BACKGROUND: The mammalian Leukocyte Receptor Complex (LRC) chromosomal region may contain gene families for the killer cell immunoglobulin-like receptor (KIR) and/or leukocyte immunoglobulin-like receptor (LILR) collections as well as various framing genes. This complex region is well described in humans, mice, and some domestic animals. Although single KIR genes are known in some Carnivora, their complements of LILR genes remain largely unknown due to obstacles in the assembly of regions of high homology in short-read based genomes. METHODS: As part of the analysis of felid immunogenomes, this study focuses on the search for LRC genes in reference genomes and the annotation of LILR genes in Felidae. Chromosome-level genomes based on single-molecule long-read sequencing were preferentially sought and compared to representatives of the Carnivora. RESULTS: Seven putatively functional LILR genes were found across the Felidae and in the Californian sea lion, four to five genes in Canidae, and four to nine genes in Mustelidae. They form two lineages, as seen in the Bovidae. The ratio of functional genes for activating LILRs to inhibitory LILRs is slightly in favor of inhibitory genes in the Felidae and the Canidae; the reverse is seen in the Californian sea lion. This ratio is even in all of the Mustelidae except the Eurasian otter, which has a predominance of activating LILRs. Various numbers of LILR pseudogenes were identified. CONCLUSIONS: The structure of the LRC is rather conservative in felids and the other Carnivora studied. The LILR sub-region is conserved within the Felidae and has slight differences in the Canidae, but it has taken various evolutionary paths in the Mustelidae. Overall, the process of pseudogenization of LILR genes seems to be more frequent for activating receptors. Phylogenetic analysis found no direct orthologues across the Carnivora which corroborate the rapid evolution of LILRs seen in mammals.
- MeSH
- Canidae * MeSH
- Carnivora * genetika MeSH
- Felidae * MeSH
- fylogeneze MeSH
- genomika MeSH
- lachtani * MeSH
- leukocyty MeSH
- lidé MeSH
- Mustelidae * MeSH
- myši MeSH
- receptory imunologické genetika MeSH
- receptory KIR genetika MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
NK buňky hrají u alogenní transplantace kostní dřeně významnou roli, nejen při eradikaci zbývajících nádorových buněk, ale ovlivňují i rozvoj reakce štěpu proti hostiteli. Je tedy třeba porozumět jejich regulaci a tomu, jakým způsobem může reakce imunitního systému pacienta NK buňky dárce ovlivňovat. Inhibice a aktivace NK buněk je řízena celou řadou receptorů, které reagují na široké spektrum ligandů. Ať už inhibičních, které signalizují NK buňkám, že je cílová buňka v pořádku nebo aktivačních, které vyjadřují nějaké poškození cílové buňky. Mezi nejprozkoumanější receptory patří KIR a dále NKG2D se svými ligandy MICA a MICB. Přehledu jejich role v transplantaci kostní dřeně se věnuje tato práce.
NK cells play an important role in allogeneic stem cell transplantation; not only as effector cells in the eradication of remaining cancer cells but also as potential inducers of graft versus host disease. Hence, it is important to understand their regulation and how the patient’s immune system affects donor NK cells. NK cell inhibition or activation is directed by many receptors which interact with a broad spectrum of ligands. Inhibition ligands signal that the target cell is healthy, and activating ligands reflect that the cell is damaged. The most investigated receptors are KIR together with the NKG2D receptor with its ligands MICA and MICB. This work describes their role in stem cell transplantation.
- MeSH
- akutní myeloidní leukemie * imunologie terapie MeSH
- haplotypy genetika MeSH
- HLA antigeny MeSH
- homologní transplantace MeSH
- lektinové receptory NK-buněk - podrodina K analýza genetika MeSH
- lidé MeSH
- ligandy MeSH
- polymorfismus genetický MeSH
- receptory buněk NK * imunologie klasifikace MeSH
- receptory KIR analýza genetika MeSH
- transplantace kostní dřeně MeSH
- transplantační imunologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
BACKGROUND: Hepatitis B virus (HBV) infection is one of the most common infections worldwide, having negative impact on world health due to the tendency for chronification with late complications such as liver cirrhosis and hepatocellular carcinoma. Natural killer (NK) cells as part of innate antiviral defense influence the clinical course of HBV infection: elimination of the virus or chronic disease. AIM: Therefore, we investigated the polymorphisms of the main gene systems, regulating NK-cell function: killer cell immunoglobulin-like receptors (KIRs) and their appropriate HLA class I ligands in 144 HBV infected patients (124 chronic carriers and 20 spontaneously recoved) and 126 ethnically matched healthy controls from the Bulgarian population in a case-control study. METHODS: KIRs and HLA ligands were determined by PCR-SSP or PCR high-resolution typing methods. RESULTS: KIR2DL5B allele variant was significantly less frequent in spontaneously recovered (SR) patients compared to healthy controls (10.0% vs. 45.5%, Pcorr=0.006). The presence of KIR3DL1*004 allele was higher in chronic HBV carriers (CH) than in controls (33.1% vs. 17.6%, Pcorr=0.036). Additionally, SR patients differed from healthy individuals by the lower frequency of HLA-Bw4Ile80 group ligands (30.0% vs 63.7%, P=0.015). Three KIR genotypes were found more frequent in healthy in comparison with HBV infected individuals: ID2 (13.5% vs 5.6%, P=0.025), KIR genotype containing 6 activating KIRs (18.0% vs 7.6%, P=0.017), and KIR genotype composed of 4 activating and 5 inhibitory KIRs (23.8% vs 5.6%, P=0.001). CONCLUSION: These data suggest that inherited KIR and HLA class I ligand polymorphisms may influence the clinical course of HBV infection.
Předmětem naší práce je analýza vlivu imunologických parametrů s cílem optimalizace rutinního výběru nepříbuzných dárců krvetvorných buněk. Základním požadavkem úspěšnosti transplantace je shoda mezi dárcem a příjemcem v HLA systému I. a II. třídy. Využití genetických metod pro určení shody v HLA I. třídy znamenalo v našem souboru zlepšení přežití transplantovaných pacientů. Další zpřesnění genetických metod ale již žádné významné zlepšení nepřineslo. U souboru 240 dárců byla sledována míra shody v HLA-DPB1, pouze 8,2 % z nich bylo shodných se svými pacienty. Dalších 114 dárců mělo neshody tolerovatelné dle klinického prognostického modelu DPB1 T-Cell Epitope Algorithm. Netolerovatelné neshody byly detekovány u 37 % dárců. KIR genotyp, který ovlivňuje potransplantační průběh především u pacientů s akutní myeloidní leukemií (AML), byl testován u 347 dárců, 70 % bylo zařazeno do kategorie „neutrální“, 19,3 % bylo v kategorii „lepší“ a 10, 7 % v kategorii „nejlepší“ dle Donor KIR B-content group calculator. Zastoupení jednotlivých kategorií se nelišilo mezi skupinou neselektovaných dárců a dárců vybraných pro transplantaci pro pacienty s AML. Do rutinního výběru dárců bylo zařazeno vyhledání dle tolerovatelnosti neshod v HLA-DPB1, kategorie KIR jsou pouze doplňkovým parametrem aktuálního algoritmu výběru dárců.
The aim of our work was to analyse the influence of immunological parameters in order to optimize routine selection of unrelated stem cell donors. Match in HLA class I and II between the donor and the recipient is the essential requirement for success of the transplantation. The use of genetic methods for match determination in HLA class I improved survival of transplanted patients in our cohort. Further refinement of genetic methods has not resulted in any significant improvement. In a group of 240 donors, the match rate in HLA-DPB1 was monitored, only 8.2% were comletely matched with their patients. Another 114 donors had mismatches tolerable in the DPB1 T-Cell Epitope Algorithm clinical prognostic model. Intolerable mismatches were detected in 37% of donors. The KIR genotype, which affects the post-transplantation course especially in patients with acute myeloid leukemia (AML), was tested in 347 donors, 70% were classified as “neutral”, 19.3% were in “better” and 10.7% in “best” category by Donor KIR B-content group calculator. The representation of individual categories did not differ between the group of non-selected donors and donors selected for transplantation for patients with AML. Routine selection of donors included a search according to the tolerability of mismatches in HLA-DPB1, KIR categories are only a supplementary parameter of the current donor selection algorithm.
- MeSH
- HLA antigeny genetika imunologie MeSH
- lidé MeSH
- nepříbuzný dárce MeSH
- prospektivní studie MeSH
- receptory KIR genetika imunologie MeSH
- retrospektivní studie MeSH
- transplantace hematopoetických kmenových buněk * MeSH
- výběr dárců * MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
Relapsed acute myeloid leukemia (AML) is a significant post-transplant complication lacking standard treatment and associated with a poor prognosis. Cellular therapy, which is already widely used as a treatment for several hematological malignancies, could be a potential treatment alternative. Natural killer (NK) cells play an important role in relapse control but can be inhibited by the leukemia cells highly positive for HLA class I. In order to restore NK cell activity after their ex vivo activation, NK cells can be combined with conditioning target cells. In this study, we tested NK cell activity against KG1a (AML cell line) with and without two types of pretreatment-Ara-C treatment that induced NKG2D ligands (increased activating signal) and/or blocking of HLA-KIR (killer-immunoglobulin-like receptors) interaction (decreased inhibitory signal). Both treatments improved NK cell killing activity. Compared with target cell killing of NK cells alone (38%), co-culture with Ara-C treated KG1a target cells increased the killing to 80%. Anti-HLA blocking antibody treatment increased the proportion of dead KG1a cells to 53%. Interestingly, the use of the combination treatment improved the killing potential to led to the death of 85% of KG1a cells. The combination of Ara-C and ex vivo activation of NK cells has the potential to be a feasible approach to treat relapsed AML after hematopoietic stem cell transplantation.
- MeSH
- akutní myeloidní leukemie imunologie terapie MeSH
- buňky NK účinky léků imunologie transplantace MeSH
- cytarabin farmakologie MeSH
- imunosupresiva farmakologie MeSH
- imunoterapie metody MeSH
- klinické zkoušky jako téma MeSH
- kultivované buňky MeSH
- lektinové receptory NK-buněk - podrodina K imunologie MeSH
- lidé MeSH
- nádorové buněčné linie MeSH
- receptory KIR imunologie MeSH
- signální transdukce MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Imunoterapie představuje perspektivní léčebnou modalitu, která se rychle etablovala u léčbě celé řady malignit. Předpoklad jejího účinku u nádorů hlavy a krku vyplývá z vysoké mutační nálože těchto nádorů. Klinické studie fáze I byly v souladu s těmito preklinickými předpoklady a studie fáze II a III, které následovaly, potvrdily efektivitu nivolumabu ve druhé paliativní linii a v případě pembrolizumabu i v první linii léčby recidivujících a metastatických nádorů hlavy a krku, kde prokázaly superioritu nad současnými standardy léčby. V tuto chvíli bohužel ani jedna molekula i přes probíhající registrace nemá úhradu z veřejného zdravotního pojištění v této indikaci.
Immunotherapy represents a perspective treatment modality which has quickly established its position in several tumor types. Due to the high mutation burden of head and neck tumors there was an assumption of immunotherapy efficacy. The phase I clinical trials were in line with these preclinical assumptions and phase II and III trials have confirmed the effectivity of nivolumab in second palliative lines and in the case of pemrolizumab as weel as in the first palliative line of recurrent and methastatic head and neck cancer where they have showed superiority over current treatment standards. Unfortunatelly, at this moment despite ongoing registrations in this indication the insurance reimbursement is lacking so far.
- Klíčová slova
- lirilumab, pembrolizumab, durvalumab, studie KEYNOTE,
- MeSH
- antigen CTLA-4 antagonisté a inhibitory MeSH
- antigeny CD274 antagonisté a inhibitory MeSH
- antitumorózní látky terapeutické užití MeSH
- cetuximab terapeutické užití MeSH
- imunoterapie metody MeSH
- ipilimumab terapeutické užití MeSH
- lidé MeSH
- monoklonální protilátky terapeutické užití MeSH
- nádory hlavy a krku * farmakoterapie imunologie MeSH
- nivolumab terapeutické užití MeSH
- protokoly antitumorózní kombinované chemoterapie MeSH
- receptory KIR antagonisté a inhibitory MeSH
- toll-like receptor 8 antagonisté a inhibitory MeSH
- Check Tag
- lidé MeSH
BACKGROUND: The selection of optimal donor is crucial for successful hematopoietic stem cell transplantation (HSCT). Thereby, it is appropriate to know, in addition to basic human leukocyte antigen (HLA) gene matches, other immunogenic or nonimmunogenic parameters predicting the outcome of transplant. OBJECTIVE: A unified approach is necessary to provide a comprehensive view of the patient-donor compatibility characterization outside of standard HLA genes. The approach should be applicable as a tool for optimizing procedures for extended donor typing and/or verification typing of a donor. METHODS: The study used the summary, unification, and innovation of existing practical knowledge and experience of the Czech National Marrow Donor Registry of various factors beyond HLA matching with impact on transplant outcome. RESULTS: An information technology system-implemented procedure (a verification algorithm) is presented as the decision support approach for prematurely discarding less suitable donors from the transplantation process. It is intended primarily for the transplant specialist to help establish optimal procedures for verifying and determining donor critical factors. CONCLUSIONS: A process defining HLAs, killer cell immunoglobulin-like receptors, and cytokine typing strategies was proposed to provide support to a transplant specialist in refining the choice of a suitable donor.
- MeSH
- algoritmy * MeSH
- HLA antigeny imunologie MeSH
- lidé MeSH
- receptory KIR imunologie MeSH
- registrace MeSH
- systémy pro podporu klinického rozhodování * MeSH
- testování histokompatibility metody MeSH
- transplantace hematopoetických kmenových buněk metody MeSH
- výběr dárců metody MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Československo MeSH
GABAB receptors are the G-protein coupled receptors for the main inhibitory neurotransmitter in the brain, GABA. GABAB receptors were shown to associate with homo-oligomers of auxiliary KCTD8, KCTD12, KCTD12b, and KCTD16 subunits (named after their T1 K(+)-channel tetramerization domain) that regulate G-protein signaling of the receptor. Here we provide evidence that GABAB receptors also associate with hetero-oligomers of KCTD subunits. Coimmunoprecipitation experiments indicate that two-thirds of the KCTD16 proteins in the hippocampus of adult mice associate with KCTD12. We show that the KCTD proteins hetero-oligomerize through self-interacting T1 and H1 homology domains. Bioluminescence resonance energy transfer measurements in live cells reveal that KCTD12/KCTD16 hetero-oligomers associate with both the receptor and the G-protein. Electrophysiological experiments demonstrate that KCTD12/KCTD16 hetero-oligomers impart unique kinetic properties on G-protein-activated Kir3 currents. During prolonged receptor activation (one min) KCTD12/KCTD16 hetero-oligomers produce moderately desensitizing fast deactivating K(+) currents, whereas KCTD12 and KCTD16 homo-oligomers produce strongly desensitizing fast deactivating currents and nondesensitizing slowly deactivating currents, respectively. During short activation (2 s) KCTD12/KCTD16 hetero-oligomers produce nondesensitizing slowly deactivating currents. Electrophysiological recordings from hippocampal neurons of KCTD knock-out mice are consistent with these findings and indicate that KCTD12/KCTD16 hetero-oligomers increase the duration of slow IPSCs. In summary, our data demonstrate that simultaneous assembly of distinct KCTDs at the receptor increases the molecular and functional repertoire of native GABAB receptors and modulates physiologically induced K(+) current responses in the hippocampus. SIGNIFICANCE STATEMENT: The KCTD proteins 8, 12, and 16 are auxiliary subunits of GABAB receptors that differentially regulate G-protein signaling of the receptor. The KCTD proteins are generally assumed to function as homo-oligomers. Here we show that the KCTD proteins also assemble hetero-oligomers in all possible dual combinations. Experiments in live cells demonstrate that KCTD hetero-oligomers form at least tetramers and that these tetramers directly interact with the receptor and the G-protein. KCTD12/KCTD16 hetero-oligomers impart unique kinetic properties to GABAB receptor-induced Kir3 currents in heterologous cells. KCTD12/KCTD16 hetero-oligomers are abundant in the hippocampus, where they prolong the duration of slow IPSCs in pyramidal cells. Our data therefore support that KCTD hetero-oligomers modulate physiologically induced K(+) current responses in the brain.
- MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- draslíkové kanály genetika metabolismus MeSH
- elektrofyziologické jevy genetika MeSH
- excitační postsynaptické potenciály genetika MeSH
- kinetika MeSH
- křečci praví MeSH
- metoda terčíkového zámku MeSH
- mozek - chemie genetika MeSH
- myši knockoutované MeSH
- myši MeSH
- receptory GABA-B genetika metabolismus MeSH
- receptory KIR metabolismus MeSH
- receptory spřažené s G-proteiny metabolismus MeSH
- zvířata MeSH
- Check Tag
- křečci praví MeSH
- mužské pohlaví MeSH
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
NK cells represent a potential tool for adoptive immunotherapy against tumors. Membrane-bound Hsp70 acts as a tumor-specific marker enhancing NK cell activity. Using flow cytometry the effect of in vitro stimulation with IL-2 or IL-15 alone or in combination with Hsp70-derived 14-mer peptide (TKD) on cell surface expression of NK activatory receptors (CD16, NKG2D, NKG2C, NKp46, NKp44, NKp30, KIR2DL4, DNAM-1, and LAMP1) and NK inhibitory receptors (NKG2A, KIR2DL2/L3, LIR1/ILT-2, and NKR-P1A) in healthy individuals was studied. Results were expressed as the percentage of receptor expressing cells and the amount of receptor expressed by CD3(-)CD56(+) cellular population. CD94, NKG2D, NKp44, NKp30, KIR2DL4, DNAM-1, LAMP1, NKG2A, and NKR-P1A were upregulated after the stimulation with IL-2 or IL-15 alone or in combination with TKD. KIR2DL2/L3 was upregulated only by IL-15 and IL-15/TKD. Concurrently, an increase in a number of NK cells positive for CD94, NKp44, NKp30, KIR2DL4, and LAMP1 was observed. IL-15 and IL-15/TKD caused also cell number rise positive for KIR2DL2/L3 and NKR-P1A. Cell number positive for NKG2C and NKG2A was increased only by IL-2 and IL-2/TKD. The diverse effect of IL-2 or IL-15 w or w/o TKD on cell surface expression was observed in CD16, NKp46, and LIR1/ILT-2.
- MeSH
- buňky NK účinky léků metabolismus MeSH
- diferenciační antigeny T-lymfocytů metabolismus MeSH
- interleukin-15 farmakologie MeSH
- interleukin-2 farmakologie MeSH
- kultivované buňky MeSH
- lektinové receptory NK-buněk - podrodina B metabolismus MeSH
- lektinové receptory NK-buněk - podrodina C metabolismus MeSH
- lektinové receptory NK-buněk - podrodina K metabolismus MeSH
- leukocyty mononukleární účinky léků metabolismus MeSH
- lidé MeSH
- membránové glykoproteiny asociované s lyzozomy metabolismus MeSH
- peptidy chemie farmakologie MeSH
- proteiny tepelného šoku HSP70 chemie MeSH
- receptor 1 spouštějící přirozenou cytotoxicitu metabolismus MeSH
- receptor 2 spouštějící přirozenou cytotoxicitu metabolismus MeSH
- receptor 3 spouštějící přirozenou cytotoxicitu metabolismus MeSH
- receptory IgG metabolismus MeSH
- receptory KIR2DL2 MeSH
- receptory KIR2DL4 metabolismus MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Invariant natural killer T (iNKT) cells play an important role in the immune response against various infectious agents. In this study we investigated their role in human defense against the varicella zoster virus. We observed decreased numbers of iNKT cells in patients who failed to control latent varicella zoster virus infection, e.g. underwent several reactivations of the virus. The residual population of iNKT cells expressed significantly higher levels of inhibitory receptor CD158a that was further up-regulated in the course of acute viral infection. Both of these abnormalities might contribute to impaired control of varicella zoster virus in human.
- MeSH
- aktivace lymfocytů imunologie MeSH
- buňky NK imunologie metabolismus patologie MeSH
- CD antigeny metabolismus MeSH
- cytokiny metabolismus MeSH
- herpes zoster imunologie patologie MeSH
- lektinové receptory NK-buněk - podrodina K metabolismus MeSH
- lidé středního věku MeSH
- lidé MeSH
- NKT buňky imunologie metabolismus patologie MeSH
- počet lymfocytů MeSH
- podskupiny lymfocytů imunologie metabolismus patologie MeSH
- receptory KIR2DL1 metabolismus MeSH
- T-lymfocyty imunologie metabolismus patologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
