RESUMO
Fibrosing chronic graft-versus-host disease (cGVHD) is a debilitating complication of allogeneic stem cell transplantation (alloSCT). A driver of fibrosis is the kynurenine (Kyn) pathway, and Kyn metabolism patterns and cytokines may influence cGVHD severity and manifestation (fibrosing versus gastrointestinal [GI] cGVHD). Using a liquid chromatography-tandem mass spectrometry approach on sera obtained from 425 patients with allografts, we identified high CXCL9, high indoleamine-2,3-dioxygenase (IDO) activity, and an activated Kyn pathway as common characteristics in all cGVHD subtypes. Specific Kyn metabolism patterns could be identified for non-severe cGVHD, severe GI cGVHD, and fibrosing cGVHD, respectively. Specifically, fibrosing cGVHD was associated with a distinct pathway shift toward anthranilic and kynurenic acid, correlating with reduced activity of the vitamin-B2-dependent kynurenine monooxygenase, low vitamin B6, and increased interleukin-18. The Kyn metabolite signature is a candidate biomarker for severe fibrosing cGVHD and provides a rationale for translational trials on prophylactic vitamin B2/B6 supplementation for cGVHD prevention.
Assuntos
Doença Enxerto-Hospedeiro/sangue , Ácido Cinurênico/sangue , Cinurenina/sangue , Riboflavina/sangue , Transplante de Células-Tronco , Vitamina B 6/sangue , Adolescente , Adulto , Idoso , Quimiocina CXCL9/sangue , Quimiocina CXCL9/genética , Feminino , Fibrose , Regulação da Expressão Gênica , Doença Enxerto-Hospedeiro/genética , Doença Enxerto-Hospedeiro/patologia , Humanos , Indolamina-Pirrol 2,3,-Dioxigenase/sangue , Indolamina-Pirrol 2,3,-Dioxigenase/genética , Interleucina-18/sangue , Interleucina-18/genética , Quinurenina 3-Mono-Oxigenase/sangue , Quinurenina 3-Mono-Oxigenase/genética , Leucemia/genética , Leucemia/metabolismo , Leucemia/patologia , Leucemia/terapia , Linfoma/genética , Linfoma/metabolismo , Linfoma/patologia , Linfoma/terapia , Masculino , Redes e Vias Metabólicas/genética , Pessoa de Meia-Idade , Estudos Retrospectivos , Índice de Gravidade de Doença , Transdução de Sinais , Transplante Homólogo , Triptofano/sangue , ortoaminobenzoatos/sangueRESUMO
BACKGROUND: Chronic graft-versus-host disease (cGVHD) represents a double-edged sword. In its nonsevere form, cGVHD associates with better control of the malignant disease, thus highlighting graft-versus-leukemia effects. However, severe cGVHD leads to debilitating morbidity and increased nonrelapse mortality. The prediction of severe cGVHD, in particular at disease onset, is therefore of high importance for ensuing clinical decisions and overall success of allogeneic stem cell transplantations. CXC-chemokine ligand 9 (CXCL9) is an interferon-inducible chemokine of the CXC family and is increased in cGVHD. Endothelial activation and stress index (EASIX) was shown to predict death after acute graft-versus-host disease. We explored CXCL9 and EASIX as predictors of severe cGVHD. METHODS: Sera and clinical data of 480 patients were available who survived at least 6 months following allogeneic stem cell transplantation without steroid-refractory acute graft-versus-host disease and without early relapse. CXCL9 and EASIX were measured on day +100 and onset of cGVHD. RESULTS: Development of nonsevere cGVHD was significantly associated with improved overall survival (hazard ratio 0.53, P < 0.001). CXCL9 serum levels at the onset of cGVHD predicted the development of severe cGVHD later on (hazard ratio 1.33, P = 0.02). In contrast, EASIX at the onset of cGVHD was not associated with cGVHD severity but was a significant independent risk factor for overall mortality and nonrelapse mortality. CONCLUSIONS: CXCL9 levels at the onset of cGVHD can help to predict severe courses of the disease and have potential for optimizing tailored administration of immunosuppressive therapy.