Variation in granzyme B levels at rest was tightly linked to the lytic hit and downstream killing of major histocompatibility complex-deficient target cells. Together, these data provide insights into how variation in genetically hardwired receptor pairs tunes the releasable granzyme B pool in NK cells, resulting in predictable hierarchies in global NK cell function.
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| 5. |
- Samuelsson, Pär, et al.
(författare)
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Comparison of Grey-Box ODE Models for Ladle Heat Transfer and Steel Temperature Losses
- 2009
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Ingår i: SteelSim09, 3rd International Conference on Simulation and Modelling of Metallurgical Processes in Steelmaking. - Leoben, Österrike.
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Konferensbidrag (refereegranskat)abstract
- Most steelmaking ladle modelling strategies are based either on pure physical modelling or statistical relations. In this paper, a relatively simple model for steel temperature and ladle temperatures based on ordinary differential equations is presented and compared with a number of more complex ODE models. The model is semi-physical since the model structure is obtained mainly from physical relations, but the model parameters are calibrated using collected process data and a systematic calibration methodology. A main objective has been to obtain a model suitable for on-line purposes. Different model expansions are compared to the reference model. It is found that a simple model structure gives a good trade off between accuracy and complexity.
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| 6. |
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| 7. |
- Samuelsson, Pär, et al.
(författare)
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ODE-based modelling and calibration of temperatures in steelmaking ladles
- 2010
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Ingår i: IEEE Transactions on Control Systems Technology. - 1063-6536 .- 1558-0865. ; 18:2, s. 474-479
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Tidskriftsartikel (refereegranskat)abstract
- This brief considers modelling of steel and wall temperatures in steelmaking ladles used as liquid steel transportation vessels. Two measurement campaigns in order to collect data for model calibration and validation were conducted at the facilities of a Swedish stainless steel manufacturer. The process data were utilized in order to calibrate and validate an ordinary differential equation (ODE) model using a grey-box approach. The grey-box approach is justified since model structure and parameters are only partially known and few data are available for calibration. It is concluded that even though the model structure is non-complicated, the model shows promising accuracy for the steel temperature estimation. The model will be further evaluated in online simulations at the steel mill.
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| 8. |
- Samuelsson, Pär, et al.
(författare)
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On-line Simulation of Heat Transfer Models for Steelmaking Ladles Using ODE Model
- 2009
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Ingår i: Proceedings of Steelsim 2009. - Leoben, Österrike.
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Konferensbidrag (refereegranskat)abstract
- This paper describes the on-line implementation and evaluation of a model describing heat transfer in steelmaking ladles. The implemented model is based on ordinary differential equations which ensures a short computation time. Model calibration was performed utilizing a grey-box approach using real process data in order to describe the specific ladles used by a Swedish steel manufacturer. The main purpose has been to design and implement a simulation prototype for on-line simulation in the steel mill. To evaluate the model and the implementation, simulation of 14 steel charges was performed in real-time in the steel mill. Further evaluation of different models and different conditions is needed, although the performed experiment seems promising.
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| 9. |
- Sohlberg, Björn
(författare)
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Control of a pickling process using a grey box model
- 2007
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Ingår i: Automation in Mining, Mineral and Metal Processing. - Quebec.
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Konferensbidrag (refereegranskat)abstract
- This paper deals with model predictive control using a grey box model. The process is modelled using a priori information and unknown parts are described as general continuous nonlinear functions, which are approximated by means of Taylor series including higher order terms. In the Taylor series, the partial derivatives are estimated from measured data by minimising the maximum likelihood function. The grey box model is used to design and tune a model predictive controller to control the pickling process. The process is a bottle neck in the production line and the simulation shows that the production can be increased approximately 15 % by using the controller.
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| 10. |
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