Journal Article

Genetic variants of the HLA-G/LILRB1 ligand-receptor axis in donors or recipients are prognostic covariates for rejection after living kidney transplantation

Hölzenbein, Julian, Gruenen, Nina, Horn, Peter Alexander, Witzke, Oliver, Heinemann, Falko M., Reinold, Johanna, Gäckler, Anja, Wilde, Benjamin, Rebmann, Vera, Busch, Yannik, Heinold, Andreas, Schramm, Sabine, Rohn, Hana, Peter, Wolfgang

2026

Overview

HLA-G is a non-classical HLA class I molecule that promotes transplant tolerance. It engages the inhibitory receptor LILRB1 on immune effector cells, suppressing cytotoxic responses and inflammation, while promoting tolerogenic and regulatory immune phenotypes. Polymorphisms in the 3' untranslated region (3'UTR) modulate HLA-G expression levels, and promoter variants influence receptor expression. The combined effect on kidney transplant (KTx) rejection has not been systematically studied. Living donor-recipient pairs undergoing KTx were genotyped for nine variants in the 3'UTR region and two single nucleotide polymorphisms (SNPs) in the promoter (PROMO) regions. Haplotypes were arranged for both loci. Clinical endpoints were biopsy-proven T cell-mediated rejection (TCMR) within one year and antibody-mediated rejection (AMR) within five years post-transplant. Donor positivity for 3'UTR-1 or UTR-2 or negative for UTR-3 haplotype were associated with a significantly higher risk of TCMR in both univariate or multivariate analyses. Recipients lacking the -PROMO CG haplotype also had an increased TCMR risk. The combination of an 3'UTR-2 positive donor with a -PROMO CG haplotype negative recipient was found to be an independent predictor of TCMR. In contrast, HLA-G 3'UTR variants were not associated with AMR, while the presence of the recipient -PROMO CG haplotype emerged as an independent AMR risk factor. Donor 3'UTR and recipient -PROMO haplotypes define a functional immunogenetic axis that differentially influence TCMR and AMR. These results support the clinical potential of HLA-G/LILRB1 genetic profiling to improve donor selection in living KTx and to guide the development of novel rejection therapies.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: 3' Untranslated Regions / acute cellular rejection / Adult / Antibodies / Antigens / Antigens, CD / Biopsy / Cytotoxicity / Effector cells / Female / Genetic diversity / Genotype / Graft rejection / Graft Rejection - diagnosis / Graft Rejection - etiology / Graft Rejection - genetics / Graft Rejection - immunology / Haplotypes / Histocompatibility antigen HLA / HLA-G 3´UTR-1 / HLA-G 3´UTR-2 / HLA-G Antigens - genetics / HLA-G Antigens - immunology / Humans / ILT-2 / Immune response / Immunogenetics / Immunological tolerance / Ischemia / Kidney transplantation / Kidney Transplantation - adverse effects / Kidney transplants / Leukocyte Immunoglobulin-like Receptor B1 - genetics / Leukocytes / Ligands / LILRB1 / Living Donors / Lymphocytes / Lymphocytes T / Male / Middle Aged / Original Research / Phenotypes / Polymorphism / Polymorphism, Single Nucleotide / Prognosis / Risk factors / Single-nucleotide polymorphism / Software / Survival analysis / Transplant Recipients