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.
- 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
Numerous associations of HLA variants with susceptibility to diseases, namely, those with an immunopathological component, have been described to date. The strongest HLA associations were incorporated into the standard algorithms for the diagnostics. Disease-associated HLA variants are routinely detected by various techniques including DNA-based assays. For the identification of HLA markers or their combinations with the highest diagnostic value and those with frequent clinical indications (e.g., HLA-B*27, -B*57:01, -DQ2/-DQ8, -DQB1*06:02), diagnostic tests that focus on a single or limited number of specific HLA antigens/alleles, have already been developed; the use of complete typing for particular HLA loci is a relevant alternative. Importantly, external proficiency testing (EPT) became an integral part of good laboratory practice for HLA disease associations in accredited laboratories and not only supports correct "technical" identification of the associated HLA variants, but also adequate interpretation of the results to the clinicians. In the present article selected aspects of EPT for HLA disease associations related to population genetics are reviewed and discussed with the emphasis on the optimal level of HLA typing resolution, population-based differences in disease associated HLA alleles within the allelic group, distribution and linkage disequilibrium of HLA alleles in particular populations and interpretation of the presence of less common HLA variants/haplotypes. In conclusion, the laboratories that perform and interpret the tests to the clinicians, producers of the certified diagnostics and EPT providers should consider, among others, the genetic characteristics of the populations in order to optimise the diagnostic value of the tests for disease-associated HLA variants.
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
HLA-A*29:172 allele differs from HLA-A*29:01:01:01 by one missense single C/G nucleotide exchange in codon 77.
- 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
- Publikační typ
- abstrakt z konference MeSH
- Publikační typ
- abstrakt z konference MeSH
All renal transplant recipients should undergo a regular screening for BK viral (BKV) viremia. Gradual reduction of immunosuppression is recommended in patients with persistent plasma BKV viremia for 3 weeks after the first detection, reflecting the presence of probable or suspected BKV-associated nephropathy. Reduction of immunosuppression is also a primary intervention in biopsy proven nephropathy associated with BKV (BKVN). Thus, allograft biopsy is not required to treat patients with BKV viremia with stabilized graft function. There is a lack of proper randomised clinical trials recommending treatment in the form of switching from tacrolimus to cyclosporin-A, from mycophenolate to mTOR inhibitors or leflunomide, or the additive use of intravenous immunoglobulins, leflunomide or cidofovir. Fluoroquinolones are not recommended for prophylaxis or therapy. There are on-going studies to evaluate the possibility of using a multi-epitope anti-BKV vaccine, administration of BKV-specific T cell immunotherapy, BKV-specific human monoclonal antibody and RNA antisense oligonucleotides. Retransplantation after allograft loss due to BKVN can be successful if BKV viremia is definitively removed, regardless of allograft nephrectomy.
- MeSH
- imunosupresiva terapeutické užití MeSH
- leflunomid terapeutické užití MeSH
- lidé MeSH
- nemoci ledvin * farmakoterapie MeSH
- polyomavirové infekce * diagnóza farmakoterapie MeSH
- transplantace ledvin * MeSH
- viremie diagnóza farmakoterapie MeSH
- virus BK * genetika MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- Publikační typ
- abstrakt z konference MeSH
AIM: It remains unclear, why only some patients form alloantibodies against foreign RBC antigens. Transfusion of red blood cell (RBC) products and pregnancy are the most relevant causes of immunization against RBC alloantigens. Here we investigated the relationship between RBC alloantibodies, Rh phenotype, and HLA phenotype among patients with multiple RBC alloantibodies METHODS: In a group of 124 multi-responders ‒ including both pregnant women and transplant recipients ‒ we analysed the distribution of HLA-Class II variants in subgroups of multi-responders to RBC alloantigens according to their Rh status. RESULTS: As expected, the RhD-negative phenotype was overrepresented in our alloimmunized group (49.2 %) compared to in the general population. Importantly, HLA-DRB1*15 carriers were significantly overrepresented among D-negative multi-responders compared to D-positive multi-responders (Pc = 0.045). Furthermore, the linked HLA-DRB1*13, HLA-DQB1*06, and HLA-DQA1*01 variants were more frequent in individuals with the DCCee phenotype than in other RhD-positive phenotypes. CONCLUSION: Our present findings showed that RBC multispecific alloimmunization was associated with particular HLA-Class II variants based on Rh status (Tab. 3, Ref. 22).
