Polymorphisms in CXCR3 ligands predict early CXCL9 recovery and severe chronic GVHD

Hao Dai,Olaf Penack,Aleksandar Radujkovic,Rajiv Kumar,Sivaramakrishna P Rachakonda,Peter Dreger,Thomas Luft,Igor W Blau,Olga Blau,Carsten Müller-Tidow

doi:10.1038/s41408-021-00434-2

Abstract

Chronic graft-versus-host disease (cGVHD) is a major cause of mortality and morbidity after allogeneic stem cell transplantation (alloSCT). The individual risk of severe cGVHD remains difficult to predict and may involve CXCR3 ligands. This study investigated the role of single-nucleotide polymorphisms (SNPs) of CXCL4, CXCL9, CXCL10, and CXCL11, and their day +28 serum levels, in cGVHD pathogenesis. Eighteen CXCR3 and CXCL4, CXCL9–11 SNPs as well as peri-transplant CXCL9–11 serum levels were analyzed in 688 patients without (training cohort; n = 287) or with statin-based endothelial protection cohort (n = 401). Clinical outcomes were correlated to serum levels and SNP status. Significant polymorphisms were further analyzed by luciferase reporter assays. Findings were validated in an independent cohort (n = 202). A combined genetic risk comprising four CXCR3 ligand SNPs was significantly associated with increased risk of severe cGVHD in both training cohort (hazard ratio (HR) 2.48, 95% confidence interval (CI) 1.33–4.64, P = 0.004) and validation cohort (HR 2.95, 95% CI 1.56–5.58, P = 0.001). In reporter assays, significantly reduced suppressive effects of calcineurin inhibitors in constructs with variant alleles of rs884304 (P < 0.001) and rs884004 (P < 0.001) were observed. CXCL9 serum levels at day +28 after alloSCT correlated with both genetic risk and risk of severe cGVHD (HR 1.38, 95% CI 1.10–1.73, P = 0.006). This study identifies patients with high genetic risk to develop severe cGVHD.

Highlights

Chronic graft-versus-host disease is a leading cause of morbidity and mortality after allogeneic stem cell transplantation1–3. cGVHD encompasses dysregulated immune responses, chronic inflammation, and fibrosis, with various manifestations resembling autoimmune diseases[4]
We investigated the interplay of serum CXCR3 ligand concentrations and selected polymorphisms with regard to the incidence of severe cGVHD after allogeneic stem cell transplantation (alloSCT)
We previously demonstrated that CXCL9 levels correlate with the risk of developing severe cGVHD when measured at the onset of mild symptoms[8]

Summary

Introduction

Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic stem cell transplantation (alloSCT)1–3. cGVHD encompasses dysregulated immune responses, chronic inflammation, and fibrosis, with various manifestations resembling autoimmune diseases[4]. Chronic graft-versus-host disease (cGVHD) is a leading cause of morbidity and mortality after allogeneic stem cell transplantation (alloSCT). CGVHD encompasses dysregulated immune responses, chronic inflammation, and fibrosis, with various manifestations resembling autoimmune diseases[4]. Non-severe cGVHD is associated with better overall survival because of an increased graft-versus-leukemia (GVL) effect, while severe cGVHD. CXCR3 ligands include interferon-γ (IFN-γ)-inducible chemokines of the CXC family such as CXCL9, CXCL10, and CXCL1113–15, as well as CXCL4 (PF4) and CXCL4V1 (PF4V1)[16,17]. CXCR3+ Th1 can increase local secretion of IFN-γ in inflamed tissues, which in turn stimulates CXCR3 ligand expression. The interplay between CXCR3 pathway and IFN-γ can lead to excessive immune responses and amplified inflammation[18]. CXCR3 overexpression was found in a B cell subset that is expanded in cGVHD patients[19].

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Results

Conclusion