Cellular senescence marker p16INK4a and NFKB1 gene polymorphisms in lower gastro-intestinal acute graft versus host disease

Adam Kuba; Ludek Raida; Svetlana Brychtova; Patrik Flodr; Frantisek Mrazek; Eva Kriegova; Edgar Faber; Tomas Papajik

doi:10.1016/j.trim.2022.101768

Cellular senescence marker p16^INK4a and NFKB1 gene polymorphisms in lower gastro-intestinal acute graft versus host disease

Transpl Immunol. 2023 Feb:76:101768. doi: 10.1016/j.trim.2022.101768. Epub 2022 Dec 2.

Authors

Adam Kuba¹, Ludek Raida², Svetlana Brychtova³, Patrik Flodr³, Frantisek Mrazek⁴, Eva Kriegova⁴, Edgar Faber², Tomas Papajik²

Affiliations

¹ Department of Hemato-Oncology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic. Electronic address: adam.kuba@fnol.cz.
² Department of Hemato-Oncology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
³ Department of Clinical and Molecular Pathology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.
⁴ Department of Immunology, University Hospital and Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.

PMID: 36470572
DOI: 10.1016/j.trim.2022.101768

Abstract

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 p16^INK4a 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 p16^INK4a 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 p16^INK4a 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 p16^INK4a 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 p16^INK4a expression, respectively (p = 0.04). The rs3774959 AA and GG/AG genotype were present among 43 and 82% of patients with p16^INK4a expression, respectively (p = 0.02). Expression of p16^INK4a 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.

Keywords: Cellular senescence; Graft versus host disease; Lower-gastrointestinal graft versus host disease; NFKB1 gene; p16INK4a.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Cellular Senescence / genetics
Cyclin-Dependent Kinase Inhibitor p16* / genetics
Female
Gastrointestinal Diseases* / etiology
Graft vs Host Disease* / genetics
Graft vs Host Disease* / metabolism
Hematopoietic Stem Cell Transplantation* / adverse effects
Humans
Male
NF-kappa B p50 Subunit* / genetics
Polymorphism, Single Nucleotide
Retrospective Studies

Substances

Cyclin-Dependent Kinase Inhibitor p16
NF-kappa B p50 Subunit
NFKB1 protein, human