Steroid conversion (HSD11B1, HSD11B2, H6PD) and receptor genes (NR3C1, NR3C2) were examined in kidney-transplant recipients with "operational tolerance" and chronic rejection (CR), independently and within the context of 88 tolerance-associated genes. Associations with cellular types were explored. Peripheral whole-blood gene-expression levels (RT-qPCR-based) and cell counts were adjusted for immunosuppressant drug intake. Tolerant (n = 17), stable (n = 190) and CR patients (n = 37) were compared. Healthy controls (n = 14) were used as reference. The anti-inflammatory glucocorticoid receptor (NR3C1) and the cortisol-activating HSD11B1 and H6PD genes were up-regulated in CR and were lowest in tolerant patients. The pro-inflammatory mineralocorticoid gene (NR3C2) was downregulated in stable and CR patients. NR3C1 was associated with neutrophils and NR3C2 with T-cells. Steroid conversion and receptor genes, alone, enabled classification of tolerant patients and were major contributors to gene-expression signatures of both, tolerance and CR, alongside known tolerance-associated genes, revealing a key role of steroid regulation and response in kidney transplantation.
- MeSH
- chronická nemoc MeSH
- imunologická tolerance * účinky léků genetika MeSH
- lidé MeSH
- multivariační analýza MeSH
- plocha pod křivkou MeSH
- počet buněk MeSH
- pravděpodobnost MeSH
- prednisolon aplikace a dávkování farmakologie MeSH
- protein - isoformy metabolismus MeSH
- receptory glukokortikoidů metabolismus MeSH
- regresní analýza MeSH
- regulace genové exprese účinky léků MeSH
- rejekce štěpu etiologie genetika imunologie MeSH
- steroidy farmakologie MeSH
- transplantace ledvin škodlivé účinky MeSH
- upregulace účinky léků MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We and others have previously described signatures of tolerance in kidney transplantation showing the differential expression of B cell-related genes and the relative expansions of B cell subsets. However, in all of these studies, the index group-namely, the tolerant recipients-were not receiving immunosuppression (IS) treatment, unlike the rest of the comparator groups. We aimed to assess the confounding effect of these regimens and develop a novel IS-independent signature of tolerance. Analyzing gene expression in three independent kidney transplant patient cohorts (232 recipients and 14 tolerant patients), we have established that the expression of the previously reported signature was biased by IS regimens, which also influenced transitional B cells. We have defined and validated a new gene expression signature that is independent of drug effects and also differentiates tolerant patients from healthy controls (cross-validated area under the receiver operating characteristic curve [AUC] = 0.81). In a prospective cohort, we have demonstrated that the new signature remained stable before and after steroid withdrawal. In addition, we report on a validated and highly accurate gene expression signature that can be reliably used to identify patients suitable for IS reduction (approximately 12% of stable patients), irrespective of the IS drugs they are receiving. Only a similar approach will make the conduct of pilot clinical trials for IS minimization safe and hence allow critical improvements in kidney posttransplant management.
- MeSH
- B-lymfocyty účinky léků imunologie metabolismus MeSH
- biologické markery metabolismus MeSH
- chronické selhání ledvin komplikace chirurgie MeSH
- dospělí MeSH
- hodnoty glomerulární filtrace MeSH
- imunologická tolerance účinky léků imunologie MeSH
- imunosupresiva terapeutické užití MeSH
- lidé středního věku MeSH
- lidé MeSH
- následné studie MeSH
- přežívání štěpu účinky léků imunologie MeSH
- prognóza MeSH
- prospektivní studie MeSH
- rejekce štěpu diagnóza farmakoterapie etiologie metabolismus MeSH
- rizikové faktory MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- transplantace ledvin škodlivé účinky MeSH
- vyšetření funkce ledvin MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
2nd ed. xvii, 472 s. : il. ; 27 cm
- MeSH
- autoimunitní nemoci genetika MeSH
- genetická predispozice k nemoci MeSH
- histokompatibilita fyziologie MeSH
- HLA antigeny * MeSH
- transplantační imunologie MeSH
- Konspekt
- Patologie. Klinická medicína
- NLK Obory
- alergologie a imunologie
- NLK Publikační typ
- kolektivní monografie
[ 1st ed.] 186 s. : tab., grafy, přeruš. lit.,rejstř. ; 24 cm
- Klíčová slova
- HLA systém,
- MeSH
- autoimunita MeSH
- autoimunitní nemoci diagnóza MeSH
- HLA antigeny MeSH
- hlavní histokompatibilní komplex genetika MeSH
- molekulární biologie MeSH
- T-lymfocyty imunologie MeSH
- Publikační typ
- monografie MeSH
