Levine JE, Logan BR, Wu J et al.Acute graft-versus-host disease biomarkers measured during therapy can predict treatment outcomes: a Blood and Marrow Transplant Clinical Trials Network study. Blood 119:3854-3860

University of Michigan Blood and Marrow Transplant Program, Ann Arbor, USA.
Blood (Impact Factor: 10.45). 03/2012; 119(16):3854-60. DOI: 10.1182/blood-2012-01-403063
Source: PubMed

ABSTRACT Acute graft-versus-host disease (GVHD) is the primary limitation of allogeneic hematopoietic cell transplantation, and once it develops, there are no reliable diagnostic tests to predict treatment outcomes. We hypothesized that 6 previously validated diagnostic biomarkers of GVHD (IL-2 receptor-α; tumor necrosis factor receptor-1; hepatocyte growth factor; IL-8; elafin, a skin-specific marker; and regenerating islet-derived 3-α, a gastrointestinal tract-specific marker) could discriminate between therapy responsive and nonresponsive patients and predict survival in patients receiving GVHD therapy. We measured GVHD biomarker concentrations from samples prospectively obtained at the initiation of treatment, day 14, and day 28, on a multicenter, randomized, 4-arm phase 2 clinical trial for newly diagnosed acute GVHD. We found that at each of 3 time points, GVHD onset, 2 weeks into treatment, and 4 weeks into treatment, a 6-protein biomarker panel predicted for the important clinical outcomes of day 28 posttherapy nonresponse and mortality at day 180 from onset. GVHD biomarker panels can be used for early identification of patients at high or low risk for treatment nonresponsiveness or death, and they may provide opportunities for early intervention and improved survival after hematopoietic cell transplantation. The study was registered in as NCT00224874.

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Available from: John Eric Levine, Sep 27, 2015
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    • "Owing to their versatility and reliability, ELISAs have been used to detect HIV/AIDS4, malaria5, cancer67 and inflammatory/autoimmune diseases89, among numerous other pathologies. However, conventional singleplex ELISA formats are limited by high reagent costs, inefficient use of patient samples and an inability to prevent antibody cross-reactions when multiplexed1011. "
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    ABSTRACT: Accurate disease diagnosis, patient stratification and biomarker validation require the analysis of multiple biomarkers. This paper describes cross-reactivity-free multiplexing of enzyme-linked immunosorbent assays (ELISAs) using aqueous two-phase systems (ATPSs) to confine detection antibodies at specific locations in fully aqueous environments. Antibody cross-reactions are eliminated because the detection antibody solutions are co-localized only to corresponding surface-immobilized capture antibody spots. This multiplexing technique is validated using plasma samples from allogeneic bone marrow recipients. Patients with acute graft versus host disease (GVHD), a common and serious condition associated with allogeneic bone marrow transplantation, display higher mean concentrations for four multiplexed biomarkers (HGF, elafin, ST2 and TNFR1) relative to healthy donors and transplant patients without GVHD. The antibody co-localization capability of this technology is particularly useful when using inherently cross-reactive reagents such as polyclonal antibodies, although monoclonal antibody cross-reactivity can also be reduced. Because ATPS-ELISA adapts readily available antibody reagents, plate materials and detection instruments, it should be easily transferable into other research and clinical settings.
    Scientific Reports 05/2014; 4:4878. DOI:10.1038/srep04878 · 5.58 Impact Factor
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    • "Furthermore, although there are no reliable diagnostic tests to predict treatment, with the exception of six previously validated diagnostic biomarkers of GVHD (IL-2 receptor-α; tumour necrosis factor receptor-1; hepatocyte growth factor; IL-8; elafin, a skin-specific marker; and regenerating islet-derived 3-α, a gastrointestinal tract-specific marker) (16), a novel acute GVHD risk score has been created to define high-risk acute GVHD at the onset (17). "
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    ABSTRACT: Graft-versus-host disease (GVHD) is a common and often fatal complication of bone marrow transplantation. Antigen-presenting cells from donor and recipient play a critical role in the initiation and maintenance of GVHD. CD83, which is expressed in activated lymphocytes and dendritic cells, is regarded as a marker of mature dendritic cells. Targeting CD83 using soluble CD83 molecules or antibodies has been demonstrated to have therapeutic effects against GVHD in preclinical models. Understanding the biological function of CD83 and the underlying mechanisms through which targeting CD83 attenuates GVHD is likely to greatly improve current treatments and provide new methods for the treatment of GVHD.
    Experimental and therapeutic medicine 06/2013; 5(6):1545-1550. DOI:10.3892/etm.2013.1033 · 1.27 Impact Factor
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    • "The expression of these molecules on PB donor T cells correlates with the identified cell migration phase and strongly associates with aGVHD induction in allo-HCT suggesting their potential usefulness as predictive markers. Recently, research efforts have focused on the identification of reliable predictive markers to identify patients at risk before aGVHD onset with some potential biomarkers being investigated thoroughly [18,19]. Different combinations of these biomarkers have been used to predict treatment response and survival of aGVHD patients, but a predictive marker panel to reliably identify patients at risk for aGVHD is still lacking. "
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    ABSTRACT: Background Acute graft-versus-host disease (aGVHD) poses a major limitation for broader therapeutic application of allogeneic hematopoietic cell transplantation (allo-HCT). Early diagnosis of aGVHD remains difficult and is based on clinical symptoms and histopathological evaluation of tissue biopsies. Thus, current aGVHD diagnosis is limited to patients with established disease manifestation. Therefore, for improved disease prevention it is important to develop predictive assays to identify patients at risk of developing aGVHD. Here we address whether insights into the timing of the aGVHD initiation and effector phases could allow for the detection of migrating alloreactive T cells before clinical aGVHD onset to permit for efficient therapeutic intervention. Methods Murine major histocompatibility complex (MHC) mismatched and minor histocompatibility antigen (miHAg) mismatched allo-HCT models were employed to assess the spatiotemporal distribution of donor T cells with flow cytometry and in vivo bioluminescence imaging (BLI). Daily flow cytometry analysis of peripheral blood mononuclear cells allowed us to identify migrating alloreactive T cells based on homing receptor expression profiles. Results We identified a time period of 2 weeks of massive alloreactive donor T cell migration in the blood after miHAg mismatch allo-HCT before clinical aGVHD symptoms appeared. Alloreactive T cells upregulated α4β7 integrin and P-selectin ligand during this migration phase. Consequently, targeted preemptive treatment with rapamycin, starting at the earliest detection time of alloreactive donor T cells in the peripheral blood, prevented lethal aGVHD. Conclusions Based on this data we propose a critical time frame prior to the onset of aGVHD symptoms to identify alloreactive T cells in the peripheral blood for timely and effective therapeutic intervention.
    BMC Medicine 05/2013; 11(1):134. DOI:10.1186/1741-7015-11-134 · 7.25 Impact Factor
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