Jednou z reakcí na pandemii COVID-19 byl celosvětový nárůst počtu kryokonzervací krvetvorných buněk odebraných nepříbuzným dárcům z registrů, především kvůli horší dostupnosti dárců a problémům s transportem produktů. Ačkoli je kryokonzervace logisticky výhodná, nelze opominout vyšší riziko nevyužití již odebraného štěpu především z důvodu komplikace na straně příjemce. Cílem práce bylo retrospektivně zhodnotit podíl kryokonzervací dárců z Českého národního registru dárců kostní dřeně (ČNRDD) v období před pandemií COVID-19, během a po pandemii COVID-19 a analyzovat nepodané štěpy krvetvorných buněk vč. důvodů jejich nepodání. Primárním cílem bylo zjistit, jak se změnil podíl kryokonzervovaných štěpů odebraných v daných obdobích pro transplantační centra (TC) v ČR a v zahraničí. Z celkového počtu 374 štěpů odebraných v období 2018–2023 bylo kryokonzervováno 72 (19 %). V období před pandemií (2018–2/2020) bylo odebráno 152 štěpů, z toho byly provedeny pouze 2 kryokonzervace (1,3 %), 1 pro TC v ČR a 1 pro zahraniční TC. V období pandemie COVID-19 (3/2020–2022) bylo odebráno celkem 144 štěpů, 58 bylo kryokonzervovaných (40 %), 28 (19 %) pro pacienty z českých TC a 20 (14 %) pro zahraniční. V postpandemickém období (rok 2023) bylo odebráno 78 štěpů, 22 bylo kryokonzervovaných (28 %), 8 (10 %) pro pacienty z českých TC a 14 (18 %) pro nemocné ze zahraničí. Za celé období 2018–2023 nebyly příjemcům podány 3 štěpy (0,8 %), všechny pocházely z období pandemie COVID-19 (1 z roku 2020 a 2 z roku 2022) a byly odebrány pro pacienty ze zahraničních TC. Důvodem nepodání štěpů bylo ve 2 případech úmrtí pacienta a v 1 případě odmítnutí transplantace nemocným. Naše analýza prokazuje pokles podílu kryokonzervovaných štěpů v postpandemickém období pro pacienty z českých TC, zatímco podíl kryokonzervací pro nemocné ze zahraničních TC má nadále mírně vzestupný trend. I přes zjištěné nízké procento nevyužitých štěpů je nutné brát v úvahu negativní etický dopad zničení štěpu z pohledu nepříbuzných dárců krvetvorných buněk.
One of the responses the COVID-19 pandemic has been a worldwide increase the number of cryopreserved hematopoietic cells from unrelated donors, mainly due to poorer availability of donors and problems with product transportation. Although cryopreservation is logistically advantageous, the higher risk of not using graft cannot be ignored. We retrospectively evaluated the cryopreservation of donors from the Czech National Register of Bone Marrow Donors (CNMDR) in the period before, during and after the COVID-19 and analyzed unused grafts, including the reasons. The primary goal was to evaluate how cryopreserved grafts collected in given periods for transplant centers (TC) in the Czech Republic and abroad has changed. Of the total number of 374 grafts collected in the period 2018–2023, 72 (19%) were cryopreserved. In the period before the pandemic (2018–2/2020), 152 grafts collected and only 2 cryopreservations performed (1.3%), 1 for TC in the CR and 1 for foreign. During the period of the COVID-19 pandemic (3/2020–2022), a total of 144 grafts collected, 58 cryopreserved (40%), 28 (19%) for patients from CR and 20 (14%) for forein. In the post-pandemic (year 2023), 78 grafts taken, 22 cryopreserved (28%), 8 (10%) for patients from CR and 14 (18%) for patients from abroad. For period 2018–2023, 3 grafts (0.8%) were not used, all from the period of COVID-19 (1 from 2020 and 2 from 2022) and were collected for patients from foreign TCs. The reason for not-used grafts was in 2 cases death of the patient and 1 patient refused transplant. Our analysis shows a decrease in cryopreserved grafts in the post-pandemic period for patients from CR, while for patients from foreign TCs continues to show a slightly upward trend. Despite the detected low percentage of unused grafts, it is necessary to perceive the negative ethical impact of the destruction of the graft from the point of view of the donors.
- MeSH
- alografty statistika a číselné údaje MeSH
- COVID-19 MeSH
- darování krve statistika a číselné údaje MeSH
- kmenové buňky MeSH
- krevní bankovnictví * metody statistika a číselné údaje MeSH
- kryoprezervace * statistika a číselné údaje MeSH
- lidé MeSH
- nepříbuzný dárce MeSH
- procedury zbytečné metody MeSH
- registrace MeSH
- Check Tag
- lidé MeSH
The guidelines for the implementation and reporting of HLA nomenclature for the World Marrow Donor Association have served as a reliable standard for communication of HLA data in the hematopoietic cell transplantation process. Wider use of next-generation sequencing made a special provision of the guidelines increasingly pertinent: how to communicate novel HLA alleles. Novel alleles need to be recognized by the WHO Nomenclature Committee for Factors of the HLA system to obtain official allele designations. Until then they have to be handled according to the specific rules. Leaving the actual rules basically unchanged we give some advice on how to communicate novel alleles to best facilitate the search process for cases where novel alleles are identified on donor or patient side.
Závěrečná zpráva o řešení grantu Agentury pro zdravotnický výzkum MZ ČR
nestr.
Allogeneic haematopoietic cell transplantation is a standard therapy for severe hematologic malignancies. Despite the improvement of search for optimal donors, frequent complications such as graft-versus-host disease or relapses still occur. The number of potential donors is steadily increasing and it is often possible to choose the best donor from several alternative donors. Many transplant centers have already introduced a selection based on other criteria than the commonly used HLA match. Match/mismatch in other molecules that can affect the outcome of transplantation (e.g. KIR receptors) are being widely investigated. In addition to KIR receptors, it is possible to determine the match/mismatch in other receptors and their ligands. In the Czech Republic, the standard HLA criterion is HLA match and HLA-DPB permissive, and in some diseases the KIR haplotype is determined. The inclusion of secondary or tertiary criterion for choosing the best donor requires knowledge about polymorphisms in key molecules within the Czech population.
Alogenní transplantace hematopoetických buněk je standardní terapií závažných hematologických malignit. I přes zdokonalování vyhledávání vhodných dárců se stále vyskytují časté komplikace jako reakce štěpu proti hostiteli či relaps. Počet dárců v registrech stále stoupá a mnohdy je možné vybírat pro jednoho pacienta z několika alternativních dárců. Mnohá transplantační centra již zavedla výběr na základě dalších kritérií, než je běžně používaná shoda v „klasických“ HLA genech např. permisivitu HLA-DPB neshod. Stále více se vyšetřují i shody/neshody v molekulách, s potenciálem vlivu na výsledek transplantace, jako např. KIR receptory NK buněk. Vedle KIRů je možné stanovit i shodu/neshodu v jiných receptorech a jejich ligandech a tyto údaje mohou být použity při volbě nejlepšího dárce. V ČR je standardním kritériem HLA shoda, případně permisivita HLA-DPB, u myeloidních malignit se určuje genotyp KIR. Začlenění dalšího kritéria vyžaduje představu o míře polymorfizmů v klíčových molekulách v rámci české populace, aby se zvolilo nejlepší sekundární či terciární kritérium pro výběr dárce.
- MeSH
- alografty MeSH
- interakce mezi receptory a ligandy MeSH
- lektinové receptory NK-buněk - podrodina K MeSH
- ligandy MeSH
- polymorfismus genetický MeSH
- receptory buněk NK MeSH
- receptory KIR MeSH
- transplantace hematopoetických kmenových buněk MeSH
- výběr dárců MeSH
- Geografické názvy
- Česká republika MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- transplantologie
- genetika, lékařská genetika
- epidemiologie
- NLK Publikační typ
- závěrečné zprávy o řešení grantu AZV MZ ČR
- Publikační typ
- abstrakt z konference MeSH
NKG2D and its ligands, MICA and MICB, are known as the key regulators of NK cells. NK cells are the first reconstituted cells after the allogeneic hematopoietic stem cell transplantation (HSCT); therefore, it is crucial to understand their role in HSCT outcome. In the presented study, we investigated the single amino acid changes across the exons 2-4 of MICA and MICB genes, and point mutations within the NKG2D gene, which defines the type of NKG2D haploblock (HNK/LNK) in the donors (n = 124), as well as in patients with acute myeloid leukemia (n = 78). In our cohort, we found that graft from a donor with at least one MICA allele containing glycine at position 14 (MICA-14Gly) is significantly associated with deterioration of a patient's overall survival (OS) (p < 0.05). We also observed a negative effect of MICB-58 (Lys → Glu) polymorphism on relapse-free survival (RFS), although it was not statistically significant in multivariate analysis (p = 0.069). To our knowledge, this is the first work describing the role of MICA-14 and MICB-58 polymorphisms on HSCT outcome.
- Publikační typ
- časopisecké články MeSH
Natural killer cells possess key regulatory function in various malignant diseases, including acute myeloid leukemia. NK cell activity is driven by signals received through ligands binding activating or inhibitory receptors. Their activity towards elimination of transformed or virally infected cells can be mediated through MICA, MICB and ULBP ligands binding the activating receptor NKG2D. Given the efficiency of NK cells, potential target cells developed multiple protecting mechanisms to overcome NK cells killing on various levels of biogenesis of NKG2D ligands. Targeted cells can degrade ligand transcripts via microRNAs or modify them at protein level to prevent their presence at cell surface via shedding, with added benefit of shed ligands to desensitize NKG2D receptor and avert the threat of destruction via NK cells. NK cells and their activity are also indispensable during hematopoietic stem cell transplantation, crucial treatment option for patients with malignant disease, including acute myeloid leukemia. Function of both NKG2D and its ligands is strongly affected by polymorphisms and particular allelic variants, as different alleles can play variable roles in ligand-receptor interaction, influencing NK cell function and HSCT outcome differently. For example, role of amino acid exchange at position 129 in MICA or at position 98 in MICB, as well as the role of other polymorphisms leading to different shedding of ligands, was described. Finally, match or mismatch between patient and donor in NKG2D ligands affect HSCT outcome. Having the information beyond standard HLA typing prior HSCT could be instrumental to find the best donor for the patient and to optimize effects of treatment by more precise patient-donor match. Here, we review recent research on the NKG2D/NKG2D ligand biology, their regulation, description of their polymorphisms across the populations of patients with AML and the influence of particular polymorphisms on HSCT outcome.
- MeSH
- akutní myeloidní leukemie genetika imunologie mortalita terapie MeSH
- buňky NK imunologie metabolismus MeSH
- individualizovaná medicína metody MeSH
- jednonukleotidový polymorfismus MeSH
- lektinové receptory NK-buněk - podrodina K genetika metabolismus MeSH
- lidé MeSH
- ligandy MeSH
- lokální recidiva nádoru epidemiologie genetika MeSH
- MHC antigeny I. třídy genetika metabolismus MeSH
- přežití bez známek nemoci MeSH
- transplantace hematopoetických kmenových buněk * MeSH
- výběr dárců metody MeSH
- výsledek terapie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
- Publikační typ
- abstrakt z konference MeSH
Genetic and transcriptional heterogeneity of Chronic lymphocytic leukaemia (CLL) limits prevention of disease progression. Longitudinal single-cell transcriptomics represents the state-of-the-art method to profile the disease heterogeneity at diagnosis and to inform about disease evolution. Here, we apply single-cell RNA-seq to a CLL case, sampled at diagnosis and relapse, that was treated with FCR (Fludarabine, Cyclophosphamide, Rituximab) and underwent a dramatic decrease in CD19 expression during disease progression. Computational analyses revealed a major switch in clones' dominance during treatment. The clone that expanded at relapse showed 17p and 3p chromosomal deletions, and up-regulation of pathways related to motility, cytokine signaling and antigen presentation. Single-cell RNA-seq uniquely revealed that this clone was already present at low frequency at diagnosis, and it displays feature of plasma cell differentiation, consistent with a more aggressive phenotype. This study shows the benefit of single-cell profiling of CLL heterogeneity at diagnosis, to identify clones that might otherwise not be recognized and to determine the best treatment options.
- Publikační typ
- kazuistiky MeSH
Killer-immunoglobulin-like receptors (KIRs) are critical natural killer (NK) cell regulators. The expression of KIRs is a dynamic process influenced by many factors. Their ligands-HLA(Human Leukocyte Antigen) class I molecules-are expressed on all nucleated cells that keep NK cells under control. In hematopoietic stem cell transplantation (HSCT), NK cells play an essential role in relapse protection. In the presented pilot study, we characterized the dynamic expression of inhibitory KIRS (iKIRs), which protect cells against untoward lysis, in donors and patients during the first three months after HSCT using flow cytometry. The expression of all iKIRs was highly variable and sometimes correlated with patients' clinical presentation and therapy regiment. Cyclophosphamide (Cy) in the graft-versus-host disease (GvHD) prevention protocol downregulated KIR2DL1 to just 25% of the original donor value, and the FEAM (Fludarabine + Etoposid + Ara-C + Melphalan) conditioning protocol reduced KIR2DL3. In lymphoid neoplasms, there was a slightly increased KIR2DL3 expression compared to myeloid malignancies. Additionally, we showed that the ex vivo activation of NK cells did not alter the level of iKIRs. Our study shows the influence of pre- and post-transplantation protocols on iKIR expression on the surface of NK cells and the importance of monitoring their cell surface.
- Publikační typ
- časopisecké články MeSH
A catalog of common, intermediate and well-documented (CIWD) HLA-A, -B, -C, -DRB1, -DRB3, -DRB4, -DRB5, -DQB1 and -DPB1 alleles has been compiled from over 8 million individuals using data from 20 unrelated hematopoietic stem cell volunteer donor registries. Individuals are divided into seven geographic/ancestral/ethnic groups and data are summarized for each group and for the total population. P (two-field) and G group assignments are divided into one of four frequency categories: common (≥1 in 10 000), intermediate (≥1 in 100 000), well-documented (≥5 occurrences) or not-CIWD. Overall 26% of alleles in IPD-IMGT/HLA version 3.31.0 at P group resolution fall into the three CIWD categories. The two-field catalog includes 18% (n = 545) common, 17% (n = 513) intermediate, and 65% (n = 1997) well-documented alleles. Full-field allele frequency data are provided but are limited in value by the variations in resolution used by the registries. A recommended CIWD list is based on the most frequent category in the total or any of the seven geographic/ancestral/ethnic groups. Data are also provided so users can compile a catalog specific to the population groups that they serve. Comparisons are made to three previous CWD reports representing more limited population groups. This catalog, CIWD version 3.0.0, is a step closer to the collection of global HLA frequencies and to a clearer view of HLA diversity in the human population as a whole.
