Isabel P Neuringer

University of North Carolina at Chapel Hill, North Carolina, United States

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Publications (43)246.45 Total impact

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    ABSTRACT: Epithelial injury is often detected in lung allografts however its relation to rejection pathogenesis is unknown. We hypothesized that sterile epithelial injury can lead to alloimmune activation in the lung. We performed adoptive transfer of mismatched splenocytes into recombinant activating gene 1 (Rag1) deficient mice to induce an alloimmune status, then exposed these mice to naphthalene to induce sterile epithelial injury. We evaluated lungs for presence of alloimmune lung injury, endoplasmic reticulum (ER) stress, and hyaluronan expression, examined the effect of ER stress induction on hyaluronan expression and lymphocyte trapping by bronchial epithelia in vitro, and examined airways from patients with bronchiolitis obliterans syndrome (BOS) and normal controls histologically. We found that Rag1 deficient mice which received mismatched splenocytes and naphthalene injection displayed bronchial epithelial ER stress, peribronchial hyaluronan expression, and lymphocytic bronchitis. Bronchial epithelial ER stress led to the expression of lymphocyte-trapping hyaluronan cables in vitro. Blockade of hyaluronan binding ameliorated naphthalene-induced lymphocytic bronchitis. ER stress was present histologically in over 40% of bronchial epithelia of BOS patients, and associated with subepithelial hyaluronan deposition. We conclude that sterile bronchial epithelial injury in the context of alloimmunity can lead to sustained ER stress, and promote allograft rejection through hyaluronan expression.
    AJP Lung Cellular and Molecular Physiology 04/2014; 306(11). DOI:10.1152/ajplung.00353.2013 · 4.08 Impact Factor
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    Isabel P Neuringer
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    ABSTRACT: Posttransplant lymphoproliferative disease (PTLD) after lung transplantation occurs due to immunosuppressant therapy which limits antiviral host immunity and permits Epstein-Barr viral (EBV) replication and transformation of B cells. Mechanistically, EBV survives due to latency, escape from cytotoxic T cell responses, and downregulation of host immunity to EBV. Clinical presentation of EBV may occur within the lung allograft early posttransplantation or later onset which is more likely to be disseminated. Improvements in monitoring through EBV viral load have provided a means of earlier detection; yet, sensitivity and specificity of EBV load monitoring after lung transplantation may require further optimization. Once PTLD develops, staging and tissue diagnosis are essential to appropriate histopathological classification, prognosis, and guidance for therapy. The overall paradigm to treat PTLD has evolved over the past several years and depends upon assessment of risk such as EBV-naïve status, clinical presentation, and stage and sites of disease. In general, clinical practice involves reduction in immunosuppression, anti-CD20 biologic therapy, and/or use of plasma cell inhibition, followed by chemotherapy for refractory PTLD. This paper focuses upon the immunobiology of EBV and PTLD, as well as the clinical presentation, diagnosis, prognosis, and emerging treatments for PTLD after lung transplantation.
    Clinical and Developmental Immunology 03/2013; 2013(6):430209. DOI:10.1155/2013/430209 · 2.93 Impact Factor
  • Leonard J Lobo · Robert M Aris · John Schmitz · Isabel P Neuringer
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    ABSTRACT: Lung transplantation is limited by chronic lung allograft dysfunction. Acute cellular rejection (ACR) is a risk factor for allograft dysfunction; however, the role of antibody-mediated rejection (AMR) is not well characterized. This was a retrospective review from 2007 to 2011 of lung transplant recipients with human leukocyte antigen (HLA) antibody testing using Luminex (Luminex Corp, Austin, TX) single-antigen beads. Statistics included Fisher's exact test for significance. Donor-specific antibodies (DSA) developed in 13 of 44 patients. Of the 13 with DSA, 12 had cystic fibrosis compared with 18 of 31 in the non-DSA group (p = 0.035). Of those with DSAs, 23.1% occurred within the first year, and 69.2% occurred between 1 and 3 years. Twelve of 13 DSA patients had anti-HLA DQ specificity compared with 2 of 31 non-DSA patients (p = 0.0007). AMR developed in 10 of the 13 DSA patients compared with 1 of 31 non-DSA patients (p = 0.0001). The DSA group experienced 2.6 episodes/patient of cellular rejection vs 1.7 episodes/patient in the non-DSA group (p = 0.059). Bronchiolitis obliterans syndrome developed in 11 of 13 in the DSA group vs 10 of 31 in the non-DSA group (p = 0.0024). In the DSA group, 11.5% HLAs matched compared with 20.4% in the non-DSA group (p = 0.093). AMR developed in 11 of 22 patients in the non-DSA HLA group compared with 0 of 22 in the group without non-DSA HLA antibodies (p = 0.002). Survival at 1 and 3 years was 92% and 36% in the DSA group, respectively, and 97% and 65% in the non-DSA group. DSAs and non-DSAs occur frequently after lung transplantation. DSAs are prevalent in the cystic fibrosis population and are associated with AMR, bronchiolitis obliterans syndrome, and possibly, ACR.
    The Journal of heart and lung transplantation: the official publication of the International Society for Heart Transplantation 01/2013; 32(1):70-7. DOI:10.1016/j.healun.2012.10.007 · 6.65 Impact Factor
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    ABSTRACT: Long-term lung allograft survival is limited by bronchiolitis obliterans syndrome (BOS). Mannose binding lectin (MBL) belongs to the innate immune system, participates in complement activation, and may predispose to graft rejection. We investigated mannose binding (MBL) during cold ischemia and in tissue samples from explanted lungs with BOS, and assessed MBL and complement proteins in plasma post-lung transplantation relative to BOS staging. MBL was detected by immunohistochemistry lung tissue at the time of cold ischemia and in samples with BOS. MBL was assayed in the peripheral blood of 66 lung transplant patients transplanted between 1990-2007. MBL localized to vasculature and basement membrane during cold ischemia and BOS. Patients further out post-lung transplant > 5 years (n = 33), had significantly lower levels of MBL in the blood compared to lung transplant patients < 5 years with BOS Op-3 (n = 17), 1738 ± 250 ng/ml vs 3198 ± 370 ng/ml, p = 0.027, and similar levels to lung transplant patients < 5 years with BOS 0 (n = 16), 1738 ± 250 ng/ml vs 1808 ± 345 ng/ml. MBL levels in all BOS 0 (n = 30) vs. all BOS Op-3 (n = 36) were 1378 ± 275 ng/ml vs. 2578 ± 390 ng/ml, p = 0.001, respectively. C3 plasma levels in BOS 0 (n = 30) vs. BOS Op-3 (n = 36) were 101 ± 19.8 mg/ml vs. 114 ± 25.2 mg/ml, p = 0.024, respectively. MBL localizes within the lung during graft ischemia and BOS, higher levels of plasma MBL are associated with BOS Op-3 and < 5 years post-transplant, and higher level of plasma complement protein C3 was associated with BOS Op-3 clinical status. MBL may serve as a biomarker for poorer outcome post-lung transplantation.
    Respiratory research 07/2012; 13(1):56. DOI:10.1186/1465-9921-13-56 · 3.09 Impact Factor
  • Leonard J. Lobo · Isabel P. Neuringer
    American Thoracic Society 2012 International Conference, May 18-23, 2012 • San Francisco, California; 05/2012
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    ABSTRACT: The role of innate immune regulators is investigated in injury sustained from irradiation as in the clinic for cancer treatment or from a nuclear incident. The protective benefits of flagellin signaling through Toll-like receptors (TLR) in an irradiation setting warrant study of a key intracellular adaptor of TLR signaling, namely Myeloid differentiation primary response factor 88 (MyD88). The role of MyD88 in regulating innate immunity and Nuclear factor kappa-B (NF-κB)-activated responses targets this critical factor for influencing injury and recovery as well as maintaining immune homeostasis. To examine the role of MyD88, we examined immune cells and factors during acute pneumonitic and fibrotic phases in Myd88-deficient animals receiving thoracic gamma (γ)-irradiation. We found that MyD88 supports survival from radiation-induced injury through the regulation of inflammatory factors that aid in recovery from irradiation. The absence of MyD88 resulted in unresolved pulmonary infiltrate and enhanced collagen deposition plus elevated type 2 helper T cell (Th2) cytokines in long-term survivors of irradiation. These results based only on a gene deletion model suggest that alterations of MyD88-dependent inflammatory processes impact chronic lung injury. Therefore, MyD88 may contribute to attenuating long-term radiation-induced lung injury and protecting against fibrosis.
    International Journal of Radiation Biology 02/2012; 88(4):335-47. DOI:10.3109/09553002.2012.652723 · 1.69 Impact Factor
  • American Thoracic Society 2011 International Conference, May 13-18, 2011 • Denver Colorado; 05/2011
  • Isabel P Neuringer · Robert M Aris
    Transplantation 10/2010; 90(8):823-4. DOI:10.1097/TP.0b013e3181f2c99e · 3.83 Impact Factor
  • I. P. Neuringer · R. M. Aris · W. J. Brickey
    Transplantation 07/2010; 90. DOI:10.1097/00007890-201007272-00896 · 3.83 Impact Factor
  • American Thoracic Society 2010 International Conference, May 14-19, 2010 • New Orleans; 05/2010
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    ABSTRACT: Cystic fibrosis (CF) is the most common genetic disease within the white population and leads to premature respiratory failure. Approximately, 60 000 individuals are currently living with CF in North America and Europe, almost half of whom are adults. Dozens of studies across the globe indicate that CF adults have low bone density and increased rates of fractures. This genesis of the problem appears to be in late childhood to adolescence. Prevention and treatment of CF-related bone disease must address the myriad risk factors (decreased absorption of fat-soluble vitamins due to pancreatic insufficiency, altered sex hormone production, chronic lung infection with increased serum levels of proinflammatory, bone-active cytokines, malnutrition and low body weight, physical inactivity and glucocorticoid therapy) for poor bone health. This review will address the pathogenesis, diagnosis and treatment of bone disease in CF. It will also discuss best practice guidelines for optimizing bone health in patients with CF.
    Current opinion in endocrinology, diabetes, and obesity 10/2009; 16(6):407-14. DOI:10.1097/MED.0b013e3283329b16 · 3.37 Impact Factor
  • Isabel P Neuringer · Peadar Noone · Rebecca K Cicale · Ken Davis · Robert M Aris
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    ABSTRACT: Lung transplantation has become a proven therapeutic option for patients with end-stage lung disease, extending life and providing improved quality of life to those who otherwise would continue to be breathless and oxygen-dependent. Over the past 20 years, considerable experience has been gained in understanding the multitude of medical and surgical issues that impact upon patient survival. Today, clinicians have an armamentarium of tools to manage diverse problems such as primary graft dysfunction, acute and chronic allograft rejection, airway anastomotic issues, infectious complications, renal dysfunction, diabetes and osteoporosis, hematological and gastrointestinal problems, malignancy, and other unique issues that confront immunosuppressed solid organ transplant recipients.
    Expert Review of Respiratory Medicine 08/2009; 3(4):403-23. DOI:10.1586/ers.09.27
  • RM Aris · P McNeillie · C Hammett-Stabler · IP Neuringer
    American Thoracic Society 2009 International Conference, May 15-20, 2009 • San Diego, California; 04/2009
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    ABSTRACT: Elevation in Epstein-Barr virus (EBV) circulating DNA has been proposed as a marker for development of post-transplant lymphoproliferative disease (PTLD), but few published data exist in the study of lung-transplant recipients. To determine if elevated EBV DNA levels, in combination with other risk factors, were predictive of PTLD. We conducted a retrospective, single-center study examining all lung transplant recipients (n = 296) and EBV DNA levels (n = 612) using real-time TaqMan polymerase chain reaction. There were 13 cases of PTLD overall, of which 5 occurred in the era of EBV DNA monitoring. EBV DNA levels were distributed differently among seropositive and seronegative patients, with the latter having higher values (P < 0.0001). Among the cohort of pretransplantation seropositive patients, there was one diagnosed with PTLD. The EBV DNA level in this patient was elevated at the time of PTLD diagnosis (sensitivity = 100%, specificity = 100% for PTLD). Among the cohort of pretransplantation seronegative patients, there were four with a diagnosis of PTLD. In all four patients, the EBV DNA level was detectable (sensitivity = 100%, specificity = 24%), but in only two was it elevated (sensitivity = 50%, specificity = 22%). HLA-A3 expression in the recipient and/or donor conferred additional risk for PTLD among the seronegative patients (P = 0.026 to 0.003). No other PTLD risk factor was found. EBV DNA levels are a useful but imperfect predictor of PTLD in patients with lung transplants. Pretransplant EBV status affected the results of the assay and should be considered when interpreting test results. HLA-A3 was strongly linked to PTLD and may be a novel marker of PTLD risk.
    American Journal of Respiratory and Critical Care Medicine 09/2008; 178(10):1060-5. DOI:10.1164/rccm.200804-531OC · 13.00 Impact Factor
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    ABSTRACT: Lung transplantation provides a successful therapy for end-stage lung disease. However, problems such as acute and chronic lung allograft rejection, the latter also known as bronchiolitis obliterans syndrome (BOS), remain obstacles to achieving better long term outcomes. Novel biomarkers identified in peripheral blood, bronchoalveolar lavage, and lung allograft airway and parenchymal tissue are forwarding progress in the diagnosis of allograft rejection, as well as enhancing our understanding bf the immunopathogenesis of BOS. Soluble CD30 levels in peripheral blood reflect T cell activation, and BAL studies with reduced airway-epithelial associated proteins such as CCSP, and increased neutrephil chemotactic factors such as HNPs 1-3 are both linked to BOS. Analysis of transbronchial biopsy specimens for C4d complement deposition, while still in its infancy, seems to help diagnose humoral rejection, which often presents as Fulminant respiratory failure and capillaritis. Studies employing basic and translational approaches also now identify a role for innate immunity, as reflected by TLR. recipient polymorphisms serving a protective role in the lung allograft. Bacterial and viral infections prevalent in lung allograft recipients through reactivation of endogenous organisms or acquisition of new infections, exert complex immunomodulatory effects, including persistent effector T cell types, which may influence the acquisition or stability of operational tolerance. Disruption of the delicate balance between proteases and inhibitors within the allograft airway submucosa impact upon tissue repair and fibroproliferation evident in BOS. Also of great importance, autoimmunity, as manifest by the ability to recognize self collagen V epitopes, may play a role in acute rejection. Lastly, the application of genome-wide profiling, has expanded our ability to understand the biological processes involved in T cell activation, cytokine secretion, and airway injury. On the therapeutic horizon, clinical studies have demonstrated improved treatment of chronic allograft rejection with agents such as inhaled cyclosporine, everolimus, and azithromycin. The widespread use of these and newer compounds awaits additional proof of efficacy from randomized, controlled studies, which, heretofore, have not attracted the attention of prominent funding groups. Ultimately, application of basic, translational, and clinical studies towards the diminution of rejection and/or the achievement of lung allograft tolerance will propel improvements (or gains) in long term patient survival post lung transplantation.
    Current Respiratory Medicine Reviews 02/2008; 4(1):40-51. DOI:10.2174/157339808783497774
  • The Journal of Heart and Lung Transplantation 02/2008; 27(2). DOI:10.1016/j.healun.2007.11.416 · 6.65 Impact Factor
  • The Journal of Heart and Lung Transplantation 02/2007; 26(2). DOI:10.1016/j.healun.2006.11.439 · 6.65 Impact Factor
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    ABSTRACT: Propionibacterium acnes (PA) is a gram-positive anaerobic bacterium implicated as a putative etiologic agent of sarcoidosis. To characterize the pulmonary immune response to PA, C57BL/6 and BALB/c mice were intraperitoneally sensitized and intratracheally challenged with heat-killed bacteria. C57BL/6 mice challenged with PA developed a cellular immune response characterized by elevations in Th1 cytokines/chemokines, increased numbers of lymphocytes and macrophages in lung lavage fluid, and peribronchovascular granulomatous inflammation composed of T- and B-lymphocytes and epithelioid histiocytes. T-lymphocytes in the lung lavage fluid showed a marked CD4+ cell predominance. In contrast, C57BL/6 mice challenged with Staphylococcus epidermidis (SE), another gram-positive commensal of human skin, and BALB/c mice challenged with PA, showed only a modest induction of Th1 cytokines, less pulmonary inflammation, and no granulomatous changes in the lung. Enhancement of Toll-like receptor expression was seen in PA-exposed C57BL/6 mice within 24 h after exposure, suggesting that induction of innate immunity by PA contributes to the robust, polarized Th1 immune response elicited by this bacterium. These findings suggest that PA-induced pulmonary inflammation may be a useful model for testing the contributions of both bacterial and host factors in the development, maintenance, and resolution of granulomatous inflammation in the lung.
    American Journal of Respiratory Cell and Molecular Biology 10/2006; 35(3):347-56. DOI:10.1165/rcmb.2005-0285OC · 3.99 Impact Factor
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    ABSTRACT: WC and NS contributed equally. Non-tuberculous mycobacteria (NTM) frequently colonise patients with end stage cystic fibrosis (CF), but its impact on the course of the disease following lung transplantation is unknown. Lung transplant recipients with CF who underwent lung transplantation at our institution between January 1990 and May 2003 (n=146) and CF patients awaiting lung transplantation in May 2003 (n=31) were studied retrospectively. The prevalence rate of NTM isolated from respiratory cultures in patients with end stage CF referred for lung transplantation was 19.7%, compared with a prevalence rate of 13.7% for NTM isolates in CF lung transplant recipients. The overall prevalence of invasive NTM disease after lung transplantation was low (3.4%) and was predicted most strongly by pre-transplant NTM isolation (p=0.001, Fisher's exact test, odds ratio (OR) 6.13, 95% CI 3.2 to 11.4). This association was restricted to Mycobacterium abscessus (p = 0.005, Fisher's exact test, OR 7.45, 95% CI 2.9 to 16.9). While NTM disease caused significant morbidity in a small number of patients after transplantation, it was successfully treated and did not influence the post-transplant course of the disease. The isolation of NTM before transplantation in CF patients should not be an exclusion criterion for lung transplantation, but it may alert the clinician to patients at risk of recurrence following transplantation.
    Thorax 07/2006; 61(6):507-13. DOI:10.1136/thx.2005.049247 · 8.29 Impact Factor
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    I P Neuringer · S H Randell
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    ABSTRACT: Currently, there is great enthusiasm about potential stem cell therapies for intractable diseases. We previously reviewed the topic of stem cells in lung injury and repair, including the role of endogenous, tissue (somatic) stem cells and the contribution of circulating cells to the lung parenchyma. Our purpose here is to provide a concise update in this fast-moving field. New information and ongoing debate focus attention on basic issues in lung stem cell biology and highlight the need for additional studies to establish the feasibility of cell therapies to prevent or treat lung diseases.
    Monaldi archives for chest disease = Archivio Monaldi per le malattie del torace / Fondazione clinica del lavoro, IRCCS [and] Istituto di clinica tisiologica e malattie apparato respiratorio, Università di Napoli, Secondo ateneo 04/2006; 65(1):47-51.

Publication Stats

955 Citations
246.45 Total Impact Points


  • 1996–2014
    • University of North Carolina at Chapel Hill
      • • Pediatric Critical Care Medicine Division
      • • Department of Medicine
      • • Cystic Fibrosis and Pulmonary Diseases Research and Treatment Center
      North Carolina, United States
  • 2012–2013
    • Massachusetts General Hospital
      Boston, Massachusetts, United States
  • 2006
    • The Ohio State University
      Columbus, Ohio, United States