title: Human biomarker discovery and predictive models for disease progression for idiopathic pneumonia syndrome following allogeneic stem cell transplantation.
abstract: Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative therapy for many malignant and nonmalignant conditions. Idiopathic pneumonia syndrome (IPS) is a frequently fatal complication that limits successful outcomes. Preclinical models suggest that IPS represents an immune mediated attack on the lung involving elements of both the adaptive and the innate immune system. However, the etiology of IPS in humans is less well understood. To explore the disease pathway and uncover potential biomarkers of disease, we performed two separate label-free, proteomics experiments defining the plasma protein profiles of allogeneic SCT patients with IPS. Samples obtained from SCT recipients without complications served as controls. The initial discovery study, intended to explore the disease pathway in humans, identified a set of 81 IPS-associated proteins. These data revealed similarities between the known IPS pathways in mice and the condition in humans, in particular in the acute phase response. In addition, pattern recognition pathways were judged to be significant as a function of development of IPS, and from this pathway we chose the lipopolysaccaharide-binding protein (LBP) protein as a candidate molecular diagnostic for IPS, and verified its increase as a function of disease using an ELISA assay. In a separately designed study, we identified protein-based classifiers that could predict, at day 0 of SCT, patients who: 1) progress to IPS and 2) respond to cytokine neutralization therapy. Using cross-validation strategies, we built highly predictive classifier models of both disease progression and therapeutic response. In sum, data generated in this report confirm previous clinical and experimental findings, provide new insights into the pathophysiology of IPS, identify potential molecular classifiers of the condition, and uncover a set of markers potentially of interest for patient stratification as a basis for individualized therapy.
authors.affiliation: Center for Proteomics and Bioinformatics, Case Western Reserve University School of Medicine, Cleveland, Ohio 44106, USA.
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Schlatzer
authors.forename: Jean-Eudes
authors.initials: JE
authors.lastname: Dazard
authors.forename: Rob M
authors.initials: RM
authors.lastname: Ewing
authors.forename: Serguei
authors.initials: S
authors.lastname: Ilchenko
authors.forename: Sara E
authors.initials: SE
authors.lastname: Tomcheko
authors.forename: Saada
authors.initials: S
authors.lastname: Eid
authors.forename: Vincent
authors.initials: V
authors.lastname: Ho
authors.forename: Greg
authors.initials: G
authors.lastname: Yanik
authors.forename: Mark R
authors.initials: MR
authors.lastname: Chance
authors.forename: Kenneth R
authors.initials: KR
authors.lastname: Cooke
mesh_terms: D000209:Acute-Phase Proteins / Q000302:isolation & purification / Q000378:metabolism; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000302:isolation & purification / Q000378:metabolism*; D053801:Capillary Electrochromatography; D016022:Case-Control Studies; D018450:Disease Progression; D000068800:Etanercept; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007074:Immunoglobulin G / Q000627:therapeutic use; D008954:Models, Biological; D011014:Pneumonia / Q000097:blood* / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D025341:Principal Component Analysis; D040901:Proteomics; D018124:Receptors, Tumor Necrosis Factor / Q000627:therapeutic use; D015203:Reproducibility of Results; D014184:Transplantation, Homologous / Q000009:adverse effects
chemical_list: D000209:Acute-Phase Proteins; D000894:Anti-Inflammatory Agents, Non-Steroidal; D015415:Biomarkers; D001798:Blood Proteins; D007074:Immunoglobulin G; D018124:Receptors, Tumor Necrosis Factor; D000068800:Etanercept