[Show abstract][Hide abstract] 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 01/2013; 2013:430209. · 3.06 Impact Factor
[Show abstract][Hide abstract] 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. · 3.54 Impact Factor
[Show abstract][Hide abstract] 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; 13:56. · 3.64 Impact Factor
[Show abstract][Hide abstract] 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. · 1.90 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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. · 11.04 Impact Factor
[Show abstract][Hide abstract] 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. · 4.15 Impact Factor
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] 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.
[Show abstract][Hide abstract] ABSTRACT: The state of tolerance allows long term graft survival without immunosuppressants. Lung transplantation tolerance has not been consistently achieved in either small or large animal models.
The mechanisms and effectiveness of a tolerance induction protocol consisting of donor specific transfusion (DST; day 0) and a short course of co-stimulatory blockade (anti-CD154 antibody; days -7, -4, 0 and +4) were studied in the mouse heterotopic tracheal transplant model of chronic lung rejection. C57BL/6 mice received BALB/c tracheal grafts (day 0) and were treated with DST alone, anti-CD154 alone, the combination (DST/anti-CD154), or no treatment. No non-specific immunosuppressants were used.
DST/anti-CD154 in combination, but neither treatment alone, markedly prolonged the lumen patency and survival (>100 days) of fully histo-incompatible allografts (p<0.05 versus control allografts at every time point studied up to 16 weeks) without immunosuppression. This protocol was donor antigen specific as third party grafts (C3H) were promptly rejected. In addition, DST/anti-CD154 did not result in mixed chimerism but induced transplantation tolerance via a peripheral mechanism(s), which included significantly reduced cytotoxic T cell activity (p<0.001) and a significantly increased percentage of CD4+CD25+ cells (p = 0.03).
The DST/anti-CD154 protocol successfully induced and maintained long term, donor specific tolerance in the mouse heterotopic airway graft model of chronic lung rejection. This finding may lead us closer to successful tolerance induction in lung transplantation.
[Show abstract][Hide abstract] ABSTRACT: Calcineurin inhibitors (CIs) cyclosporin and tacrolimus form the basis for immunosuppression in lung transplantation, yet also exert biological effects on nonlymphoid tissue. With the advent of inhaled cyclosporin, we hypothesize that the airway epithelium is also subject to CI effects at high doses. The aim of this study was to identify human tracheobronchial epithelial cell (hTBEC) calcineurin gene expression and quantify effects of CIs on hTBEC growth, interleukin-1-beta stimulated IL-8 production and hTBEC phenotype. Cyclophillin B and FK-associated binding protein, calcineurin A (alpha and beta), and NFATC3 and NFAT5 were detected in hTBEC cultures by RT-PCR. Acute and chronic cyclosporine treatment 1000 ng/mL significantly inhibited hTBEC proliferation, while tacrolimus did not (range of 10 ng/mL to 1000 ng/mL for acute treatment, 50 ng/mL for chronic treatment). Cyclosporin at 10,000 ng/mL significantly increased LDH release by well-differentiated hTBEC cultures (n = 6) and trended towards significance at 1000 ng/mL. IL1-beta stimulated IL-8 production was significantly increased in rapidly growing hTBEC cultures (n = 8) treated with cyclosporin (p = 0.049). Prolonged treatment of well-differentiated hTBECs at air-liquid-interface (ALI) with cyclosporin 1000 ng/mL significantly reduced intact multilayered mucociliary epithelium (p = 0.009). Inhibition of hTBEC growth, stimulation of IL-8 production and long-term effects on mucociliary phenotype and intact multi-layered epithelium suggest that cyclosporin may have a direct toxic effect on airway epithelium after transplantation.
American Journal of Transplantation 12/2005; 5(11):2660-70. · 6.19 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: More effective immunosuppressants are needed to improve lung-transplantation survival. PX3.102 is a novel immunosuppressant isolated from a mixture of traditional Chinese herbs. We tested its protective role on chronic lung rejection in the heterotopic tracheal transplant model. C57BL/6 mice received BALB/c tracheal grafts and were treated with PX3.102, cyclosporine A, or vehicle. PX3.102 improved tracheal allograft lumen patency (*P<0.01 vs. vehicle and P=0.14 vs. cyclosporine A) but not epithelialization (P>0.2 vs. vehicle). Subsequent in vitro studies demonstrated that PX3.10 was toxic to fully differentiated human tracheal epithelial cells in a dose-dependent manner. PX3.102 markedly suppressed antigen-specific lymphocyte proliferation in vitro at a concentration 10 times lower than cyclosporine A. In conclusion, PX3.102, a promising and potent immunosuppressant, although exhibiting toxicity to airway epithelial cells at high doses, is effective in inhibiting chronic airway allograft rejection.