Biomarkers of immune activation to screen for severe, acute GVHD

Kj, August; Ky, Chiang; Rm, Bostick; Wd, Flanders; Waller, EK; Langston, Amelia; Worthington-White, Diana; Rowland, P.; Kf, Moore; Hj, Khoury; Jt, Horan

doi:10.1038/bmt.2010.165

Cited by 40 publications

(35 citation statements)

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“…53,54,56,[59][60][61] Recently, August et al reported that sIL-2R, TNFR1, and CD8 have high predictive values for aGVHD occurrence. 62 A recent study by Rezvani et al found that a decrease of 0.5 g/dL in serum albumin from pretransplantation levels predicted the development of grade 3 or 4 aGVHD and overall survival 6 months after initiation of aGVHD treatment in a cohort of 401 patients with aGVHD grades 2-4 after reduced intensity HSCT. 76 Because measuring serum albumin concentration is easy and inexpensive, the authors suggest incorporating albumin into the set of other validated biomarkers to improve the prediction of aGVHD severity and mortality.…”

Section: Target-specific Biomarkers Of Agvhdmentioning

confidence: 99%

“…A good example of such a marker is sIL-2R␣, which was shown in a prospective study to be elevated at days 7 and 15 after HCST and to predict severe aGVHD with 57% sensitivity and 82% specificity. 62 Biomarkers of GVHD have also recently been used to follow the response to GVHD treatment. 79 However, the key to developing useful surrogate end points is to identify biomarkers that reflect fundamental aspects of the treatment's effects on disease pathogenesis.…”

Section: Decision-making Strategiesmentioning

confidence: 99%

“…53 Similarly, TNF-␣ and its receptors, particularly TNFR1 concentrations, were higher in aGVHD patients than in patients without GVHD. [58][59][60][61][62] The same precautions used to evaluate sIL-2R␣ levels in other transplantation-related complications should be considered when evaluating TNF-␣ and TNFR1. The roles of TNF-␣/TNFR1 and IL-2/IL-2R␣ in aGVHD pathogenesis are supported by evidence suggesting that antibodies directed against TNFR1 or IL-2R␣ are effective therapies for steroid-refractory aGVHD.…”

Section: Biomarkers Identified Using the Pathology Of Agvhd Systemic mentioning

confidence: 99%

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Discovery and validation of graft-versus-host disease biomarkers

Paczesny

2013

Blood

130

114

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Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the most effective tumor immunotherapy available. Although allo-HSCT provides beneficial graft-versus-tumor effects, acute GVHD (aGVHD) is the primary source of morbidity and mortality after HSCT. Diagnosis of aGVHD is typically based on clinical symptoms in one or more of the main target organs (skin, liver, gastrointestinal tract) and confirmed by biopsy. However, currently available diagnostic and staging tools often fail to identify patients at higher risk of GVHD progression, unresponsiveness to therapy, or death. In addition, there are shortcomings in the prediction of GVHD before clinical signs develop, indicating the urgent need for noninvasive and reliable laboratory tests. Through the continuing evolution of proteomics technologies seen in recent years, plasma biomarkers have been identified and validated as promising diagnostic tools for GVHD and prognostic tools for nonrelapse mortality. These biomarkers may facilitate timely and selective therapeutic intervention but should be more widely validated and incorporated into a new grading system for risk stratification of patients and better-customized treatment. This review identifies biomarkers for detecting GVHD, summarizes current information on aGVHD biomarkers, proposes future prospects for the blinded evaluation of these biomarkers, and discusses the need for biomarkers of chronic GVHD. (Blood. 2013;121(4):585-594) IntroductionAllogeneic hematopoietic stem cell transplantation (allo-HSCT) is a widely used therapy for a variety of malignant and nonmalignant hematologic diseases. In malignant disease, the donor immune system recognizes residual tumor cells as foreign and eradicates them by immunologic means, known as the graft-versustumor (GVT) effect. Unfortunately, donor immune cells may also attack normal host tissue, particularly the skin, liver, and gastrointestinal (GI) tract, resulting in acute GVHD (aGVHD). GVHD remains one of the major barriers to a more widespread and successful application of allo-HSCT. Known risk factors that increase the incidence and severity of aGVHD include the use of HLA-mismatched unrelated donors rather than HLA-matched sibling donors. 1 A major barrier to GVHD research and treatment is that diagnosis and prognosis rely almost entirely on the presence of clinical symptoms and should be confirmed by biopsy of the involved target organs. No currently used laboratory tests can predict the risk of developing GVHD, responsiveness to treatment, or patient survival. The importance of biomarkers in HSCT settings is crucial because the ability to identify patients at high risk for GVHD early in their transplantation and treatment course has important therapeutic consequences, including more stringent monitoring and/or preventive care. The ability to identify patients who will not respond to traditional treatment and are at particularly high risk for subsequent morbidity and mortality could enable tailored treatment plans, such as additional immunosuppressive...

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Section: Target-specific Biomarkers Of Agvhdmentioning

confidence: 99%

Section: Decision-making Strategiesmentioning

confidence: 99%

Section: Biomarkers Identified Using the Pathology Of Agvhd Systemic mentioning

confidence: 99%

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Discovery and validation of graft-versus-host disease biomarkers

Paczesny

2013

Blood

130

114

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“…We were, however, unable to assess cytopenias and NK activity accurately when the peripheral blood cell count was poor due to the influence of chemotherapy, including conditioning regimens. In addition, it was considered that the serum levels of sIL-2R might be unreliable when diagnosing HPS in patients who had received allo-HCT, especially during the early phase, because it is well known that the serum levels of sIL-2R are substantially elevated in patients with active acute graft-versus-host-disease (aGVHD), and allogeneic immune responses likely cause an increase in these levels (23,24). We therefore used the modified HLH-2004 criteria when diagnosing HPS before engraftment in allo-HCT patients, as follows: we diagnosed HPS when a patient showed pathological findings of hemophagocytosis and fulfilled at least three of the following four criteria: 1) a fever; 2) splenomegaly; 3) hypertriglyceridemia and/or hypofibrinogenemia; and 4) a serum ferritin level !…”

Section: Definition Of Hpsmentioning

confidence: 99%

Plasma Levels of Presepsin (Soluble CD14-subtype) as a Novel Prognostic Marker for Hemophagocytic Syndrome in Hematological Malignancies

et al. 2016

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Objective Recent studies suggest that presepsin (soluble CD14-subtype) is a useful diagnostic and prognostic marker for sepsis, with secretion by activated macrophages potentially dependent on phagocytosis of microorganisms. As hemophagocytosis is one of the major characteristics in patients with hemophagocytic syndrome (HPS), we hypothesized that presepsin may reflect the phagocytic activity and be a useful prognostic marker for HPS. Therefore, we aimed to assess the prognostic potential of presepsin in secondary HPS in adult patients with hematological malignancies. Methods Between April 2006 and August 2014, we retrospectively examined consecutive patients with HPS whose blood samples were available at our institution and compared the prognostic value of the following in HPS, singly and in combination: plasma presepsin, serum soluble interleukin (IL)-2 receptor (sIL-2R), ferritin, tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), IL-6 and IL-10. Results A total of 14 patients were enrolled. The median age of the patients was 46.5 years (range, 22-65). In univariable Cox models, there were no significant variables associated with the prognosis. However, in 12 evaluable patients, only the combination of higher median values of presepsin (>1,935 pg/mL) and sIL-2R (>4,585 U/mL) at the onset of HPS was significantly associated with the 90-day mortality (hazard ratio 14.5; 95% CI, 1.47-143.36; p=0.02). Conclusion These results suggest that a composite model of plasma presepsin and serum sIL-2R levels at the onset of HPS might be a novel predictor of the prognosis of patients with hematological malignancies and secondary HPS.

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“…5 Recently, a strong association was observed between soluble tumor necrosis factor receptor 1 (sTNFR1) levels and the development of aGvHD, although the low sensitivity of sTNFR1 determination reduces the clinical utility of this biomarker. 6 Donor gene-expression profiles (GEP) can also be used to predict the occurrence of chronic GvHD in the recipient. 7 Although only a pilot study, Buzzeo et al identified a GEP signature of aGvHD, independent of tissue localization, in patients undergoing allogeneic HSCT.…”

Section: Introductionmentioning

confidence: 99%

A molecular and computational diagnostic approach identifies FOXP3, ICOS, CD52 and CASP1 as the most informative biomarkers in acute graft-versus-host disease

Cuzzola¹,

Fiasché²,

Iacopino

et al. 2012

Haematologica

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The online version of this article has a Supplementary Appendix. BackgroundAcute graft-versus-host disease is a severe complication of allogeneic stem cell transplantation in which the functional immune cells of the donor recognize the recipient as foreign and mount an immunological attack. There is an urgent need for better diagnostic instruments for the assessment of acute graft-versus-host disease. In the present study, a novel bioinformatics framework was used to identify gene expression patterns associated with acute graft-versushost disease in patients undergoing allogeneic hematopoietic stem cell transplantation. Design and MethodsPeripheral blood cells were collected prospectively from patients who did develop acute graftversus-host disease (YES) and from those who did not (NO). Gene expression profiling was performed using a panel of 47 candidate genes potentially involved in alloreactive responses. The entire population of YES/NO acute graft-versus-host disease patients formed the experimental validation set. Personalized modeling based on a gene selection technique was applied to identify the most significant mRNA transcripts, which were then used to profile individual data samples for training and testing the classification/prediction framework. ResultsA leave-one-out cross-validation procedure was performed to investigate the robustness of the classification framework producing the following results: 100% on the training dataset and 97% on the testing dataset. According to our integrated methodology, transcripts for FOXP3, ICOS, CD52 and CASP1, genes involved in immune alloreactive responses and participating in immune cell interactions, were identified as the most informative biomarkers in allogeneic stem cell transplant recipients experiencing acute graft-versus-host disease. ConclusionsThis study demonstrates that the integrated methodology proposed is useful for the selection of valid gene targets for the diagnosis of acute graft-versus-host disease, producing satisfactory accuracy over independent clinical features of the allogeneic transplanted population.

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Biomarkers of immune activation to screen for severe, acute GVHD

Cited by 40 publications

References 17 publications

Discovery and validation of graft-versus-host disease biomarkers

Discovery and validation of graft-versus-host disease biomarkers

Plasma Levels of Presepsin (Soluble CD14-subtype) as a Novel Prognostic Marker for Hemophagocytic Syndrome in Hematological Malignancies

A molecular and computational diagnostic approach identifies FOXP3, ICOS, CD52 and CASP1 as the most informative biomarkers in acute graft-versus-host disease

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