HLA-A*29:172 allele differs from HLA-A*29:01:01:01 by one missense single C/G nucleotide exchange in codon 77.

• Klíčová slova
• HLA, allogeneic transplantation, new alleles, polymorphism, typing,
• MeSH
• alely MeSH
• exony genetika   MeSH
• exprese genu MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé MeSH
• sekvence nukleotidů MeSH
• sekvenční analýza DNA MeSH
• sekvenční seřazení MeSH
• testování histokompatibility MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• HLA-A29 antigen MeSH Prohlížeč

BACKGROUND: Lower gastrointestinal (GI) graft versus host disease (GVHD) represents a severe complication in allogeneic hematopoietic stem cell transplant (HSCT) recipients with high rates of transplant-related mortality. Deregulated innate immunity reactions are the features of its pathogenesis. Cellular senescence has been considered a program of the innate immunity. We focused on lower GI GVHD from the perspective of cellular senescence. OBJECTIVE: We analyzed the impact of p16INK4a expression, a hallmark of cellular senescence, in intestinal biopsies of patients with lower GI GVHD symptoms and NFKB1 gene polymorphisms (rs3774937 C/T and rs3774959 A/G) on HSCT outcome. STUDY DESIGN: Fifty-two single-center patients who presented with symptoms of lower GI GVHD were analyzed in a retrospective manner. Two SNPs located in the NFKB1 gene regions (rs3774937 C/T and rs3774959 A/G) were genotyped from the peripheral blood samples collected before the start of the conditioning. All patients underwent proctosigmoidoscopy with biopsy of the mucosa. The expression of p16INK4a was analyzed in normal intestinal crypts and stroma. RESULTS: Fifty-two patients (50% male) received HSCT for hematological diseases (acute leukemias in 67%) and developed lower GI symptoms. Patients with p16INK4a expression in the intestinal stroma were in lower risk of developing histological grade 3-4 aGVHD (RR 0.18 [95% CI 0.05-0.65]; p = 0.009). The multivariate linear regression confirmed the independent effect of p16INK4a expression on time of the lower GI aGVHD symptoms onset (Coef. 38.9 [95% CI 12.7-65.1]; p = 0.005). The NFKB1 rs3774937 CC and TT/TC genotype were present in 40 and 80% of patients with p16INK4a expression, respectively (p = 0.04). The rs3774959 AA and GG/AG genotype were present among 43 and 82% of patients with p16INK4a expression, respectively (p = 0.02). Expression of p16INK4a was associated with no clinical variable but NFKB1 genotype. CONCLUSIONS: Our results address possible new mechanisms that may lead to better understanding of HSCT-related immune complications. Cellular senescence may bring novel approaches in GVHD diagnostics and therapy.

• Klíčová slova
• Cellular senescence, Graft versus host disease, Lower-gastrointestinal graft versus host disease, NFKB1 gene, p16INK4a,
• MeSH
• gastrointestinální nemoci * etiologie   MeSH
• inhibitor p16 cyklin-dependentní kinasy * genetika   MeSH
• jednonukleotidový polymorfismus MeSH
• lidé MeSH
• nemoc štěpu proti hostiteli * genetika   metabolismus   MeSH
• NF-kappa B - podjednotka p50 * genetika   MeSH
• retrospektivní studie MeSH
• stárnutí buněk genetika   MeSH
• transplantace hematopoetických kmenových buněk * škodlivé účinky   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• inhibitor p16 cyklin-dependentní kinasy * MeSH
• NF-kappa B - podjednotka p50 * MeSH
• NFKB1 protein, human MeSH Prohlížeč

Graft-versus-host disease (GVHD) represents a significant cause of mortality after allogeneic hematopoietic stem cell transplantation (HSCT). NF-kB system is a master regulator of innate immunity responses. It controls the expression of various cytokines and chemokines many of which are involved in GVHD pathogenesis. Chemo(radio) therapy administered during conditioning induces DNA damage and activates DNA damage response (DDR) signaling resulting in irreversible cell cycle arrest - cellular senescence which has been described to be associated with robust pro-inflammatory secretion mostly controlled by NF-kB. The NFKB1 gene encodes the DNA-binding subunit of the NF-kB complex. Using the candidate gene approach, we analyzed possible association of two single-nucleotide polymorphisms (SNPs) rs3774937 C/T and rs3774959 A/G of the NFKB1 gene with GVHD and transplant-related mortality (TRM) occurrence in 109 recipients allografted from HLA-identical donor. Both SNPs in recipients were found to be strongly associated with acute GVHD. Nevertheless, no significant association with chronic GVHD and TRM was found. Presented pilot results contribute to pre-clinical observations and suggest that NF-kB may be an important regulator of HSCT-related inflammatory reactions such as acute GVHD. Novel pathogenic mechanisms of GVHD may arise from perspectives of DDR and cellular senescence where NF-kB plays an essential role.

• Klíčová slova
• Allogeneic hematopoietic stem cell transplantation, Cellular senescence, Graft-versus-host disease, NFKB1 gene, Senescence-associated secretory phenotype, Single-nucleotide polymorphism,
• MeSH
• alografty MeSH
• dospělí MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• míra přežití MeSH
• nemoc štěpu proti hostiteli genetika   mortalita   terapie   MeSH
• NF-kappa B - podjednotka p50 genetika   MeSH
• pilotní projekty MeSH
• přežití po terapii bez příznaků nemoci MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• pozorovací studie MeSH
• Názvy látek
• NF-kappa B - podjednotka p50 MeSH
• NFKB1 protein, human MeSH Prohlížeč

Although complex approaches in haematopoietic stem cell transplantation (aHSCT) improved substantially in the last decades, considerable proportion of patients still suffer from life-threatening complications including graft versus host disease (GvHD). Great effort has therefore been dedicated to identification of biomarkers of the aHSCT outcome. Recently, prognostic scores for the prediction of GvHD and non-relapse mortality based on circulating molecules, such as tumour necrosis factor receptor-1, IL-33receptor (ST2) and regenerating islet-derived 3-alpha were proposed and evaluated in multicentre studies. Furthermore, several biomarkers, for example, ST2, represent promising targets for therapeutic intervention in severe GvHD. These results bring us closer to the clinical strategies to effectively control complications following aHSCT, and therefore to the tailored stem cell therapy with higher benefits for the patients.

• Klíčová slova
• allograft/allogeneic transplantation, biomarkers, graft versus host disease, immune response,
• MeSH
• biologické markery krev   MeSH
• hematologické nádory krev   diagnóza   terapie   MeSH
• homologní transplantace škodlivé účinky   MeSH
• lidé MeSH
• nemoc štěpu proti hostiteli krev   diagnóza   MeSH
• prediktivní hodnota testů MeSH
• prognóza MeSH
• transplantace hematopoetických kmenových buněk * škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH
• Názvy látek
• biologické markery MeSH

The identification of a novel HLA-B*35:279 allele in a Czech patient is described. This allele is identical to the B*35:03:01 variant except the G/A nucleotide exchange at position 652 of the HLA-B gene that corresponds to the amino acid substitution from valine to isoleucine in alpha 3 domain of the HLA-B antigen.

• MeSH
• alely * MeSH
• HLA-B antigeny genetika   imunologie   izolace a purifikace   MeSH
• lidé MeSH
• sekvence nukleotidů MeSH
• substituce aminokyselin MeSH
• testování histokompatibility MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• Geografické názvy
• Česká republika MeSH
• Názvy látek
• HLA-B antigeny MeSH

Polymorphisms of genes involved in innate and adaptive immunity have become an object of major interest in regard to hematopoietic stem cell transplantation (HSCT) complications. Regimen-related gastrointestinal toxicity (RR-GIT) is the dominant complication during the pre-engraftment period and has been linked to increased risk of graft-versus-host disease (GVHD) development. According to our hypothesis, functional variants of genes participating in DNA damage response (DDR) may have an impact on the extent of tissue damage caused by the conditioning regimen. In our single-center study, we analyzed 62 patients who underwent HSCT from HLA-identical donors after reduced conditioning. The patients were genotyped for 5 single nucleotide polymorphisms (SNPs, rs4585 T/G, rs189037 A/G, rs227092 T/G, rs228590 C/T, and rs664677 T/C) of the ATM gene-the essential member of the DDR pathways, using allele-specific matrix-assisted laser desorption/ionization, time-of-flight (MALDI-TOF) mass spectrometry assay. Because of almost absolute linkage disequilibrium observed among all 5 SNPs, association of 2 major ATM haplotypes (ATM1/ATM2) with RR-GIT and acute GVHD (aGVHD) was analyzed. Importantly, the univariate and multivariate analysis showed that patients homozygous for ATM2 haplotype (rs4585*T, rs189037*A, rs227092*T, rs228590*C, and rs664677*T) are more likely to suffer from high-grade RR-GIT than ATM1 homozygous patients. The association with aGVHD was not significant. To our knowledge, this is the first report showing the ATM gene variability in relation to RR-GIT in the allogeneic HSCT setting.

• Klíčová slova
• ATM gene, Acute graft-versus-host disease, Allogeneic hematopoietic stem cell transplantation, Gastrointestinal toxicity, Single-nucleotide polymorphism,
• MeSH
• akutní nemoc MeSH
• alely MeSH
• analýza přežití MeSH
• ATM protein genetika   imunologie   MeSH
• dárci tkání MeSH
• dospělí MeSH
• exprese genu MeSH
• frekvence genu MeSH
• gastrointestinální trakt účinky léků   imunologie   patologie   MeSH
• haplotypy MeSH
• hematologické nádory genetika   imunologie   mortalita   terapie   MeSH
• homologní transplantace MeSH
• jednonukleotidový polymorfismus * MeSH
• lidé středního věku MeSH
• lidé MeSH
• myeloablativní agonisté aplikace a dávkování   škodlivé účinky   MeSH
• nemoc štěpu proti hostiteli genetika   imunologie   mortalita   MeSH
• příprava pacienta k transplantaci metody   MeSH
• prognóza MeSH
• prospektivní studie MeSH
• protein - isoformy genetika   imunologie   MeSH
• transplantace hematopoetických kmenových buněk * MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• ATM protein, human MeSH Prohlížeč
• ATM protein MeSH
• myeloablativní agonisté MeSH
• protein - isoformy MeSH