WordNet

with the wind abaft the beam; "a ship sailing large"
a garment size for a large person
above average in size or number or quantity or magnitude or extent; "a large city"; "set out for the big city"; "a large sum"; "a big (or large) barn"; "a large family"; "big businesses"; "a big expenditure"; "a large number of newspapers"; "a big group of scientists"; "large areas of the world" (同)big
at a distance, wide of something (as of a mark)
fairly large or important in effect; influential; "played a large role in the negotiations"
having broad power and range and scope; "taking the large view"; "a large effect"; "a large sympathy"
an agranulocytic leukocyte that normally makes up a quarter of the white blood cell count but increases in the presence of infection (同)lymph cell

PrepTutorEJDIC

(同じ種類のものと比較して,形・体積・数量などが)『大きい』,多い,広い / (考えなどが)広範囲な,幅の広い,寛大な / 大きく / 自慢して,誇大に
(砂糖などが)粒の,粒状の / (紙・革などが)表面がざらざらしている

Wikipedia preview

出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/08/11 03:11:22」(JST)

wiki en

Natural killer cells or NK cells are a type of cytotoxic lymphocyte critical to the innate immune system. The role NK cells play is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to viral-infected cells and respond to tumor formation, acting at around 3 days after infection. Typically, immune cells detect major histocompatibility complex (MHC) presented on infected cell surfaces, triggering cytokine release, causing lysis or apoptosis. NK cells are unique, however, as they have the ability to recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named “natural killers” because of the initial notion that they do not require activation to kill cells that are missing “self” markers of MHC class 1.^[1] This role is especially important because harmful cells that are missing MHC 1 markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

NK cells (belonging to the group of innate lymphoid cells) are defined as large granular lymphocytes (LGL) and constitute the third kind of cells differentiated from the common lymphoid progenitor-generating B and T lymphocytes.^[2] NK cells are known to differentiate and mature in the bone marrow, lymph nodes, spleen, tonsils, and thymus, where they then enter into the circulation.^[3] NK cells differ from natural killer T cells (NKTs) phenotypically, by origin and by respective effector functions; often, NKT cell activity promotes NK cell activity by secreting IFNγ. In contrast to NKT cells, NK cells do not express T-cell antigen receptors (TCR) or pan T marker CD3 or surface immunoglobulins (Ig) B cell receptors, but they usually express the surface markers CD16 (FcγRIII) and CD56 in humans, NK1.1 or NK1.2 in C57BL/6 mice. Up to 80% of human NK cells also express CD8.

In addition to the knowledge that natural killer cells are effectors of innate immunity, recent research has uncovered information on both activating and inhibitory NK cell receptors which play important function roles including self tolerance and sustaining NK cell activity. NK cells also play a role in adaptive immune response,^[4] numerous experiments have worked to demonstrate their ability to readily adjust to the immediate environment and formulate antigen-specific immunological memory, fundamental for responding to secondary infections with the same antigen. The role of NK cells in both the innate and adaptive immune responses is becoming increasingly important in research using NK cell activity and potential cancer therapies.

1 NK cell receptors
- 1.1 Activating receptors
- 1.2 Inhibitory receptors
2 Function
- 2.1 Cytolytic granule mediated cell apoptosis
- 2.2 Antibody-dependent cell-mediated cytotoxicity
- 2.3 Cytokine-induced NK and CTL activation
- 2.4 Missing 'self' hypothesis
- 2.5 Tumor cell surveillance
- 2.6 Adaptive features of NK cells—"memory-like" and memory NK cells
- 2.7 NK cell function in pregnancy
- 2.8 NK cell evasion by tumor cells
3 History
4 New findings
- 4.1 Anticancer therapy
- 4.2 Innate resistance to HIV
5 See also
6 References
7 Further reading
8 External links

NK cell receptors

The HLA ligand for KIR

NK cell receptors can also be differentiated based on function. Natural cytotoxicity receptors directly induce apoptosis after binding to Fas ligand that directly indicate infection of a cell. The MHC-dependent receptors (described above) use an alternate pathway to induce apoptosis in infected cells. Natural killer cell activation is determined by the balance of inhibitory and activating receptor stimulation. For example, if the inhibitory receptor signaling is more prominent, then NK cell activity will be inhibited; similarly, if the activating signal is dominant, then NK cell activation will result.^[5]

Protein structure of NKG2D

NK cell receptor types (with inhibitory, as well as some activating members) are differentiated by structure, with a few examples to follow:

Protein structure of NKp44

Activating receptors

Ly49 (homodimers), relatively ancient, C-type lectin family receptors, are of multigenic presence in mice, while humans have only one pseudogenic Ly49, the receptor for classical (polymorphic) MHC I molecules.
NCR (natural cytotoxicity receptors), upon stimulation, mediate NK killing and release of IFNγ.
CD94 : NKG2 (heterodimers), a C-type lectin family receptor, is conserved in both rodents and primates and identifies nonclassical (also nonpolymorphic) MHC I molecules such as HLA-E. Expression of HLA-E at the cell surface is dependent on the presence of nonamer peptide epitope derived from the signal sequence of classical MHC class I molecules, which is generated by the sequential action of signal peptide peptidase and the proteasome. Though indirect, this is a way to survey the levels of classical (polymorphic) HLA molecules.
CD16 (FcγIIIA) plays a role in antibody-dependent cell-mediated cytotoxicity; in particular, they bind IgG.

Inhibitory receptors

Killer-cell immunoglobulin-like receptors (KIRs) belong to a multigene family of more recently evolved Ig-like extracellular domain receptors; they are present in nonhuman primates, and are the main receptors for both classical MHC I (HLA-A, HLA-B, HLA-C) and nonclassical HLA-G in primates. Some KIRs are specific for certain HLA subtypes. Most KIRs are inhibitory and dominant. Regular cells express MHC class 1, so are recognised by KIR receptors and NK cell killing is inhibited.^[3]
ILT or LIR (leukocyte inhibitory receptors) — are recently discovered members of the Ig receptor family.
Ly49 (homodimers) have both activating and inhibitory isoforms. They are highly polymorphic on the population level; though they are structurally unrelated to KIRs, they are the functional homologues of KIRs in mice, including the expression pattern. Ly49s are receptor for classical (polymorphic) MHC I molecules.

Function

Cytolytic granule mediated cell apoptosis

NK cells are cytotoxic; small granules in their cytoplasm contain proteins such as perforin and proteases known as granzymes. Upon release in close proximity to a cell slated for killing, perforin forms pores in the cell membrane of the target cell, creating an aqueous channel through which the granzymes and associated molecules can enter, inducing either apoptosis or osmotic cell lysis. The distinction between apoptosis and cell lysis is important in immunology: lysing a virus-infected cell could potentially only release the virions, whereas apoptosis leads to destruction of the virus inside. α-defensins, antimicrobial molecules, are also secreted by NK cells, and directly kill bacteria by disrupting their cell walls in a manner analogous to that of neutrophils.^[3]

Antibody-dependent cell-mediated cytotoxicity

Infected cells are routinely opsonized with antibodies for detection by immune cells. Antibodies that bind to antigens can be recognised by FcϒRIII (CD16) receptors expressed on NK cells, resulting in NK activation, release of cytolytic granules and consequent cell apoptosis. This is a major killing mechanism of some monoclonal antibodies like rituximab (Rituxan), ofatumumab (Azzera), and others. The contribution of antibody-dependent cell-mediated cytotoxicity to tumor cell killing can be measured with a specific test that uses NK-92 that has been transfected with a high-affinity FcR. Results are compared to the "wild type" NK-92 that does not express the FcR.^[6]

Cytokine-induced NK and CTL activation

Cytokines play a crucial role in NK cell activation. As these are stress molecules released by cells upon viral infection, they serve to signal to the NK cell the presence of viral pathogens in the affected area. Cytokines involved in NK activation include IL-12, IL-15, IL-18, IL-2, and CCL5. NK cells are activated in response to interferons or macrophage-derived cytokines. They serve to contain viral infections while the adaptive immune response generates antigen-specific cytotoxic T cells that can clear the infection. NK cells work to control viral infections by secreting IFNγ and TNFα. IFNγ activates macrophages for phagocytosis and lysis, and TNFα acts to promote direct NK tumor cell killing. Patients deficient in NK cells prove to be highly susceptible to early phases of herpes virus infection.

Missing 'self' hypothesis

Schematic diagram indicating the complementary activities of cytotoxic T cells and NK cells

For NK cells to defend the body against viruses and other pathogens, they require mechanisms that enable the determination of whether a cell is infected or not. The exact mechanisms remain the subject of current investigation, but recognition of an "altered self" state is thought to be involved. To control their cytotoxic activity, NK cells possess two types of surface receptors: activating receptors and inhibitory receptors, including killer-cell immunoglobulin-like receptors. Most of these receptors are not unique to NK cells and can be present in some T cell subsets, as well.

These inhibitory receptors recognize MHC class I alleles, which could explain why NK cells preferentially kill cells that possess low levels of MHC class I molecules. This mode of NK cell target interaction is known as "missing-self recognition", a term coined by Klas Kärre and co-workers in the late 90s. MHC class I molecules are the main mechanism by which cells display viral or tumor antigens to cytotoxic T cells. A common evolutionary adaptation to this is seen in both intracellular microbes and tumors: the chronic down-regulation of MHC I molecules, which makes affected cells invisible to T cells, allowing them to evade T cell-mediated immunity. NK cells apparently evolved as an evolutionary response to this adaptation (the loss of the MHC eliminates CD4/CD8 action, so another immune cell evolved to fulfill the function). ^[7]

Tumor cell surveillance

Natural killer cells often lack antigen-specific cell surface receptors, so are part of innate immunity, i.e. able to react immediately with no prior exposure to the pathogen. In both mice and humans, NKs can be seen to play a role in tumor immunosurveillance by directly inducing the death of tumor cells (NKs act as cytolytic effector lymphocytes), even in the absence of surface adhesion molecules and antigenic peptides. This role of NK cells is critical to immune success particularly because T cells are unable to recognize pathogens in the absence of surface antigens.^[1] Tumor cell detection results in activation of NK cells and consequent cytokine production and release.

If tumor cells do not cause inflammation, they will also be regarded as self and will not induce a T cell response. A number of cytokines are produced by NKs, including tumor necrosis factor α (TNFα), IFNγ, and interleukin (IL-10). TNFα and IL-10 act as proinflammatory and immunosuppressors, respectively. The activation of NK cells and subsequent production of cytolytic effector cells impacts macrophages, dendritic cells, and neutrophils, which subsequently enables antigen-specific T and B cell responses. Instead of acting via antigen-specific receptors, lysis of tumor cells by NK cells is mediated by alternative receptors, including NKG2D, NKp44, NKp46, NKp30, and DNAM.^[5] NKG2D is a disulfide-linked homodimer which recognizes a number of ligands, including ULBP and MICA, which are typically expressed on tumor cells.

NK cells, along with macrophages and several other cell types, express the Fc receptor (FcR) molecule (FC-gamma-RIII = CD16), an activating biochemical receptor that binds the Fc portion of antibodies. This allows NK cells to target cells against which a humoral response has been mobilized and to lyse cells through ADCC. This response depends on the affinity of the Fc receptor expressed on NK cells, which can have high, intermediate, and low affinity for the Fc portion of the antibody or IgG. This affinity is determined by the nucleotide status in position 158 of the gene, which can code phenylalanine (F allele) or valine (V allele). Individuals with high-affinity FcRgammRIII (158 V/V allele) respond better to antibody therapy. This has been shown for lymphoma patients who received the antibody Rituxan. Patients who express the 158 V/V allele had a better antitumor response. Only 15–25% of the population expressed the 158 V/V allele. To determine the ADCC contribution of monoclonal antibodies, NK-92 cells (a "pure" NK cell line) has been transfected with the gene for the high-affinity FcR.

Adaptive features of NK cells—"memory-like" and memory NK cells

The ability to generate memory cells following a primary infection and the consequent rapid immune activation and response to succeeding infections by the same antigen is fundamental to the role T and B cells play in the adaptive immune response. For many years, NK cells have been considered to be a part of the innate immune system. However, recently increasing evidence suggests that NK cells can display several features that are usually attributed to adaptive immune cells (e.g. T cell responses) such as expansion and contraction of subsets, increased longevity and a form of immunological memory, characterized by a more potent response upon secondary challenge with the same antigen. ^[8]^[9] These exciting new data have been generated in a diverse set of experimental systems. In mice the majority of research was carried out with murine cytomegalovirus (MCMV) and in models of hapten-hypersensitivity reactions. In humans most studies focused on the expansion of an NK cell subset carrying the activating receptor NKG2C. This expansion was observed primarily in response to Human Cytomegalovirus (HCMV) but other infections, e.g. Hantavirus, have been reported to trigger expansion of NKG2C+ NK cells as well.

NK cell function in pregnancy

As the majority of pregnancies involve two parents who are not tissue-matched, successful pregnancy requires the mother's immune system to be suppressed. NK cells are thought to be an important cell type in this process.^[10] These cells are known as "uterine NK cells" (uNK cells) and they differ from peripheral NK cells. They are in the CD56^bright NK cell subset, potent at cytokine secretion, but with low cytotoxic ability and relatively similar to peripheral CD56^bright NK cells, with a slightly different receptor profile.^[10] These uNK cells are the most abundant leukocytes present in utero in early pregnancy, representing about 70% of leukocytes here, but from where they originate remains controversial.^[11]

These NK cells have the ability to elicit cell cytotoxicity in vitro, but at a lower level than peripheral NK cells, despite containing perforin.^[12] Lack of cytotoxicity in vivo may be due to the presence of ligands for their inhibitory receptors. Trophoblast cells downregulate HLA-A and HLA-B to defend against cytotoxic T cell-mediated death. This would normally trigger NK cells by missing self recognition; however, these cells survive. The selective retention of HLA-E (which is a ligand for NK cell inhibitory receptor NKG2A) and HLA-G (which is a ligand for NK cell inhibitory receptor KIR2DL4) by the trophoblast is thought to defend it against NK cell-mediated death.^[10]

Uterine NK cells have shown no significant difference in women with recurrent miscarriage compared with controls. However, higher peripheral NK cell percentages occur in women with recurrent miscarriages than in control groups.^[13]

NK cells secrete a high level of cytokines which help mediate their function. Some important cytokines they secrete include TNF-α, IL-10, IFN-γ, and TGF-β, among others.^[10] For example, IFN-γ dilates and thins the walls of maternal spiral arteries to enhance blood flow to the implantation site.^[14]

NK cell evasion by tumor cells

By shedding decoy NKG2D soluble ligands, tumor cells have evolved a process by which they are able to avoid immune responses. These soluble NKG2D ligands bind to NK cell NKG2D receptors, activating a false NK response and consequently creating competition for the receptor site.^[1] This method of evasion occurs in prostate cancer. In addition, prostate cancer tumors can evade CD8 cell recognition due to their ability to downregulate expression of MHC class 1 molecules. This example of immune evasion actually highlights NK cells' importance in tumor surveillance and response, as CD8 cells can consequently only act on tumor cells in response to NK-initiated cytokine production (adaptive immune response).^[15]

History

In early experiments on cell-mediated cytotoxicity against tumor target cells, both in cancer patients and animal models, investigators consistently observed what was termed a "natural" reactivity; that is, a certain population of cells seemed to be able to lyse tumor cells without having been previously sensitized to them. As these discoveries were inconsistent with the established model at the time, many initially considered these observations to be artifacts.^[16] However, by 1973, 'natural killing' activity was established across a wide variety of species, and the existence of a separate lineage of cells possessing this ability was postulated.

The discovery that a unique type of lymphocyte was responsible for “natural” or spontaneous cytotoxicity was made in the early 1970s by doctoral student Rolf Kiessling and postdoctoral fellow Hugh Pross, in the mouse,^[17] and by Hugh Pross and doctoral student Mikael Jondal in the human.^[18]^[19] The mouse and human work was carried out under the supervision of professors Eva Klein and Hans Wigzell, respectively, of the Karolinska Institute, Stockholm. Kiessling’s research involved the well-characterized ability of T lymphocytes to lyse tumor cells against which they had been previously immunized. Pross and Jondal were studying cell-mediated cytotoxicity in normal human blood and the effect of the removal of various receptor-bearing cells on this cytotoxicity. Later that same year, Ronald Herberman published similar data with respect to the unique nature of the mouse effector cell.^[20] The human data were confirmed, for the most part, by West et al.^[21] using similar techniques and the same erythroleukemic target cell line, K562. K562 is highly sensitive to lysis by human NK cells and, over the decades, the K562 ⁵¹chromium-release assay has become the most commonly used assay to detect human NK functional activity.^[22] Its almost universal use has meant that experimental data can be compared easily by different laboratories around the world.

Using discontinuous density centrifugation, and later monoclonal antibodies, natural killing ability was mapped to the subset of large, granular lymphocytes known today as NK cells. The demonstration that density gradient-isolated large granular lymphocytes were responsible for human NK activity, made by Timonen and Saksela in 1980,^[23] was the first time that NK cells had been visualized microscopically, and was a major breakthrough in the field.

New findings

Anticancer therapy

Since NK cells recognize target cells when they express nonself HLA antigens (but not self), autologous (patients' own) NK cell infusions have not shown any antitumor effects. Instead, investigators are working on using allogeneic cells from peripheral blood, which requires that all T cells be removed before infusion into the patients to remove the risk of graft versus host disease, which can be fatal. This can be achieved using an immunomagnetic column (CliniMACS). In addition, because of the limited number of NK cells in blood (only 10% of lymphocytes are NK cells), their number needs to be expanded in culture. This can take a few weeks and the yield is donor-dependent. A simpler way to obtain high numbers of pure NK cells is to expand NK-92 cells whose cells continuously grow in culture and can be expanded to clinical grade numbers in bags or bioreactors.^[24] Clinical studies have shown it to be well tolerated and some antitumor responses have been seen in patients with lung cancer, melanoma, and lymphoma.^[25]^[26]

Infusions of T cells engineered to express a chimeric antigen receptor that recognizes an antigen molecule on leukemia cells could induce remissions in patients with advanced leukemia. Logistical challenges are present for expanding T cells and investigators are working on applying the same technology to peripheral blood NK cells and NK-92.

In a study at Boston Children's Hospital, in coordination with Dana-Farber Cancer Institute, whereby immunocompromised mice had contracted lymphomas from EBV infection, an NK-activating receptor called NKG2D was fused with a stimulatory Fc portion of the EBV antibody. The NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients. In a transplantation model of LMP1-fueled lymphomas, the NKG2D-Fc fusion proved capable of reducing tumor growth and prolonging survival of the recipients.

Innate resistance to HIV

Recent research suggests specific KIR-MHC class 1 gene interactions might control innate genetic resistance to certain viral infections, including HIV and its consequent development of AIDS.^[3] Certain HLA allotypes have been found to determine the progression of HIV to AIDS; an example is the HLA-B57 and HLA-B27 alleles, which have been found to delay progression from HIV to AIDS. This is evident because patients expressing these HLA alleles are observed to have lower viral loads and a more gradual decline in CD4⁺ T cells numbers. Despite considerable research and data collected measuring the genetic correlation of HLA alleles and KIR allotypes, a firm conclusion has not yet been drawn as to what combination provides decreased HIV and AIDS susceptibility.

NK cells can impose immune pressure on HIV, which had previously been described only for T cells and antibodies.^[27] HIV mutates to avoid NK cell activity.^[27]

References

^ ^a ^b ^c Vivier, E., Raulet, D.H., Moretta, A., Caligiuri, M.A., Zitvogel, L., Lanier, L.L., Yokoyama, W.M. & Ugolini, S.; Raulet; Moretta; Caligiuri; Zitvogel; Lanier; Yokoyama; Ugolini (2011). "Innate or Adaptive Immunity? The Example of Natural Killer Cells". Science 331 (6013): 44–49. doi:10.1126/science.1198687.
^ Roitt I, Brostoff J, Male D (2001). Immunology (6th ed.), 480p. St. Louis: Mosby, ISBN 0-7234-3189-2.
^ ^a ^b ^c ^d Iannello, A., Debbeche, O., Samarani, S., Ahmad, A; Debbeche; Samarani; Ahmad (2008). "'Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS'". Journal of Leukocyte Biology 84: 1–26. doi:10.1189/jlb.0907650.
^ Arina, A., Murillo, O., Dubrot, J., Azpilikueta, A., Alfaro, C., PÃrez-Gracia, J.,L., Bendandi, M., Palencia, B., HervÃ¡s-Stubbs, S. & Melero, I.; Murillo; Dubrot; Azpilikueta; Alfaro; Pérez-Gracia; Bendandi; Palencia; Hervás-Stubbs; Melero (2007). "'Cellular liaisons of natural killer lymphocytes in immunology and immunotherapy of cancer'". Expert Opinion on Biological Therapy 5 (5): 599–615. doi:10.1517/14712598.7.5.599.
^ ^a ^b Terunuma, H., Deng, X., Dewan, Z., Fujimoto, S., Yamamoto, N.; Deng; Dewan; Fujimoto; Yamamoto (2008). "Potential role of NK cells in the induction of immune responses: implications for NK cell-based immunotherapy for cancers and viral infections". International Reviews of Immunology 27 (3): 93–110. doi:10.1080/08830180801911743. PMID 18437601.
^ Smyth, M.J., Hayakawa, Y., Takeda, K., Yagita.; Pickett (2002). "New aspects of natural-killer-cell surveillance and therapy of cancer". Nature Reviews Genetics 2 (11): 850–852. doi:10.1038/nrg928.
^ Lodoen, M.,B. & Lanier, L.,L.; Lanier (2005). "Viral modulation of NK cell immunity". Nature Reviews Microbiology 3: 59–69. doi:10.1038/nrmicro1066.
^ Rölle, Alexander (September 2013). "Memory of infections: an emerging role for natural killer cells". PLoS Pathogens 9 (9): e1003548. doi:10.1371/journal.ppat.1003548. PMID 24086127.
^ Pyzik, M. & Vidal, S.,M.; Vidal (2009). "'NK cells stroll down the memory lane'". Immunology and Cell Biology 87 (4): 261–263. doi:10.1038/icb.2009.10.
^ ^a ^b ^c ^d Lash, G.E.; Robson, S.C.; Bulmer, J.N. (2010). "Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua". Placenta 31 (S): 87–92. doi:10.1016/j.placenta.2009.12.022. PMID 20061017.
^ Bulmer, Judith N.; Williams, Paula J.; Lash, Gendie E. (2010). "Immune cells in the placental bed". Int J Dev Biol 54 (2–3): 281–294. doi:10.1387/ijdb.082763jb. PMID 19876837.
^ Kopcow, Hernan D. et al. (2005). "Human decidual NK cells form immature activating synapses and are not cytotoxic". Proc Natl Acad Sci USA 102 (43): 15563–15568. doi:10.1073/pnas.0507835102. PMC 1266146. PMID 16230631.
^ Seshadri, S.; Sunkara, S. K. (2013). "Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis". Human Reproduction Update 20 (3): 429–438. doi:10.1093/humupd/dmt056. ISSN 1355-4786. PMID 24285824.
^ Ashkar, Ali A.; James P. Di Santo; B. Anne Croy (2000-07-17). "Interferon γ Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy". The Journal of Experimental Medicine 192 (2): 259–270. doi:10.1084/jem.192.2.259. ISSN 0022-1007. PMC 2193246. PMID 10899912. Retrieved 2014-11-04.
^ O'Leary, J.,G., Goodarzi, M., Drayton, D.,L. & von Andrian, U.,H.; Goodarzi; Drayton; von Andrian (2006). "'T cell-and B cell-independent adaptive immunity mediated by natural killer cells'". Nature Immunology 7 (5): 507–516. doi:10.1038/ni1332.
^ Oldham R (1983). "Natural killer cells: Artifact to reality: An odyssey in biology". Cancer Metastasis Reviews 2 (4): 323–36. doi:10.1007/BF00048565. PMID 6375859.
^ Kiessling R., Klein E., Pross H., Wigzell H.; Klein; Pross; Wigzell (1975). "Natural" killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell". Eur. J. Immunol 5 (2): 117–121. doi:10.1002/eji.1830050209. PMID 1086218.
^ Pross HF, Jondal M; Jondal (August 1975). "Cytotoxic lymphocytes from normal donors. A functional marker of human non-T lymphocytes". Clin. Exp. Immunol. 21 (2): 226–35. PMC 1538269. PMID 810282.
^ Jondal M, Pross H; Pross (April 1975). "Surface markers on human b and t lymphocytes. VI. Cytotoxicity against cell lines as a functional marker for lymphocyte subpopulations". Int. J. Cancer 15 (4): 596–605. doi:10.1002/ijc.2910150409. PMID 806545.
^ Herberman RB, Nunn ME, Holden HT, Lavrin DH; Nunn; Holden; Lavrin (August 1975). "Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells". Int. J. Cancer 16 (2): 230–9. doi:10.1002/ijc.2910160205. PMID 1080480.
^ West, WH; Cannon, GB; Kay, HD; Bonnard, GD; Herberman, RB (January 1977). "Natural cytotoxic reactivity of human lymphocytes against a myeloid cell line: characterization of effector cells.". Journal of immunology (Baltimore, Md. : 1950) 118 (1): 355–61. PMID 299761.
^ Pross HF, Baines MG, Rubin P, Shragge P, Patterson MS; Baines; Rubin; Shragge; Patterson (January 1981). "Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity". J. Clin. Immunol. 1 (1): 51–63. doi:10.1007/BF00915477. PMID 7334070.
^ Timonen T, Saksela E; Saksela (1980). "Isolation of human NK cells by density gradient centrifugation". J. Immunol. Methods 36 (3–4): 285–91. doi:10.1016/0022-1759(80)90133-7. PMID 7430655.
^ Gong J, Maki G, Klingemann H. Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells" Leukemia 1994; 8: 652-58
^ Arai S, Meagher R, Swearingen M, et al. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 2008;10:625-32
^ Tonn T, Becker S, Esser R, Schwabe D, Seifried E. Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92. J Hematother Stem Cell Res 2001;10:535-44.
^ ^a ^b Alter, Galit; Heckerman, David; Schneidewind, Arne; Fadda, Lena; Kadie, Carl M.; Carlson, Jonathan M.; Oniangue-Ndza, Cesar; Martin, Maureen; Li, Bin; Khakoo, Salim I.; Carrington, Mary; Allen, Todd M.; Altfeld, Marcus (August 4, 2011). "HIV-1 adaptation to NK-cell-mediated immune pressure". Nature 476 (7358): 96–100. doi:10.1038/nature10237. PMID 21814282.

External links

Video of natural killer cell
CopeWithCytoKines Portal to definitions of NK-Cells and closely related topics
http://www.hfea.gov.uk/fertility-treatment-options-reproductive-immunology.html Reproductive immunology and fertility treatment
http://www.cambridgenetwork.co.uk/news/article/default.aspx?objid=58465
Binns C (June 19, 2006), Natural Body Guards: How Your Killer Cells Get Motivated. Livescience.com. Retrieved on 2007-10-20.
Natural Killer Cells at the US National Library of Medicine Medical Subject Headings (MeSH)
Nkcells.info - MediaWiki based information platform specializing on natural killer cells
Large granular lymphocyte entry in the public domain NCI Dictionary of Cancer Terms

UpToDate Contents

全文を閲覧するには購読必要です。 To read the full text you will need to subscribe.

1. 大顆粒T細胞リンパ球性白血病の臨床症状、病理学的特徴、および診断 clinical manifestations pathologic features and diagnosis of t cell large granular lymphocyte leukemia
2. 大顆粒リンパ球性白血病の治療 treatment of large granular lymphocyte leukemia
3. ナチュラルキラー（NK）細胞大顆粒リンパ球性白血病 natural killer nk cell large granular lymphocyte leukemia
4. 関節リウマチにおける大顆粒リンパ球性白血病 large granular lymphocyte leukemia in rheumatoid arthritis
5. リンパ球増加症またはリンパ球減少症を有する患者へのアプローチ approach to the patient with lymphocytosis or lymphocytopenia

English Journal

Dasatinib, large granular lymphocytosis, and pleural effusion: Useful or adverse effect?

Paydas S.Author information Cukurova University, Faculty of Medicine, Department of Oncology, Adana, Turkey. Electronic address: sepay@cu.edu.tr.AbstractDasatinib is a second generation tyrosine kinase inhibitor approved for clinical use in first line and imatinib-resistant chronic myeloid leukemia and Philadelphia positive (Ph+) acute lymphoblastic leukemia. In addition to BCR-ABL1, dasatinib inhibits TEC kinases and SRC family kinases and is more potent than imatinib in the treatment of Ph+ leukemias. In the last 3 years, increases in cytotoxic T and natural-killer cells in peripheral blood samples have been reported in cases treated by dasatinib. The awareness of the clonal expansion of large granular lymphocytes and beneficial effect of these clonal cells increased the interest to dasatinib in cases receiving this drug. Clonal expansion of large granular lymphocytes is an important effect of dasatinib therapy, shown to be an off-target phenomenon associated with pleural effusion and better clinical response. The benefit of dasatinib-induced lymphocytosis and its underlying mechanism of this are important points for clinicians working in hematology and oncology.
Critical reviews in oncology/hematology.Crit Rev Oncol Hematol.2014 Feb;89(2):242-7. doi: 10.1016/j.critrevonc.2013.10.005. Epub 2013 Oct 12.
Dasatinib is a second generation tyrosine kinase inhibitor approved for clinical use in first line and imatinib-resistant chronic myeloid leukemia and Philadelphia positive (Ph+) acute lymphoblastic leukemia. In addition to BCR-ABL1, dasatinib inhibits TEC kinases and SRC family kinases and is more
PMID 24210599

Lack of common TCRA and TCRB clonotypes in CD8(+)/TCRαβ(+) T-cell large granular lymphocyte leukemia: a review on the role of antigenic selection in the immunopathogenesis of CD8(+) T-LGL.

Sandberg Y1, Kallemeijn MJ1, Dik WA1, Tielemans D1, Wolvers-Tettero IL1, van Gastel-Mol EJ1, Szczepanski T2, Pol Y1, Darzentas N3, van Dongen JJ1, Langerak AW1.Author information 1Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands.21] Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands [2] Department of Pediatric Hematology and Oncology, Medical University of Silesia, Zabrze, Poland.3Institute of Agrobiotechnology, Center for Research and Technology Hellas, Thessaloniki, Greece.AbstractClonal CD8(+)/T-cell receptor (TCR)αβ(+) T-cell large granular lymphocyte (T-LGL) proliferations constitute the most common subtype of T-LGL leukemia. Although the etiology of T-LGL leukemia is largely unknown, it has been hypothesized that chronic antigenic stimulation contributes to the pathogenesis of this disorder. In the present study, we explored the association between expanded TCR-Vβ and TCR-Vα clonotypes in a cohort of 26 CD8(+)/TCRαβ(+) T-LGL leukemia patients, in conjunction with the HLA-ABC genotype, to find indications for common antigenic stimuli. In addition, we applied purpose-built sophisticated computational tools for an in-depth evaluation of clustering of TCRβ (TCRB) complementarity determining region 3 (CDR3) amino-acid LGL clonotypes. We observed a lack of clear TCRA and TCRB CDR3 homology in CD8(+)/TCRαβ(+) T-LGL, with only low level similarity between small numbers of cases. This is in strong contrast to the homology that is seen in CD4(+)/TCRαβ(+) T-LGL and TCRγδ(+) T-LGL and thus underlines the idea that the LGL types have different etiopathogenesis. The heterogeneity of clonal CD8(+)/TCRαβ(+) T-LGL proliferations might in fact suggest that multiple pathogens or autoantigens are involved.
Blood cancer journal.Blood Cancer J.2014 Jan 10;4:e172. doi: 10.1038/bcj.2013.70.
Clonal CD8(+)/T-cell receptor (TCR)αβ(+) T-cell large granular lymphocyte (T-LGL) proliferations constitute the most common subtype of T-LGL leukemia. Although the etiology of T-LGL leukemia is largely unknown, it has been hypothesized that chronic antigenic stimulation contributes to the pathogen
PMID 24413066

Large granular lymphocytosis during dasatinib therapy.

Qiu ZY, Li J, Xu W.Author information Department of Hematology; the First Affiliated Hospital of Nanjing Medical University; Jiangsu Province Hospital; Nanjing, China.AbstractDasatinib is a second generation tyrosine kinase inhibitor (TKI) approved for clinical use in patients with imatinib-resistant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Large granular lymphocytes (LGLs) are medium to large cells with eccentric nuclei and abundant cytoplasm with coarse azurophilic granules. LGL lymphocytosis is caused by a proliferation of cytotoxic (CD8+) T cells and/or NK cells. In a proportion of CML and Ph+ ALL patients, there is a significant expansion of LGLs during dasatinib therapy. LGL lymphocytosis is seen in some cases with fevers, colitis, and pleural effusions (PE), suggesting an aberrant immune response mediated by these LGLs. LGLs may participate in the elimination of the residual leukemic cells, and LGL clonal expansion is associated with excellent, long-lasting therapy responses in dasatinib-treated patients. For a more comprehensive analysis, we analyzed the morphologic, phenotypic, clinical, and functional features of the LGL subsets amplified in vivo during dasatinib therapy.
Cancer biology & therapy.Cancer Biol Ther.2013 Dec 18;15(3). [Epub ahead of print]
Dasatinib is a second generation tyrosine kinase inhibitor (TKI) approved for clinical use in patients with imatinib-resistant chronic myeloid leukemia (CML) and Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). Large granular lymphocytes (LGLs) are medium to large cells with
PMID 24352048

Japanese Journal

大顆粒リンパ球白血病 (large granular lymphocyte leukemia) 合併赤芽球癆の病態と治療

藤島直仁
臨床血液 51(8), 589-596, 2010-08-30
NAID 10026630026

Systemic T Cell Large Granular Lymphocyte Lymphoma with Multifocal White Matter Degeneration in the Brain of a Japanese Domestic Cat

TSUBOI Masaya,UCHIDA Kazuyuki,PARK Eun Sil,KOTERA Yukiko,SEKI Takahiro,TAKAHASHI Masashi,NAKAYAMA Hiroyuki
Journal of Veterinary Medical Science advpub(0), 1001220141, 2010
… On cytology, many neoplastic lymphocytic cells had fine to large cytoplasmic granules, suggesting large granular lymphocyte (LGL) lymphoma. …
NAID 130000168017

Related Pictures

★リンクテーブル★

リンク元	「大顆粒リンパ球」「LGL」
拡張検索	「large granular lymphocytes」
関連記事	「large」「granular」「lymphocyte」

「大顆粒リンパ球」

　　[★]

英: large granular lymphocyte, LGL

[show details]

大型顆粒リンパ球 : 約 5,440 件
大顆粒リンパ球 : 約 22,600 件

「LGL」

　　[★] 大顆粒リンパ球 large granular lymphocyte

「large granular lymphocytes」

　　[★] 大顆粒リンパ球 LGL

「large」

　　[★]

adj.

(比較級larger-最上級largest)大きい、大型の

関: great、massive、sizable

「granular」

　　[★]

adj.

顆粒状の、顆粒の、粒状の

関: granule、particulate

「lymphocyte」

　　[★] リンパ球

同: lymphocytes＆development

[Vivier2011-1] Vivier, E., Raulet, D.H., Moretta, A., Caligiuri, M.A., Zitvogel, L., Lanier, L.L., Yokoyama, W.M. & Ugolini, S.; Raulet; Moretta; Caligiuri; Zitvogel; Lanier; Yokoyama; Ugolini (2011). "Innate or Adaptive Immunity? The Example of Natural Killer Cells". Science 331 (6013): 44–49. doi:10.1126/science.1198687.

[Roitt-2] Roitt I, Brostoff J, Male D (2001). Immunology (6th ed.), 480p. St. Louis: Mosby, ISBN 0-7234-3189-2.

[Lannello2008-3] Iannello, A., Debbeche, O., Samarani, S., Ahmad, A; Debbeche; Samarani; Ahmad (2008). "'Antiviral NK cell responses in HIV infection: I. NK cell receptor genes as determinants of HIV resistance and progression to AIDS'". Journal of Leukocyte Biology 84: 1–26. doi:10.1189/jlb.0907650.

[Arina2007-4] Arina, A., Murillo, O., Dubrot, J., Azpilikueta, A., Alfaro, C., PÃrez-Gracia, J.,L., Bendandi, M., Palencia, B., HervÃ¡s-Stubbs, S. & Melero, I.; Murillo; Dubrot; Azpilikueta; Alfaro; Pérez-Gracia; Bendandi; Palencia; Hervás-Stubbs; Melero (2007). "'Cellular liaisons of natural killer lymphocytes in immunology and immunotherapy of cancer'". Expert Opinion on Biological Therapy 5 (5): 599–615. doi:10.1517/14712598.7.5.599.

[Terunuma2008-5] Terunuma, H., Deng, X., Dewan, Z., Fujimoto, S., Yamamoto, N.; Deng; Dewan; Fujimoto; Yamamoto (2008). "Potential role of NK cells in the induction of immune responses: implications for NK cell-based immunotherapy for cancers and viral infections". International Reviews of Immunology 27 (3): 93–110. doi:10.1080/08830180801911743. PMID 18437601.

[Smyth2002-6] Smyth, M.J., Hayakawa, Y., Takeda, K., Yagita.; Pickett (2002). "New aspects of natural-killer-cell surveillance and therapy of cancer". Nature Reviews Genetics 2 (11): 850–852. doi:10.1038/nrg928.

[Lodoen-7] Lodoen, M.,B. & Lanier, L.,L.; Lanier (2005). "Viral modulation of NK cell immunity". Nature Reviews Microbiology 3: 59–69. doi:10.1038/nrmicro1066.

[8] Rölle, Alexander (September 2013). "Memory of infections: an emerging role for natural killer cells". PLoS Pathogens 9 (9): e1003548. doi:10.1371/journal.ppat.1003548. PMID 24086127.

[9] Pyzik, M. & Vidal, S.,M.; Vidal (2009). "'NK cells stroll down the memory lane'". Immunology and Cell Biology 87 (4): 261–263. doi:10.1038/icb.2009.10.

[pmid20061017-10] Lash, G.E.; Robson, S.C.; Bulmer, J.N. (2010). "Review: Functional role of uterine natural killer (uNK) cells in human early pregnancy decidua". Placenta 31 (S): 87–92. doi:10.1016/j.placenta.2009.12.022. PMID 20061017.

[pmid19876837-11] Bulmer, Judith N.; Williams, Paula J.; Lash, Gendie E. (2010). "Immune cells in the placental bed". Int J Dev Biol 54 (2–3): 281–294. doi:10.1387/ijdb.082763jb. PMID 19876837.

[PMCid1266146-12] Kopcow, Hernan D. et al. (2005). "Human decidual NK cells form immature activating synapses and are not cytotoxic". Proc Natl Acad Sci USA 102 (43): 15563–15568. doi:10.1073/pnas.0507835102. PMC 1266146. PMID 16230631.

[SeshadriSunkara2013-13] Seshadri, S.; Sunkara, S. K. (2013). "Natural killer cells in female infertility and recurrent miscarriage: a systematic review and meta-analysis". Human Reproduction Update 20 (3): 429–438. doi:10.1093/humupd/dmt056. ISSN 1355-4786. PMID 24285824.

[14] Ashkar, Ali A.; James P. Di Santo; B. Anne Croy (2000-07-17). "Interferon γ Contributes to Initiation of Uterine Vascular Modification, Decidual Integrity, and Uterine Natural Killer Cell Maturation during Normal Murine Pregnancy". The Journal of Experimental Medicine 192 (2): 259–270. doi:10.1084/jem.192.2.259. ISSN 0022-1007. PMC 2193246. PMID 10899912. Retrieved 2014-11-04.

[15] O'Leary, J.,G., Goodarzi, M., Drayton, D.,L. & von Andrian, U.,H.; Goodarzi; Drayton; von Andrian (2006). "'T cell-and B cell-independent adaptive immunity mediated by natural killer cells'". Nature Immunology 7 (5): 507–516. doi:10.1038/ni1332.

[16] Oldham R (1983). "Natural killer cells: Artifact to reality: An odyssey in biology". Cancer Metastasis Reviews 2 (4): 323–36. doi:10.1007/BF00048565. PMID 6375859.

[17] Kiessling R., Klein E., Pross H., Wigzell H.; Klein; Pross; Wigzell (1975). "Natural" killer cells in the mouse. II. Cytotoxic cells with specificity for mouse Moloney leukemia cells. Characteristics of the killer cell". Eur. J. Immunol 5 (2): 117–121. doi:10.1002/eji.1830050209. PMID 1086218.

[18] Pross HF, Jondal M; Jondal (August 1975). "Cytotoxic lymphocytes from normal donors. A functional marker of human non-T lymphocytes". Clin. Exp. Immunol. 21 (2): 226–35. PMC 1538269. PMID 810282.

[19] Jondal M, Pross H; Pross (April 1975). "Surface markers on human b and t lymphocytes. VI. Cytotoxicity against cell lines as a functional marker for lymphocyte subpopulations". Int. J. Cancer 15 (4): 596–605. doi:10.1002/ijc.2910150409. PMID 806545.

[20] Herberman RB, Nunn ME, Holden HT, Lavrin DH; Nunn; Holden; Lavrin (August 1975). "Natural cytotoxic reactivity of mouse lymphoid cells against syngeneic and allogeneic tumors. II. Characterization of effector cells". Int. J. Cancer 16 (2): 230–9. doi:10.1002/ijc.2910160205. PMID 1080480.

[21] West, WH; Cannon, GB; Kay, HD; Bonnard, GD; Herberman, RB (January 1977). "Natural cytotoxic reactivity of human lymphocytes against a myeloid cell line: characterization of effector cells.". Journal of immunology (Baltimore, Md. : 1950) 118 (1): 355–61. PMID 299761.

[22] Pross HF, Baines MG, Rubin P, Shragge P, Patterson MS; Baines; Rubin; Shragge; Patterson (January 1981). "Spontaneous human lymphocyte-mediated cytotoxicity against tumor target cells. IX. The quantitation of natural killer cell activity". J. Clin. Immunol. 1 (1): 51–63. doi:10.1007/BF00915477. PMID 7334070.

[23] Timonen T, Saksela E; Saksela (1980). "Isolation of human NK cells by density gradient centrifugation". J. Immunol. Methods 36 (3–4): 285–91. doi:10.1016/0022-1759(80)90133-7. PMID 7430655.

[24] Gong J, Maki G, Klingemann H. Characterization of a human cell line (NK-92) with phenotypical and functional characteristics of activated natural killer cells" Leukemia 1994; 8: 652-58

[25] Arai S, Meagher R, Swearingen M, et al. Infusion of the allogeneic cell line NK-92 in patients with advanced renal cell cancer or melanoma: a phase I trial. Cytotherapy 2008;10:625-32

[26] Tonn T, Becker S, Esser R, Schwabe D, Seifried E. Cellular immunotherapy of malignancies using the clonal natural killer cell line NK-92. J Hematother Stem Cell Res 2001;10:535-44.

[Alter_et_al.-27] Alter, Galit; Heckerman, David; Schneidewind, Arne; Fadda, Lena; Kadie, Carl M.; Carlson, Jonathan M.; Oniangue-Ndza, Cesar; Martin, Maureen; Li, Bin; Khakoo, Salim I.; Carrington, Mary; Allen, Todd M.; Altfeld, Marcus (August 4, 2011). "HIV-1 adaptation to NK-cell-mediated immune pressure". Nature 476 (7358): 96–100. doi:10.1038/nature10237. PMID 21814282.

匿名

検索

案内

large granular lymphocyte