Kynurenine pathway activation and deviation to anthranilic and kynurenic acid in fibrosing chronic graft-versus-host disease

Orsatti, Laura; Stiehl, Thomas; Dischinger, Katharina; Speziale, Roberto; Pasquale, Pamela di; Monteagudo, Edith; Müller‐Tidow, Carsten; Radujkovic, Aleksandar; Dreger, Peter; Luft, Thomas

doi:10.1016/j.xcrm.2021.100409

Cited by 10 publications

(8 citation statements)

References 46 publications

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“…Regarding cGVHD aggravation, we observed an association between a stronger vaccination response and shorter time to onset of symptoms (Figure 2b). To corroborate that the identified patients suffered cGVHD, we measured four cytokines that were previously found to be associated with GVHD and/or poor outcome post alloSCT (IL18, ANG2, CXCL9/MIG, IFNg) [4][5][6]9]. Concordantly, cytokine levels were significantly higher (Il18, ANG2, IFNg) in patients with suspected cGVHD aggravation (Figure 2c).…”

Section: Resultssupporting

confidence: 52%

Humoral Responses and Chronic GVHD Exacerbation after COVID-19 Vaccination Post Allogeneic Stem Cell Transplantation

et al. 2022

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The COVID-19 pandemic threatens patients with a compromised immune and endothelial system, including patients who underwent allogeneic stem cell transplantation (alloSCT). Thus, there is an unmet need for optimizing vaccination management in this high-risk cohort. Here, we monitored antibodies against SARS-CoV-2 spike protein (anti-S1) in 167 vaccinated alloSCT patients. Humoral immune responses were detectable in 81% of patients after two vaccinations with either mRNA-, vector-based, or heterologous regimens. Age, B-cell counts, time interval from vaccination, and the type of vaccine determined antibody titres in patients without systemic immunosuppression (sIS). Similar to a healthy control cohort, mRNA vaccine-based regimens induced higher titres than vector-based vaccines. Patients on two or more immunosuppressants rarely developed immunity. In contrast, 62% and 45% of patients without or on only one immunosuppressant, respectively, showed a strong humoral vaccination response (titre > 100). Exacerbation of cGVHD upon vaccination was observed in 6% of all patients and in 22% of patients receiving immunosuppression for cGVHD. cGVHD exacerbation and low antibody titres were both associated with higher angiopoietin-2 (ANG2) serum levels. In conclusion, mRNA-based vaccines elicit strong humoral responses in alloSCT patients in the absence of double sIS. Biomarkers such as ANG2 might help with weighing cGVHD risk versus beneficial responses.

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Section: Resultssupporting

confidence: 52%

Humoral Responses and Chronic GVHD Exacerbation after COVID-19 Vaccination Post Allogeneic Stem Cell Transplantation

et al. 2022

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“…This finding has recently been confirmed by Orsatti et al. ( 62 ) in a cohort of 425 patients, including 190 without cGvHD as a control group.…”

Section: Resultssupporting

confidence: 65%

Use of the NIH consensus criteria in cellular and soluble biomarker research in chronic graft-versus-host disease: A systematic review

Milošević

Babić²,

Iovino³

et al. 2022

Front. Immunol.

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ObjectivesChronic graft-versus-host disease (cGvHD) is the most frequent cause of late non-relapse mortality after allogeneic haematopoietic stem cell transplantation (alloHCT). Nevertheless, established biomarkers of cGvHD are still missing. The National Institutes of Health (NIH) Consensus Development Project on Criteria for Clinical Trials in cGvHD provided recommendations for biomarker research. We evaluated to which extent studies on cellular and soluble biomarkers in cGvHD published in the last 10 years complied with these recommendations. Also, we highlight the most promising biomarker candidates, verified in independent cohorts and/or repeatedly identified by separate studies.MethodsWe searched Medline and EMBASE for “cGvHD”, “biomarkers”, “soluble” and “cells” as MeSH terms or emtree subject headings, and their variations on July 28th, 2021, limited to human subjects, English language and last ten years. Reviews, case reports, conference abstracts and single nucleotide polymorphism studies were excluded. Criteria based on the set of recommendations from the NIH group for biomarker research in cGvHD were used for scoring and ranking the references.ResultsA total of 91 references encompassing 15,089 participants were included, 54 prospective, 17 retrospective, 18 cross-sectional, and 2 studies included both prospective and retrospective cohorts. Thirty-five papers included time-matched controls without cGvHD and 20 studies did not have any control subjects. Only 9 studies were randomized, and 8 were multicentric. Test and verification cohorts were included in 11 studies. Predominantly, diagnostic biomarkers were explored (n=54). Assigned scores ranged from 5-34. None of the studies fulfilled all 24 criteria (48 points). Nevertheless, the scores improved during the last years. Three cell subsets (CXCR3+CD56bright NK cells, CD19+CD21low and BAFF/CD19+ B cells) and several soluble factors (BAFF, IL-15, CD163, DKK3, CXCL10 and the panel of ST2, CXCL9, MMP3 and OPN) had the highest potential as diagnostic and/or prognostic biomarkers in cGvHD.ConclusionDespite several limitations of this review (limited applicability for paediatric population, definition of verification, missing data on comorbidities), we identified promising candidate biomarkers for further evaluation in multicentre collaborative studies. This review confirms the importance of the NIH consensus group criteria for improving the quality and reproducibility of cGvHD biomarker research.

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“…In line, IDO serum levels were also higher in the statin group. Higher IDO activity in statin patients might also result from the association between statins and CXCL9 levels in our multivariate analyses, as we had shown a strong association between IDO and CXCL9, but not IL18 in a previous study 31 . Tryptophan metabolism has been shown to play a pivotal role in the immune system with diverse effects 20,44 .…”

Section: Discussionmentioning

confidence: 58%

“…Higher IDO activity in statin patients might also result from the association between statins and CXCL9 levels in our multivariate analyses, as we had shown a strong association between IDO and CXCL9, but not IL18 in a previous study. 31 Tryptophan metabolism has been shown to play a pivotal role in the immune system with diverse effects. 20,44 Increased IDO activity enhances tryptophan catabolism and leads to an accumulation of kynurenine and its downstream metabolites, which was shown to induce Treg differentiation by Aryl hydrocarbon receptor (AhR) pathway activation.…”

Section: Discussionmentioning

confidence: 99%

“…Serum levels of Kyn were measured by liquid chromatography‐tandem mass spectrometry (LC‐MSMS). A method for simultaneous quantification of all metabolites in a single run was used as described 31 . Serum from patients was collected before and on day 100 post‐alloSCT and frozen at −80°C at the biobank of Medical Department V at Heidelberg University Hospital until usage.…”

Section: Methodsmentioning

confidence: 99%

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Statin‐based endothelial prophylaxis and outcome after allogeneic stem cell transplantation

Pabst

Schreck

Benner

et al. 2022

Eur J Clin Investigation

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Background Allogeneic haematopoietic stem cell transplantation (alloSCT) often remains the only curative therapy for hematologic malignancies. Although the management of transplant‐associated adverse events considerably improved over the last decades, nonrelapse mortality (NRM) remains a challenge, and endothelial dysfunction was identified as a major contributor to NRM. Methods Statin‐based endothelial prophylaxis (SEP) has been implemented in the standard of care in our transplant centre to reduce NRM caused by endothelial injury. Here, we retrospectively analysed the impact of SEP on clinical outcome in a cohort of 347 alloSCT patients. Results SEP (n = 209) was associated with significantly reduced NRM (hazard ratio 0.61, 95% CI 0.38–0.96) and better overall survival (OS) after acute graft‐versus‐host disease (HR 0.59, 95% CI 0.37–0.93). Subgroup analyses showed that the NRM benefit was mainly found in patients with an intermediate endothelial activation and stress index (EASIX), while relapse risk was not affected. On day 100 post‐alloSCT, patients receiving SEP had significantly higher levels of the rate‐limiting enzyme of tryptophan metabolism, indoleamine 2,3‐dioxygenase (IDO), higher kynurenine to tryptophan ratios as a proxy of IDO activity and tended to have lower levels of the endothelial injury marker ST2 (p = .055). No significant differences in interferon‐gamma or IL18 levels were observed. These biomarker signatures suggest that the beneficial effects of SEP might be mediated by both endothelial protection and immunomodulation. Conclusions Together, these data suggest that SEP improves NRM and OS post‐alloSCT in particular in patients with intermediate endothelial risk and provide first mechanistic clues about its potential mode of action.

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Kynurenine pathway activation and deviation to anthranilic and kynurenic acid in fibrosing chronic graft-versus-host disease

Cited by 10 publications

References 46 publications

Humoral Responses and Chronic GVHD Exacerbation after COVID-19 Vaccination Post Allogeneic Stem Cell Transplantation

Humoral Responses and Chronic GVHD Exacerbation after COVID-19 Vaccination Post Allogeneic Stem Cell Transplantation

Use of the NIH consensus criteria in cellular and soluble biomarker research in chronic graft-versus-host disease: A systematic review

Statin‐based endothelial prophylaxis and outcome after allogeneic stem cell transplantation

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