Publications by authors named "Robert B Love"

47 Publications

Donation after circulatory death: the current state and technical approaches to organ procurement.

Curr Opin Organ Transplant 2015 Apr;20(2):127-32

Division of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaukee, Wisconsin, USA.

Purpose Of Review: In this review, we discuss the current state of donation after circulatory death (DCD). We define the DCD donor and describe the current protocols in management of the DCD patient. We then discuss current techniques in organ procurement of the lung and abdominal organs.

Recent Findings: Although donation after brain death is preferable to DCD, recent data have demonstrated acceptable early outcomes in both thoracic and abdominal organ transplant. In spite of advancements in surgical techniques and organ preservation, much has yet to be learned to minimize warm ischemia time and reperfusion injury in the DCD population.

Summary: In light of the continually growing disparity between organ supply and demand, DCD has regained traction as a means to increase the donor pool.
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http://dx.doi.org/10.1097/MOT.0000000000000179DOI Listing
April 2015

Clinical neurology in lung transplantation.

Handb Clin Neurol 2014 ;121:1237-43

Department of Cardiothoracic Surgery, Medical College of Wisconsin, Milwaulkee, Wi, USA.

Lung transplantation is the only established therapeutic option for several end-stage respiratory diseases. Limited mostly by lack of suitable allografts, the results have measurably improved over the last decade. Numerous surgical and pharmaceutical improvements have had positive impact on outcomes. The potential for critical care issues and the need for interdisciplinary management remains paramount. Cardiac, renal, and metabolic complications are frequently encountered in the acute postoperative phase. Allograft rejection and infectious diseases as well as problems related to immunosuppressive regimen are seen later after lung transplantation. Neurologic manifestations with a range of etiologies are discussed here in this context.
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http://dx.doi.org/10.1016/B978-0-7020-4088-7.00083-3DOI Listing
April 2014

Membranous atresia of anomalous left coronary artery originating from the pulmonary artery presenting as an intravascular tumor.

J Thorac Cardiovasc Surg 2014 Mar 15;147(3):e13-4. Epub 2013 Nov 15.

Division of Cardiothoracic Surgery, Department of Surgery, Medical College of Wisconsin, Milwaukee, Wis; Herma Heart Center, Children's Hospital of Wisconsin, Milwaukee, Wis. Electronic address:

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http://dx.doi.org/10.1016/j.jtcvs.2013.09.057DOI Listing
March 2014

Pepsin concentrations are elevated in the bronchoalveolar lavage fluid of patients with idiopathic pulmonary fibrosis after lung transplantation.

J Surg Res 2013 Dec 29;185(2):e101-8. Epub 2013 Jun 29.

Department of Surgery, Loyola University Chicago Health Sciences Campus, Maywood, Illinois.

Background: Aspiration of gastroesophageal refluxate has been implicated in the pathogenesis of idiopathic pulmonary fibrosis (IPF) and the progression of bronchiolitis obliterans syndrome after lung transplantation. The goals of the present study were to identify lung transplant patients at the greatest risk of aspiration and to investigate the causative factors.

Materials And Methods: From September 2009 to November 2011, 252 bronchoalveolar lavage fluid (BALF) samples were collected from 100 lung transplant patients. The BALF pepsin concentrations and the results of transbronchial biopsy, esophageal function testing, barium swallow, and gastric emptying scan were compared among those with the most common end-stage lung diseases requiring lung transplantation: IPF, chronic obstructive pulmonary disease, cystic fibrosis, and α1-antitrypsin deficiency.

Results: Patients with IPF had higher BALF pepsin concentrations and a greater frequency of acute rejection than those with α1-antitrypsin deficiency, cystic fibrosis, or chronic obstructive pulmonary disease (P = 0.037). Moreover, the BALF pepsin concentrations correlated negatively with a lower esophageal sphincter pressure and distal esophageal amplitude; negatively with distal esophageal amplitude and positively with total esophageal acid time, longest reflux episode, and DeMeester score in those with chronic obstructive pulmonary disease; and negatively with the upright acid clearance time in those with IPF.

Conclusions: Our results suggest that patients with IPF after lung transplantation are at increased risk of aspiration and a greater frequency of acute rejection episodes, and that the risk factors for aspiration might be different among those with the most common end-stage lung diseases who have undergone lung transplantation. These results support the role of evaluating the BALF for markers of aspiration in assessing lung transplant patients as candidates for antireflux surgery.
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http://dx.doi.org/10.1016/j.jss.2013.06.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4306555PMC
December 2013

Positioning ganglioside D3 as an immunotherapeutic target in lymphangioleiomyomatosis.

Am J Pathol 2013 Jul 10;183(1):226-34. Epub 2013 May 10.

Department of Medicine, Loyola University Stritch School of Medicine, Maywood, Illinois 60153, USA.

Tumors that develop in lymphangioleiomyomatosis (LAM) as a consequence of biallelic loss of TSC1 or TSC2 gene function express melanoma differentiation antigens. However, the percentage of LAM cells expressing these melanosomal antigens is limited. Here, we report the overexpression of ganglioside D3 (GD3) in LAM. GD3 is a tumor-associated antigen otherwise found in melanoma and neuroendocrine tumors; normal expression is largely restricted to neuronal cells in the brain. We also observed markedly reduced serum antibody titers to GD3, which may allow for a population of GD3-expressing LAM cells to expand within patients. This is supported by the demonstrated sensitivity of cultured LAM cells to complement mediated cytotoxicity via GD3 antibodies. GD3 can serve as a natural killer T (NKT) cell antigen when presented on CD1d molecules expressed on professional antigen-presenting cells. Although CD1d-expressing monocyte derivatives were present in situ, enhanced NKT-cell recruitment to LAM lung was not observed. Cultured LAM cells retained surface expression of GD3 over several passages and also expressed CD1d, implying that infiltrating NKT cells can be directly cytotoxic toward LAM lung lesions. Immunization with antibodies to GD3 may thus be therapeutic in LAM, and enhancement of existing NKT-cell infiltration may be effective to further improve antitumor responses. Overall, we hereby establish GD3 as a suitable target for immunotherapy of LAM.
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http://dx.doi.org/10.1016/j.ajpath.2013.04.002DOI Listing
July 2013

Decreased incidence of cytomegalovirus infection with sirolimus in a post hoc randomized, multicenter study in lung transplantation.

J Heart Lung Transplant 2013 Jul 7;32(7):701-6. Epub 2013 May 7.

Department of Medicine, University of Chicago Medical Center, Chicago, Illinois 60611, USA.

Background: Cytomegalovirus (CMV) is the most common opportunistic infection in lung transplantation. A recent multicenter, randomized trial (the AIRSAC study) comparing sirolimus to azathioprine in lung transplant recipients showed a decreased incidence of CMV events in the sirolimus cohort. To better characterize this relationship of decreased incidence of CMV events with sirolimus, we examined known risk factors and characteristics of CMV events from the AIRSAC database.

Methods: The AIRSAC database included 181 lung transplant patients from 8 U.S.-based lung transplant centers that were randomized to sirolimus or azathioprine at 3 months post-transplantation. CMV incidence, prophylaxis, diagnosis and treatment data were all prospectively collected. Prophylaxis and treatment of CMV were at the discretion of each institution.

Results: The overall incidence of any CMV event was decreased in the sirolimus arm when compared with the azathioprine arm at 1 year after lung transplantation (relative risk [RR] = 0.67, confidence interval [CI] 0.55 to 0.82, p < 0.01). This decreased incidence of CMV events with sirolimus remained significant after adjusting for confounding factors of CMV serostatus and CMV prophylaxis.

Conclusions: These data support results from other solid-organ transplantation studies and suggest further investigation of this agent in the treatment of lung transplant recipients at high risk for CMV events.
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http://dx.doi.org/10.1016/j.healun.2013.04.010DOI Listing
July 2013

Interobserver variability in grading transbronchial lung biopsy specimens after lung transplantation.

Chest 2013 Jun;143(6):1717-1724

Columbia University Medical Center, New York, NY.

Background: Acute rejection remains a major source of morbidity after lung transplantation. Given the importance of this diagnosis, an international grading system was developed to standardize the diagnosis of acute lung-allograft rejection. The reliability of this grading system has not been adequately assessed by previous studies.

Methods: We examined the level of agreement in grading transbronchial biopsy specimens obtained from a large multicenter study (AIRSAC [Comparison of a Tacrolimus/Sirolimus/Prednisone Regimen vs Tacrolimus/Azathioprine/Prednisone Immunosuppressive Regimen in Lung Transplantation] trial). Biopsy specimens were initially graded for acute rejection and lymphocytic bronchiolitis by the site pathologist and subsequently graded by a central pathologist. Reliability of interobserver grading was evaluated using Cohen κ coefficients.

Results: A total of 481 transbronchial biopsy specimens were graded by both the site and central pathologists. The overall concordance rates were 74% and 89% for grade A and grade B biopsy specimens, respectively. When samples from biopsies performed at different time points after transplantation were assessed, there was a higher level of agreement early (≤ 6 weeks) after transplant compared with later time points for acute rejection. However, there was still only moderate agreement for both grade A (κ score 0.479; 95% CI, 0.29-0.67) and grade B (κ score 0.465; 95% CI, 0.08-0.85) rejection.

Conclusions: These results expand upon previous reports of interobserver variability in grading transbronchial biopsy specimens after lung transplantation. Given the variability in grading these specimens, we advocate further education of the histopathologic findings in lung transplant biopsy specimens, as well as revisiting the current criteria for grading transbronchial biopsy specimens to improve concordance among lung transplant pathologists.

Trial Registry: ClinicalTrials.gov; No. NCT00321906; URL: www.clinicaltrials.gov.
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http://dx.doi.org/10.1378/chest.12-2107DOI Listing
June 2013

Ontogeny and localization of the cells produce IL-2 in healthy animals.

Cytokine 2013 Mar 16;61(3):831-41. Epub 2013 Jan 16.

Department of Microbiology and Immunology, Loyola University Chicago, 2160 South First Ave., Maywood, IL 60153, USA.

IL-2 is a growth factor for activated T cells and is required for maintenance of naturally arising regulatory T cells (nTregs). Mice defective in IL-2/IL-2 receptor signaling pathways have impaired nTregs and suffer from lymphoproliferative disorders, suggesting that IL-2 is present and functional in healthy animals. However, the cellular source of IL-2 is currently unknown. To determine which cells produce IL-2 in healthy animals, we established mice carrying cre gene knock in at the il-2 locus (termed IL-2(cre)). When IL-2(cre) mice were crossed with EGFP reporter mice, EGFP was exclusively expressed by a fraction of CD4 T cells present in both lymphoid and non-lymphoid tissues. Live imaging of IL-2(cre) mice that carry the luciferase reporter showed concentrated localization of luciferase(+) cells in Peyer's patches. These cells were not observed in new born mice but appeared within 3days after birth. Reduction of antigen receptor repertoire by transgene expression reduced their number, indicating that recognition of environmental antigens is necessary for generation of these IL-2 producers in healthy animals. A substantial fraction of EGFP(+) cells also produce IL-10 and IFN-γ, a characteristic profile of type 1 regulatory T cells (Tr1). The data suggest that a group of Tr1 cells have addition roles in immune homeostasis by producing IL-2 along with other cytokines and help maintaining Tregs.
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http://dx.doi.org/10.1016/j.cyto.2012.11.026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3595346PMC
March 2013

Cellular basis of tissue regeneration by omentum.

PLoS One 2012 6;7(6):e38368. Epub 2012 Jun 6.

Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Chicago, Illinois, United States of America.

The omentum is a sheet-like tissue attached to the greater curvature of the stomach and contains secondary lymphoid organs called milky spots. The omentum has been used for its healing potential for over 100 years by transposing the omental pedicle to injured organs (omental transposition), but the mechanism by which omentum helps the healing process of damaged tissues is not well understood. Omental transposition promotes expansion of pancreatic islets, hepatocytes, embryonic kidney, and neurons. Omental cells (OCs) can be activated by foreign bodies in vivo. Once activated, they become a rich source for growth factors and express pluripotent stem cell markers. Moreover, OCs become engrafted in injured tissues suggesting that they might function as stem cells.Omentum consists of a variety of phenotypically and functionally distinctive cells. To understand the mechanism of tissue repair support by the omentum in more detail, we analyzed the cell subsets derived from the omentum on immune and inflammatory responses. Our data demonstrate that the omentum contains at least two groups of cells that support tissue repair, immunomodulatory myeloid derived suppressor cells and omnipotent stem cells that are indistinguishable from mesenchymal stem cells. Based on these data, we propose that the omentum is a designated organ for tissue repair and healing in response to foreign invasion and tissue damage.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0038368PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3368844PMC
November 2012

Pin1 protein regulates Smad protein signaling and pulmonary fibrosis.

J Biol Chem 2012 Jul 21;287(28):23294-305. Epub 2012 May 21.

Department of Pathology and Laboratory Medicine, University of Wisconsin School of Medicine and Public Health, Madison, Wisconsin 53706, USA.

Interstitial pulmonary fibrosis is caused by the excess production of extracellular matrix (ECM) by Fb in response to TGF-β1. Here, we show that the peptidyl-prolyl isomerase Pin1 modulates the production of many pro- and antifibrogenic cytokines and ECM. After acute, bleomycin injury, Pin1(-/-) mice showed reduced, pulmonary expression of collagens, tissue inhibitors of metalloproteinases, and fibrogenic cytokines but increased matrix metalloproteinases, compared with WT mice, despite similar levels of inflammation. In primary fibroblasts, Pin1 was required for TGF-β-induced phosphorylation, nuclear translocation, and transcriptional activity of Smad3. In Pin1(-/-) cells, inhibitory Smad6 was found in the cytoplasm rather than nucleus. Smad6 knockdown in Pin1(-/-) fibroblasts restored TGF-β-induced Smad3 activation, translocation, and target gene expression. Therefore, Pin1 is essential for normal Smad6 function and ECM production in response to injury or TGF-β and thus may be an attractive therapeutic target to prevent excess scarring in diverse lung diseases.
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http://dx.doi.org/10.1074/jbc.M111.313684DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3390608PMC
July 2012

Pulmonary immune changes early after laparoscopic antireflux surgery in lung transplant patients with gastroesophageal reflux disease.

J Surg Res 2012 Oct 18;177(2):e65-73. Epub 2012 Apr 18.

Department of Surgery, Loyola University Chicago, Health Sciences Campus, Maywood, Illinois, USA.

Background: The biologic mechanisms by which laparoscopic antireflux surgery (LARS) might influence the inflammatory process leading to bronchiolitis obliterans syndrome are unknown. We hypothesized that LARS alters the pulmonary immune profile in lung transplant patients with gastroesophageal reflux disease.

Methods: In 8 lung transplant patients with gastroesophageal reflux disease, we quantified and compared the pulmonary leukocyte differential and the concentration of inflammatory mediators in the bronchoalveolar lavage fluid (BALF) 4 weeks before LARS, 4 weeks after LARS, and 12 months after lung transplantation. Freedom from bronchiolitis obliterans syndrome (graded 1-3 according to the International Society of Heart and Lung Transplantation guidelines), forced expiratory volume in 1 second trends, and survival were also examined.

Results: At 4 weeks after LARS, the percentages of neutrophils and lymphocytes in the BALF were reduced (from 6.6% to 2.8%, P = 0.049, and from 10.4% to 2.4%, P = 0.163, respectively). The percentage of macrophages increased (from 74.8% to 94.6%, P = 0.077). Finally, the BALF concentration of myeloperoxide and interleukin-1β tended to decrease (from 2109 to 1033 U/mg, P = 0.063, and from 4.1 to 0 pg/mg protein, P = 0.031, respectively), and the concentrations of interleukin-13 and interferon-γ tended to increase (from 7.6 to 30.4 pg/mg protein, P = 0.078 and from 0 to 159.5 pg/mg protein, P = 0.031, respectively). These trends were typically similar at 12 months after transplantation. At a mean follow-up of 19.7 months, the survival rate was 75% and the freedom from bronchiolitis obliterans syndrome was 75%. Overall, the forced expiratory volume in 1 second remained stable during the first year after transplantation.

Conclusions: Our preliminary study has demonstrated that LARS can restore the physiologic balance of pulmonary leukocyte populations and that the BALF concentration of pro-inflammatory mediators is altered early after LARS. These results suggest that LARS could modulate the pulmonary inflammatory milieu in lung transplant patients with gastroesophageal reflux disease.
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http://dx.doi.org/10.1016/j.jss.2012.03.066DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694396PMC
October 2012

TGF-β converts apoptotic stimuli into the signal for Th9 differentiation.

J Immunol 2012 May 28;188(9):4369-75. Epub 2012 Mar 28.

Department of Microbiology and Immunology, Stritch School of Medicine, Loyola University Chicago, Maywood, IL 60153, USA.

Naturally arising CD4(+)CD25(+)FoxP3(+) regulatory T cells (nTregs) have an essential role in maintenance of immune homeostasis and peripheral tolerance. Previously, we reported that conventional CD4(+) and CD8(+) T cells undergo p53-induced CD28-dependent apoptosis (PICA) when stimulated with a combination of immobilized anti-CD3 and anti-CD28 Abs, whereas nTregs expand robustly under the same conditions, suggesting that there is a differential survival mechanism against PICA between conventional T cells and nTregs. In this study, we demonstrate that TGF-β signaling is required for nTregs to survive PICA. Conversely, when an active form of exogenous TGF-β is present, conventional T cells become resistant to PICA and undergo robust expansion instead of apoptosis, with reduction of the proapoptotic protein Bim and FoxO3a. A substantial fraction of PICA-resistant T cells expressed IL-9 (T(H)9 cells). Moreover, the presence of IL-6 along with TGF-β led to the generation of T(H)17 cells from conventional T cells. Together, the data demonstrate a novel role for TGF-β in the homeostasis of regulatory T cells and effector T cell differentiation and expansion.
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http://dx.doi.org/10.4049/jimmunol.1102698DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3331903PMC
May 2012

Low vitamin D levels are associated with increased rejection and infections after lung transplantation.

J Heart Lung Transplant 2012 Jul 3;31(7):700-7. Epub 2012 Mar 3.

Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, Loyola University Medical Center, Maywood, Illinois 60153, USA.

Background: The prevalence of vitamin D deficiency in lung disease is greater than in the general population. Vitamin D deficiency may negatively affect immune and lung function. Accordingly, we hypothesized that lung transplant recipients with vitamin D deficiency are more susceptible to rejection and infections after transplantation.

Methods: Transplant outcomes were reviewed in a retrospective cohort of 102 lung transplant recipients who had 25-hydroxyvitamin D [25(OH)D] levels drawn during the near-transplant period (100 days pre- or post-transplant).

Results: In the near-transplant period, 80% of recipients were 25(OH)D-deficient and 20% were not 25(OH)D-deficient. Episodes of acute cellular rejection in the deficient group were more frequent than in the non-deficient group [mean 1.27 (0.99 to 1.55) vs 0.52 (0.12 to 0.93), p = 0.006]. The rejection rate in the deficient group was more than double that of the the non-deficient group [IRR 2.43 (1.30 to 4.52), p = 0.005]. Infectious episodes were also more frequent in the deficient group than in the non-deficient group [mean 4.01 (3.24 to 4.79) vs 2.71 (1.47 to 3.96), p = 0.04]. The mortality rate of recipients who remained 25(OH)D-deficient 1 year after transplant was almost 5-fold higher than in recipients who were not 25(OH)D-deficient [IRR 4.79 (1.06 to 21.63), p = 0.04].

Conclusions: Low serum 25(OH)D levels in lung transplant recipients were associated with increased incidence of acute rejection and infection. The mortality of recipients who remained deficient 1 year post-transplant was higher than that of recipients who maintained normal vitamin D levels at 1 year post-transplant.
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http://dx.doi.org/10.1016/j.healun.2012.02.012DOI Listing
July 2012

The prevalence and extent of gastroesophageal reflux disease correlates to the type of lung transplantation.

Surg Laparosc Endosc Percutan Tech 2012 Feb;22(1):46-51

Swallowing Center, Departments of Surgery, Division of Pulmonary and Critical Care Medicine, Loyola University Medical Center, Stritch School of Medicine, Maywood, Illinois 60153, USA.

Background: Evidence is increasingly convincing that lung transplantation is a risk factor of gastroesophageal reflux disease (GERD). However, it is still not known if the type of lung transplant (unilateral, bilateral, or retransplant) plays a role in the pathogenesis of GERD.

Study Design: The records of 61 lung transplant patients who underwent esophageal function tests between September 2008 and May 2010, were retrospectively reviewed. These patients were divided into 3 groups based on the type of lung transplant they received: unilateral (n=25); bilateral (n=30), and retransplant (n=6). Among these groups we compared: (1) the demographic characteristics (eg, sex, age, race, and body mass index); (2) the presence of Barrett esophagus, delayed gastric emptying, and hiatal hernia; and (3) the esophageal manometric and pH-metric profile.

Results: Distal and proximal reflux were more prevalent in patients with bilateral transplant or retransplant and less prevalent in patients after unilateral transplant, regardless of the cause of their lung disease. The prevalence of hiatal hernia, Barrett esophagus, and the manometric profile were similar in all groups of patients.

Conclusions: Although our data show a discrepancy in prevalence of GERD in patients with different types of lung transplantation, we cannot determine the exact cause for these findings from this study. We speculate that the extent of dissection during the transplant places the patients at risk for GERD. On the basis of the results of this study, a higher level of suspicion of GERD should be held in patients after bilateral or retransplantation.
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http://dx.doi.org/10.1097/SLE.0b013e31824017d4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709252PMC
February 2012

Donation after cardiac death: a 29-year experience.

Surgery 2011 Oct;150(4):692-702

Division of Organ Transplantation, University of Wisconsin School of Medicine and Public Health, Madison, WI 53792-7375, USA.

Objective: To report the long-term outcomes of 1218 organs transplanted from donation after cardiac death (DCD) donors from January 1980 through December 2008.

Methods: One-thousand two-hundred-eighteen organs were transplanted into 1137 recipients from 577 DCD donors. This includes 1038 kidneys (RTX), 87 livers (LTX), 72 pancreas (PTX), and 21 DCD lungs. The outcomes were compared with 3470 RTX, 1157 LTX, 903 PTX, and 409 lung transplants from donors after brain death (DBD).

Results: Both patient and graft survival is comparable between DBD and DCD transplant recipients for kidney, pancreas, and lung after 1, 3, and 10 years. Our findings reveal a significant difference for patient and graft survival of DCD livers at each of these time points. In contrast to the overall kidney transplant experience, the most recent 16-year period (n = 396 DCD and 1,937 DBD) revealed no difference in patient and graft survival, rejection rates, or surgical complications but delayed graft function was higher (44.7% vs 22.0%; P < .001). In DCD LTX, biliary complications (51% vs 33.4%; P < .01) and retransplantation for ischemic cholangiopathy (13.9% vs 0.2%; P < .01) were increased. PTX recipients had no difference in surgical complications, rejection, and hemoglobin A1c levels. Surgical complications were equivalent between DCD and DBD lung recipients.

Conclusion: This series represents the largest single center experience with more than 1000 DCD transplants and given the critical demand for organs, demonstrates successful kidney, pancreas, liver, and lung allografts from DCD donors.
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http://dx.doi.org/10.1016/j.surg.2011.07.057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3357118PMC
October 2011

The protective role of laparoscopic antireflux surgery against aspiration of pepsin after lung transplantation.

Surgery 2011 Oct;150(4):598-606

Department of Surgery, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL 60153, USA.

Background: The goal of this study was to determine, in lung transplant patients, if laparoscopic antireflux surgery (LARS) is an effective means to prevent aspiration as defined by the presence of pepsin in the bronchoalveolar lavage fluid (BALF).

Methods: Between September 2009 and November 2010, we collected BALF from 64 lung transplant patients at multiple routine surveillance assessments for acute cellular rejection, or when clinically indicated for diagnostic purposes. The BALF was tested for pepsin by enzyme-linked immunosorbent assay (ELISA). We then compared pepsin concentrations in the BALF of healthy controls (n = 11) and lung transplant patients with and without gastroesophageal reflux disease (GERD) on pH-monitoring (n = 8 and n = 12, respectively), and after treatment of GERD by LARS (n = 19). Time to the development of bronchiolitis obliterans syndrome was contrasted between groups based on GERD status or the presence of pepsin in the BALF.

Results: We found that lung transplant patients with GERD had more pepsin in their BALF than lung transplant patients who underwent LARS (P = .029), and that pepsin was undetectable in the BALF of controls. Moreover, those with more pepsin had quicker progression to BOS and more acute rejection episodes.

Conclusion: This study compared pepsin in the BALF from lung transplant patients with and without LARS. Our data show that: (1) the detection of pepsin in the BALF proves aspiration because it is not present in healthy volunteers, and (2) LARS appears effective as a measure to prevent the aspiration of gastroesophageal refluxate in the lung transplant population. We believe that these findings provide a mechanism for those studies suggesting that LARS may prevent nonallogenic injury to the transplanted lungs from aspiration of gastroesophageal contents.
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http://dx.doi.org/10.1016/j.surg.2011.07.053DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3694415PMC
October 2011

Kv7 potassium channels in airway smooth muscle cells: signal transduction intermediates and pharmacological targets for bronchodilator therapy.

Am J Physiol Lung Cell Mol Physiol 2012 Jan 30;302(1):L120-32. Epub 2011 Sep 30.

Department of Molecular Pharmacology & Therapeutics, Loyola University Chicago, Maywood, IL 60153, USA.

Expression and function of Kv7 (KCNQ) voltage-activated potassium channels in guinea pig and human airway smooth muscle cells (ASMCs) were investigated by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), patch-clamp electrophysiology, and precision-cut lung slices. qRT-PCR revealed expression of multiple KCNQ genes in both guinea pig and human ASMCs. Currents with electrophysiological and pharmacological characteristics of Kv7 currents were measured in freshly isolated guinea pig and human ASMCs. In guinea pig ASMCs, Kv7 currents were significantly suppressed by application of the bronchoconstrictor agonists methacholine (100 nM) or histamine (30 μM), but current amplitudes were restored by addition of a Kv7 channel activator, flupirtine (10 μM). Kv7 currents in guinea pig ASMCs were also significantly enhanced by another Kv7.2-7.5 channel activator, retigabine, and by celecoxib and 2,5-dimethyl celecoxib. In precision-cut human lung slices, constriction of airways by histamine was significantly reduced in the presence of flupirtine. Kv7 currents in both guinea pig and human ASMCs were inhibited by the Kv7 channel blocker XE991. In human lung slices, XE991 induced robust airway constriction, which was completely reversed by addition of the calcium channel blocker verapamil. These findings suggest that Kv7 channels in ASMCs play an essential role in the regulation of airway diameter and may be targeted pharmacologically to relieve airway hyperconstriction induced by elevated concentrations of bronchoconstrictor agonists.
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http://dx.doi.org/10.1152/ajplung.00194.2011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3349372PMC
January 2012

A current viewpoint of lymphangioleiomyomatosis supporting immunotherapeutic treatment options.

Am J Respir Cell Mol Biol 2012 Jan;46(1):1-5

Department of Medicine, Cardinal Bernardin Cancer Center, Loyola University, Chicago, Illinois, USA.

Lymphangioleiomyomatosis (LAM) leads to hyperproliferation of abnormal smooth muscle cells in the lungs, associated with diffuse pulmonary parenchymal cyst formation and progressive dyspnea on exertion. The disease targets women of child-bearing age. Complications include pneumothoraces and chylous pleural effusions. Ten-year survival is estimated at 70%, and lung transplantation remains the only validated treatment. It has been observed that LAM cells express markers associated with melanocytic differentiation, including gp100 and MART-1. Other melanocytic markers have also been observed. The same proteins are targeted by T cells infiltrating melanoma tumors as well as by T cells infiltrating autoimmune vitiligo skin, and these antigens are regarded as relatively immunogenic. Consequently, vaccines have been developed for melanoma targeting these and other immunogenic melanocyte differentiation proteins. Preliminary data showing susceptibility of LAM cells to melanoma derived T cells suggest that vaccines targeting melanosomal antigens can be successful in treating LAM.
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http://dx.doi.org/10.1165/rcmb.2011-0215TRDOI Listing
January 2012

Donation after cardiac death lung transplantation outcomes.

Curr Opin Organ Transplant 2011 Oct;16(5):462-8

Department of Cardiothoracic Surgery, Loyola University, Chicago, Illinois, USA.

Purpose Of Review: Lung transplantation is now a well established treatment option for several end-stage respiratory diseases. Survival after lung transplantation has significantly improved over the last decade. The primary limitation to increased utilization of lung transplantation remains donor scarcity. Suitable allografts have been procured from donors after determination of neurologic death and from donors after determination of cardiac death (DDCD or DCD). Historically, the first human lung transplantation performed, utilized an allograft procured after cardiovascular death, also referred to as nonheart-beating donor.The experience at University of Wisconsin in 1993 reintroduced DCD lung transplantation with the first successful clinical case.

Recent Findings: A potential additional lung allograft source, DCD lung transplantation has been established with very acceptable outcomes observed by several centers. We provide the relevant background for the rationale of donor allograft expansion to include DCD lungs from controlled (Maastricht category III donors).

Summary: This review considers the available evidence for DCD lung transplantation and compares reported primary graft dysfunction rates and current survival data available.
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http://dx.doi.org/10.1097/MOT.0b013e32834a99acDOI Listing
October 2011

Laparoscopic antireflux surgery for gastroesophageal reflux disease after lung transplantation.

J Surg Res 2011 Oct 22;170(2):e279-86. Epub 2011 Jun 22.

Department of Surgery, Loyola University Medical Center, Stritch School of Medicine, Maywood, Illinois, USA.

Background: Although gastroesophageal reflux disease (GERD) is highly prevalent in lung transplantation, the pathophysiology of GERD in these patients is unknown. We hypothesize that the pathophysiology of GERD after lung transplantation differs from that of a control population, and that the 30-d morbidity and mortality of laparoscopic antireflux surgery (LARS) are equivalent in both populations.

Methods: We retrospectively compared the pathophysiology of GERD and the 30-d morbidity and mortality of 29 consecutive lung transplant patients with 23 consecutive patients without lung transplantation (control group), all of whom had LARS for GERD between November 2008 and May 2010.

Results: Both groups had a similar prevalence of endoscopic esophagitis and Barrett's esophagus , comparable manometric profiles, and similar prevalence of abnormal peristalsis. However, hiatal hernia was more common in controls than in lung transplant patients (57% versus 24%; P = 0.04). Lung transplant patients had a higher prevalence and severity of proximal GERD (65% versus 33%; P = 0.04). The 30-d morbidity and mortality following LARS were similar in both groups regardless of the higher surgical risk of lung transplants (median ASA class: 3 versus 2 for controls, P < 0.001).

Conclusions: These results show that despite similar manometric profiles, lung transplant patients are more prone to proximal reflux than the general population with GERD; the prevalence of endoscopic esophagitis and Barrett's esophagus is the same in both groups of patients; a hiatal hernia is uncommon after lung transplantation; and the morbidity and mortality of LARS are the same for lung transplant patients as the general population with GERD.
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http://dx.doi.org/10.1016/j.jss.2011.05.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3686158PMC
October 2011

Increased risk of venous thromboembolism with a sirolimus-based immunosuppression regimen in lung transplantation.

J Heart Lung Transplant 2011 Feb 13;30(2):175-81. Epub 2010 Oct 13.

Division of Pulmonary, Department of Medicine, Hospital of the University of Pennsylvania, Philadelphia, Pennsylvania, USA.

Background: Sirolimus (rapamycin) is a potent anti-proliferative agent with immunosuppressive properties that is increasingly being used in solid-organ and hematopoietic stem cell transplantation. In addition, this drug is being investigated for treatment of a broad range of disorders, including cardiovascular disease, malignancies, tuberous sclerosis, and lymphangeioleiomyomatosis. In this study, we found an increased risk of venous thromboembolism (VTE) in lung transplant recipients treated with a sirolimus (SIR)-based immunosuppressive regimen.

Methods: One hundred eighty-one lung transplant recipients were enrolled in a prospective, multicenter, randomized, open-label trial comparing a tacrolimus (TAC)/SIR/prednisone immunosuppression regimen with a TAC/azathioprine (AZA)/prednisone immunosuppressive regimen. The differences in rates of VTE were examined.

Results: There was a significantly higher occurrence of VTE in the SIR cohort [15 of 87 (17.2%)] compared with the AZA cohort [3 of 94 (3.2%)] (stratified log-rank statistic = 7.44, p < 0.01). When adjusted for pre-transplant diagnosis and stratified by transplant center, this difference remained essentially unchanged (hazard ratio for SIR vs AZA = 5.2, 95% confidence interval 1.4 to 19.5, p = 0.01).

Conclusion: Clinicians prescribing SIR should maintain a high level of vigilance for VTE, particularly among patients with other risk factors for this complication.
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http://dx.doi.org/10.1016/j.healun.2010.08.010DOI Listing
February 2011

Comparison of sirolimus with azathioprine in a tacrolimus-based immunosuppressive regimen in lung transplantation.

Am J Respir Crit Care Med 2011 Feb 10;183(3):379-87. Epub 2010 Sep 10.

University of Chicago Medical Center, Chicago, Illinois, USA.

Rationale: Lung transplantation has evolved into a life-saving therapy for select patients with end-stage lung diseases. However, long-term survival remains limited because of chronic rejection. Sirolimus is beneficial in preventing cardiac rejection and may decrease rejection after lung transplantation.

Objectives: To determine the potential benefit versus risk of sirolimus in lung transplantation.

Methods: We conducted a multicenter randomized, open label controlled trial comparing sirolimus (SIR) with azathioprine (AZA) in a tacrolimus-based immunosuppressive regimen in lung transplantation. The primary end point was the incidence of acute rejection at 1 year after transplantation between the two study groups.

Measurements And Main Results: One hundred eighty-one patients were randomized to be included in this study. At 1 year after transplantation, there was no significant difference in the incidence of grade A acute rejection between the two study groups. Similarly, the incidence of chronic rejection and graft survival was no different between the two study groups. Cytomegalovirus infection was decreased in the SIR arm compared with the AZA arm (relative risk, 0.67 [95% confidence interval, 0.55, 0.82]; P < 0.01). There was a higher rate of adverse events leading to early discontinuation of SIR (64%) compared with AZA (49%) during the course of this study.

Conclusions: Sirolimus, an mTOR inhibitor, did not decrease the incidence of acute rejection at 1 year compared with azathioprine in lung transplantation. These results differ from previous results in cardiac and renal transplantation and emphasize the need for multicenter randomized controlled trials in lung transplantation. Clinical trial registered with www.clinicaltrials.gov (NCT 00321906).
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http://dx.doi.org/10.1164/rccm.201005-0775OCDOI Listing
February 2011

Gastroesophageal reflux disease after lung transplantation: pathophysiology and implications for treatment.

Surgery 2010 Oct 21;148(4):737-44; discussion 744-5. Epub 2010 Aug 21.

Department of Surgery, Loyola University Medical Center, Stritch School of Medicine, Maywood, IL 60153, USA.

Background: Gastroesophageal reflux disease (GERD) is thought to be a risk factor for the development or progression of chronic rejection after lung transplantation. However, the prevalence of GERD and its risk factors, including esophageal dysmotility, hiatal hernia and delayed gastric emptying after lung transplantation, are still unknown. In addition, the prevalence of Barrett's esophagus, a known complication of GERD, has not been determined in these patients. The purpose of this study was to determine the prevalence and extent of GERD, as well as the frequency of these risk factors and complications of GERD in lung transplant patients.

Methods: Thirty-five consecutive patients underwent a combination of esophageal function testing, upper endoscopy, barium swallow, and gastric emptying scan after lung transplantation.

Results: In this patient population, the prevalence of GERD was 51% and 22% in those who had been retransplanted. Of patients with GERD,36% had ineffective esophageal motility (IEM), compared with 6% of patients without GERD (P = .037). No patient demonstrated hiatal hernia on barium swallow. The prevalence of delayed gastric emptying was 36%. The prevalence of biopsy-confirmed Barrett's esophagus was 12%.

Conclusion: Our study shows that, after lung transplantation, more than half of patients had GERD, and that GERD was more common after retransplantation. IEM and delayed gastric emptying are frequent in patients with GERD. Hiatal hernia is rare. The prevalence of Barrett's esophagus is not negligible. We conclude that GERD is highly prevalent after lung transplantation, and that delayed gastric emptying and Barrett's esophagus should always be suspected after lung transplantation because they are common risks factors and complications of GERD.
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http://dx.doi.org/10.1016/j.surg.2010.07.011DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3066258PMC
October 2010

Inhibition of bleomycin-induced pulmonary fibrosis through pre-treatment with collagen type V.

J Heart Lung Transplant 2010 Aug 14;29(8):873-80. Epub 2010 May 14.

Department of Thoracic and Cardiovascular Surgery, Loyola University, Maywood, Illinois, USA.

Background: Tolerance to collagen structures has been shown to inhibit the progression of autoimmune scleroderma and rheumatoid arthritis. More recently, tolerance induction to collagen type V (colV) in experimental models of lung transplantation was shown to ameliorate the complex pathology known as "chronic rejection." The link between colV autoimmunity and progressive graft dysfunction and subsequent development of bronchiolitis obliterans syndrome (BOS) has been established in human lung transplant recipients. We hypothesized that intravenous injection of colV inhibits development of lung fibrosis in a bleomycin-induced lung injury mouse model.

Methods: Experimental animals were injected intravenously with saline or colV 10 days before intratracheal instillation of bleomycin. Pulmonary inflammation was monitored and quantified for the presence of cells in the bronchoalveolar lavage (BAL) fluid by flow cytometry and histology of lung tissue.

Results: ColV-pre-treated animals showed a significant reduction in lung inflammation compared with non-treated animals, according to histology and morphometry. The number of inflammatory cells in the BAL fluid was significantly reduced and associated with a lower proportion of gammadelta T cells and CD4(+) T cells in the colV-pre-treated group. Matrix metalloproteinase-2 and -9 (MMP-2 and -9; also known as gelatinase A and gelatinase B, respectively) levels in the BAL fluid were significantly reduced in colV-pre-treated mice compared with the non-treated mice. In addition, intravenous injection of colV was associated with a significant reduction in the relative expression of interleukin (IL)-6, IL-17 and IL-22 in cells present in BAL fluid at 7 and 14 days after bleomycin instillation.

Conclusions: Pre-treatment by intravenous injection of colV inhibits bleomycin-induced pulmonary fibrosis by inhibiting IL-6 and IL-17 production. Fibrosis treatment in this context therefore should target induction of colV tolerance and Th17 development.
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http://dx.doi.org/10.1016/j.healun.2010.03.012DOI Listing
August 2010

Lung transplantation with donation after cardiac death donors: long-term follow-up in a single center.

J Thorac Cardiovasc Surg 2010 May;139(5):1306-15

Department of Surgery, Division of Cardiothoracic Surgery, University of Wisconsin School of Medicine and Public Health, Madison, Wis., USA.

Objective: We sought to examine long-term outcomes at the University of Wisconsin for all lung transplant recipients who received lungs from donation after cardiac death donors since the initiation of this program in 1993.

Methods: Eighteen (4.2%) of the 424 lung transplantations performed in 406 patients between January 1993 and April 2009 used lungs from donation after cardiac death donors. Outcomes for this recipient cohort were compared with those for recipients who received organs from brain-dead donors.

Results: Warm ischemic time (from withdrawal of support to reperfusion of organs) was 30 +/- 17 minutes (11-93 minutes). The patient survival rates in the donation after cardiac death group (DCD group) at 1, 3, and 5 years were 88.1% +/- 7.9%, 81.9% +/- 9.5%, and 81.9% +/- 9.5%, respectively. These survival rates were not different from those of the brain-dead donor group (BDD group, P = .66). The incidence of primary graft dysfunction in the DCD group was similar to that of the BDD group (P = .59). However, the incidence of airway complications was somewhat higher in the DCD group. Freedom from bronchiolitis obliterans syndrome at 1, 3, and 5 years in the DCD group was 80.4% +/- 10.2%, 80.4% +/- 10.2%, and 72.3% +/- 11.9%, respectively, and did not differ from the incidence of bronchiolitis obliterans syndrome in the BDD group (P = .59).

Conclusions: Our data show that the long-term patient and graft survival rates after donation after cardiac death lung transplantation were equivalent to those after brain-dead donor lung transplantation. Our findings suggest that the use of donation after cardiac death donors can safely and substantially expand the donor pool for lung transplantation.
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http://dx.doi.org/10.1016/j.jtcvs.2010.02.004DOI Listing
May 2010

Transfer of tolerance to collagen type V suppresses T-helper-cell-17 lymphocyte-mediated acute lung transplant rejection.

Transplantation 2009 Dec;88(12):1341-8

Department of Thoracic and Cardiovascular Surgery, Loyola University, Maywood, IL 60153, USA.

Background: Rat lung allograft rejection is mediated by collagen type V (col(V)) specific T-helper-cell 17 (Th17) cells. Adoptive transfer of these cells is sufficient to induce rejection pathology in isografts, whereas tolerance to col(V) suppresses allograft rejection. Therefore, we tested whether regulatory T cells from tolerant rats could suppress the Th17-mediated rejection in the syngeneic model of lung transplantation.

Methods: Rats were subjected to syngeneic left lung transplantation, and acute rejection was induced by adoptive transfer of lymph node cells from col(V)-immunized rats. Tolerance was induced by intravenous injection of col(V), and spleen lymphocytes were used for adoptive transfer. CD4+ T cells were depleted using magnetic beads. Lung isografts were analyzed using micro-positron emission tomography imaging and histochemistry. The transvivo delayed type hypersensitivity assay was used to analyze the Th17 response.

Results: Adoptive cotransfer of col(V)-specific effector cells with cells from col(V)-tolerized rats suppressed severe vasculitis and bronchiolitis with parenchymal inflammation, and the expression of interleukin (IL)-17 transcripts in mediastinal lymph nodes induced by effector cells alone. Analysis by transvivo delayed type hypersensitivity showed that the reactivity to col(V) was dependent on the presence of tumor necrosis factor-alpha and IL-17 but not interferon-gamma. Depletion of CD4+ T cells from the suppressor cell population abrogated the col(V)-specific protection.

Conclusion: Th17-mediated acute rejection after lung transplantation is ameliorated by CD4+ col(V)-specific regulatory T cells. The mechanism for this Th17 suppression is consistent with tolerance induction to col(V). The goal of transplantation treatment, therefore, should target Th17 development and not suppression of T-cell activation by suppressing IL-2.
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http://dx.doi.org/10.1097/TP.0b013e3181bcde7bDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2804859PMC
December 2009

Melanoma-associated antigen expression in lymphangioleiomyomatosis renders tumor cells susceptible to cytotoxic T cells.

Am J Pathol 2009 Dec 5;175(6):2463-72. Epub 2009 Nov 5.

Oncology Institute, Loyola University, Chicago, Illinois 60153, USA.

The antibody HMB45 is used to diagnose lymphangioleiomyomatosis, a hyperproliferative disorder of lung smooth muscle cells with mutations in both alleles of either TSC1 or TSC2. A subset of these tumor cells expresses the melanoma-associated antigens gp100 and melanoma antigen recognized by T cells (MART-1). To explore the feasibility of targeting tumors in lymphangioleiomyomatosis by melanoma immunotherapy, we therefore assessed melanoma target antigen expression and existing immune infiltration of affected tissue compared with normal lung and melanoma as well as the susceptibility of cultured lymphangioleiomyomatosis cells to melanoma reactive cytotoxic T lymphocytes in vitro. Tumors expressed tyrosinase-related proteins 1 and 2 but not tyrosinase, in addition to gp100 and MART-1, and were densely infiltrated by macrophages, but not dendritic cells or T cell subsets. Although CD8(+) lymphocytes were sparse compared with melanoma, cells cultured from lymphangioleiomyomatosis tissue were susceptible to cytotoxic, gp100 reactive, and major histocompatibility complex class I restricted CD8(+) T cells in functional assays. Responder T cells selectively clustered and secreted interferon-gamma in response to HLA-matched melanocytes and cultured lymphangioleiomyomatosis cells. This reactivity exceeded that based on detectable gp100 expression; thus, tumor cells in lymphangioleiomyomatosis may process melanosomal antigens different from melanocytic cells. Therefore, boosting immune responses to gp100 in lymphangioleiomyomatosis may offer a highly desirable treatment option for this condition.
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http://dx.doi.org/10.2353/ajpath.2009.090525DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2789635PMC
December 2009

Effect of annual influenza immunization on antibody response in lung transplant patients.

Prog Transplant 2009 Jun;19(2):153-9

University of Wisconsin, Madison 53705, USA.

Background: Influenza viral infections cause significant morbidity and mortality each season. Lung transplant patients may be at higher risk because of their underlying pathophysiology. Although annual immunization is the standard of care, its efficacy remains largely unproven. Previous studies showed poor antibody response to influenza vaccine in lung transplant patients, but no data on the antibody response in consecutive seasons have been published.

Methods: We studied antibody responses to influenza vaccine in 122 subjects: 66 lung transplant recipients, 28 control subjects, and 28 patients awaiting lung transplantation. We compared antibody response rates to individual viruses contained in influenza vaccines in consecutive years within the 3 groups. Serum antibody concentrations were measured at baseline and 2 to 4 weeks after vaccination by using the hemagglutination inhibition assay. Log-transformed antibody concentrations and incidence of serconversion and seroprotection were calculated.

Results: Median log-transformed antibody responses were similar in consecutive seasons in lung transplant subjects. Incidences of seroprotection and seroconversion did not differ between consecutive seasons in lung transplant recipients.

Conclusions: Antibody responses were similar in consecutively measured years in lung transplant subjects. Annual influenza vaccination in lung transplant subjects produces similar immune responses in 2 consecutive years, indicating that these patients are not at significantly increased risk of vaccine failure.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2872508PMC
June 2009

IL-17 producing gammadelta T cells are required for a controlled inflammatory response after bleomycin-induced lung injury.

Inflammation 2008 Jun 13;31(3):167-79. Epub 2008 Mar 13.

Department of Thoracic and CV Surgery, Loyola University, Maywood, Illinois, USA.

Background: gammadelta T cells play a key role in the regulation of inflammatory responses in epithelial tissue, and in adaptive immunity, as gammadelta T cell deficient mice have a severely impaired capacity to clear lung pathogens. gammadelta T cells regulate the initial inflammatory response to microbial invasion and thereby protect against tissue injury. Here we examined the response of gammadelta T cells to lung injury induced by bleomycin, in an effort to study the inflammatory response in the absence of any adaptive immune response to a pathogen.

Results: After lung injury by bleomycin, we localized the gammadelta T cells to the lung lesions. gammadelta T cells were the predominant source of IL-17 (as detected by flow cytometry and real-time PCR). Moreover, gammadelta T cell knockout mice showed a significant reduction in cellular infiltration into the airways, reduced expression of IL-6 in the lung, and a significant delay in epithelial repair.

Conclusion: Mouse gammadelta T cells produce IL-17 in response to lung injury and are required for an organized inflammatory response and epithelial repair. The lack of gammadelta T cells correlates with increased inflammation and fibrosis.
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http://dx.doi.org/10.1007/s10753-008-9062-6DOI Listing
June 2008

Th-17, monokines, collagen type V, and primary graft dysfunction in lung transplantation.

Am J Respir Crit Care Med 2008 Mar 3;177(6):660-8. Epub 2008 Jan 3.

Microbiology and Immunology, Director, Center for Immunobiology, Indiana University School of Medicine, Van Nuys Medical Sciences Building MS224, 635 Barnhill Drive, Indianapolis, IN 46202-5120, USA.

Rationale: The pathogenesis of primary graft dysfunction (PGD), a serious complication of lung transplantation, is poorly understood. Human studies and rodent models have shown that collagen type V (col[V]), stimulates IL-17-dependent cellular immunity after lung transplantation.

Objectives: To determine whether patients with end-stage lung disease develop pretransplant col(V)-specific cellular immunity, and if so, the impact of this response on PGD.

Methods: Trans-vivo delayed-type hypersensitivity (TV-DTH) assays were used to evaluate memory T-cell responses to col(V) in 55 patients awaiting lung transplantation. Pa(O(2))/Fi(O(2)) index data were used to assess PGD. Univariate risk factor analysis was performed to identify variables associated with PGD. Rats immunized with col(V) or irrelevant antigen underwent lung isografting to determine if prior anti-col(V) immunity triggers PGD in the absence of alloreactivity.

Measurements And Main Results: We found that 58.8% (10/17) of patients with idiopathic pulmonary fibrosis, and 15.8% (6/38) of patients without idiopathic pulmonary fibrosis tested while on the wait list for a lung transplant were col(V) DTH positive. Col(V) reactivity was CD4(+) T-cell and monocyte mediated, and dependent on IL-17, IL-1beta, and tumor necrosis factor (TNF)-alpha. Pa(O(2))/Fi(O(2)) indices were impaired significantly 6-72 hours after transplantation in col(V)-reactive versus nonreactive patients. Univariate risk factor analysis identified only preoperative TV-DTH to col(V) and ischemic time as predictors of PGD. Finally, in a rat lung isograft model, col(V) sensitization resulted in significantly lower Pa(O(2))/Fi(O(2)), increased local TNF-alpha and IL-1beta production, and a moderate-to-severe bronchiolitis/vasculitis when compared with control isografts.

Conclusions: The data suggest that activation of innate immunity by col(V)-specific Th-17 memory cells represents a novel pathway to PGD after lung transplantation.
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http://dx.doi.org/10.1164/rccm.200612-1901OCDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2267340PMC
March 2008