Prediction of graft-versus-host disease: a biomarker panel based on lymphocytes and cytokines

Budde, Holger; Papert, Susanne; Maas, Jens-Holger; Reichardt, Holger M.; Wulf, Gerald; Hasenkamp, Justin; Riggert, Joachim; Legler, Tobias J.

doi:10.1007/s00277-017-2999-5

Cited by 26 publications

(17 citation statements)

References 24 publications

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“…Furthermore, the high CD4 + :CD8 + T cell ratios in humanized mice with clinical GVHD parallels with studies in humans, in which high CD4 + :CD8 + T cell ratios indicate greater disease severity [40,41]. These observations contrast other findings in humanized NSG mice,…”

Section: Discussionsupporting

confidence: 69%

Increased splenic human CD4+:CD8+ T cell ratios, serum human interferon-γ and intestinal human interleukin-17 are associated with clinical graft-versus-host disease in humanized mice

Geraghty

Belfiore

Adhikary

et al. 2019

Transplant Immunology

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Graft-versus-host disease (GVHD) is a frequent complication following allogeneic hematopoietic stem cell transplantation (HSCT) with current therapies limited to general immunosuppression. Humanized mouse models of GVHD are emerging as valuable intermediaries to allow translation of findings from allogeneic mouse models to humans to prevent and treat this disease, but such models require further characterization. In this study, humanized mice were generated by injecting immunodeficient non-obese diabetic severe combined immunodeficiency interleukin (IL)-2 receptor γ common chain null (NSG) mice with human peripheral blood mononuclear cells (hPBMCs). Clinical GVHD development was assessed using established scoring criteria (weight loss, posture, activity, fur texture and skin integrity). Differences between humanized NSG mice that developed clinical or subclinical GVHD were then compared. Both groups of mice demonstrated similar frequencies of human leukocyte engraftment. In contrast, mice that developed clinical GVHD demonstrated increased histological damage compared to mice with subclinical GVHD. Furthermore, mice with clinical GVHD exhibited increases in the splenic human CD4 + :CD8 + T cell ratio, serum human interferon (IFN)-γ and intestinal human IL-17 expression compared to mice with subclinical GVHD. These cellular and molecular changes could be used as potential markers of disease progression in this preclinical model. This study also provides further insights into GVHD development which may be relevant to human HSCT recipients.

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Section: Discussionsupporting

confidence: 69%

Increased splenic human CD4+:CD8+ T cell ratios, serum human interferon-γ and intestinal human interleukin-17 are associated with clinical graft-versus-host disease in humanized mice

Geraghty

Belfiore

Adhikary

et al. 2019

Transplant Immunology

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“…Validating the results in independent cohorts, preferably at a different center, is crucial before a marker may be considered to be used as a biomarker (32). In addition, in future studies performing a receiver operating characteristic (ROC) analysis to assess the prognostic potential of the markers would be vital, as has been done in many biomarker studies, both for acute and cGVHD (10, 11, 13, 14, 16, 25, 28, 29, 57). Unfortunately, the sample size in this study was insufficient to perform an ROC analysis correctly.…”

Section: Discussionmentioning

confidence: 99%

“…In addition, several studies have focused on identifying cellular subsets to utilize as potential biomarkers, be it for acute (28, 29) or cGVHD (20, 24, 30, 31). …”

Section: Introductionmentioning

confidence: 99%

Combining Flow and Mass Cytometry in the Search for Biomarkers in Chronic Graft-versus-Host Disease

et al. 2017

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Chronic graft-versus-host disease (cGVHD) is a debilitating complication arising in around half of all patients treated with an allogeneic hematopoietic stem cell transplantation. Even though treatment of severe cGVHD has improved during recent years, it remains one of the main causes of morbidity and mortality in affected patients. Biomarkers in blood that could aid in the diagnosis and classification of cGVHD severity are needed for the development of novel treatment strategies that can alleviate symptoms and reduce the need for painful and sometimes complicated tissue biopsies. Methods that comprehensively profile complex biological systems such as the immune system can reveal unanticipated markers when used with the appropriate methods of data analysis. Here, we used mass cytometry, flow cytometry, enzyme-linked immunosorbent assay, and multiplex assays to systematically profile immune cell populations in 68 patients with varying grades of cGVHD. We identified multiple subpopulations across T, B, and NK-cell lineages that distinguished patients with cGVHD from those without cGVHD and which were associated in varying ways with severity of cGVHD. Specifically, initial flow cytometry demonstrated that patients with more severe cGVHD had lower mucosal-associated T cell frequencies, with a concomitant higher level of CD38 expression on T cells. Mass cytometry could identify unique subpopulations specific for cGVHD severity albeit with some seemingly conflicting results. For instance, patients with severe cGVHD had an increased frequency of activated B cells compared to patients with moderate cGVHD while activated B cells were found at a reduced frequency in patients with mild cGVHD compared to patients without cGVHD. Moreover, results indicate it may be possible to validate mass cytometry results with clinically viable, smaller flow cytometry panels. Finally, no differences in levels of blood soluble markers could be identified, with the exception for the semi-soluble combined marker B-cell activating factor/B cell ratio, which was increased in patients with mild cGVHD compared to patients without cGVHD. These findings suggest that interdependencies between such perturbed subpopulations of cells play a role in cGVHD pathogenesis and can serve as future diagnostic and therapeutic targets.

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“…Generally, recent studies have been focused on choosing a panel as GVHD markers and some have shown promising results [32][33][34] . However, some of these panels contain serum markers that require expensive commercial kits that are not routinely available in many countries.…”

Section: Discussionmentioning

confidence: 99%

Application of latent class analysis in diagnosis of graft-versus-host disease by serum markers after allogeneic haematopoietic stem cell transplantation

Amini

Kazemnejad

Rasekhi

et al. 2020

Sci Rep

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2 for a composite test is as the same as a diagnostic test. For choosing optimal cutoff point, the Youden index which mentioned before, was used for the combinations. Afterward, the cSensitivity and cSpecificity were selected. For the models, the convergence of the MCMC chains for all the LCMs (with and without covariate adjustment) was assessed using autocorrelation plots. Furthermore, the convergence was obtained by running one chain with 35,000 iterations with lag 45. The first 17,000 iterations were discarded. The Bayesian latent class models were fitted by using OpenBUGS 3.2.1 41. The R package R2OpenBUGS 42 also applied as an interface between R 3.6.2 43 and OpenBUGS. After determining the GVHD groups based on optimal composite test, in order to evaluate the association between each of continuous variables and GVHD, an independent sample t-test was performed and chi-square test was applied for each categorical variable. All comparisons were two-tailed and p-value of less than 0.05 was taken as statistically significant. Descriptive analyses were performed using R version 3.6.2.

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Prediction of graft-versus-host disease: a biomarker panel based on lymphocytes and cytokines

Cited by 26 publications

References 24 publications

Increased splenic human CD4+:CD8+ T cell ratios, serum human interferon-γ and intestinal human interleukin-17 are associated with clinical graft-versus-host disease in humanized mice

Increased splenic human CD4+:CD8+ T cell ratios, serum human interferon-γ and intestinal human interleukin-17 are associated with clinical graft-versus-host disease in humanized mice

Combining Flow and Mass Cytometry in the Search for Biomarkers in Chronic Graft-versus-Host Disease

Application of latent class analysis in diagnosis of graft-versus-host disease by serum markers after allogeneic haematopoietic stem cell transplantation

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