The Experts below are selected from a list of 924 Experts worldwide ranked by ideXlab platform
Kenneth R Cooke - One of the best experts on this subject based on the ideXlab platform.
-
defibrotide modulates pulmonary endothelial cell activation and protects against lung inflammation in pre clinical models of lps induced lung injury and Idiopathic Pneumonia Syndrome
Biology of Blood and Marrow Transplantation, 2020Co-Authors: Orly R Klein, Elizabeth Pierce, Sung Choi, Azeb Haile, Yiouli P Ktena, Megan Smith, Kenneth R CookeAbstract:Background Pulmonary dysfunction remains one of the greatest challenges to the optimization of care following allogeneic blood and marrow transplantation (alloBMT). Almost half of the Pneumonias that occur early after alloBMT are noninfectious, termed Idiopathic Pneumonia Syndrome (IPS). Injury/activation to vascular endothelial cells (ECs) are believed to be directly related to several post-BMT complications, including IPS. Hence, identifying inflammatory mechanisms contributing to EC damage and strategies to protect EC integrity and function have significant merit. We have demonstrated that TNFα contributes directly to EC injury and regulates the chemokine milieu and influx of donor cells into the lung. Laboratory insights led to clinical trials of TNFα inhibition for IPS. Many, but not all, patients with IPS respond to TNFα inhibition, underscoring the need for continued research. Results Analysis of the plasma proteome from samples derived from 3 clinical studies revealed that compared to unaffected BMT controls, patients with IPS showed marked elevations in the expression of signature cytokines, including TNFα and MCP-1. Elevated expression of molecules associated with EC injury, angiopoietin (Ang)-2, VCAM-1, and E-selectin, was also noted. Ang-2 has been shown to destabilize and further sensitize ECs to the effects of TNFα, causing enhanced expression of E- and P-selectin. Serum Ang-2 levels were elevated during IPS and correlated with response to anti-TNFα therapy. In an acute lung injury (ALI) model, IV injection of LPS to naive B6 mice results in enhanced mRNA expression of TNFα, IL-6, Ang-2, E-, and P-selectin in whole lung homogenates, and the expression of Ang-2 is regulated in part by TNFα and IL-6. EC activation was associated with increased BALF total protein and cellularity. Similar findings were noted in alloBMT mice with IPS. We hypothesized that strategies to maintain EC integrity would reduce the severity of ALI and IPS. Defibrotide (DF) is FDA approved for the treatment of BMT patients with VOD and evidence of renal or pulmonary injury. DF is believed to stabilize activated ECs and protect them from further injury. The administration of DF (50 mg/kg) IV before and after LPS injection significantly reduced mRNA expression of TNFα, IL6, Ang-2, E-, and P-selectin compared to controls. BALF showed decreased cellularity, reflecting less EC damage and leak. AlloBMT mice were treated from day -1 through day 14 with DF ip (at a dose comparable to IV) either QD or BID, and lungs were harvested from D18 to 21. Compared to controls, DF treatment reduced mRNA expression of TNFα, IL6, Ang-2, E-, and P- selectin, BALF cellularity and protein content, and lung pathology score. Conclusion The administration of DF modulates EC injury in models of ALI and IPS. Combining cytokine inhibition with agents that stabilize EC integrity may represent a novel therapeutic strategy for patients with IPS.
-
Idiopathic Pneumonia Syndrome following hematopoietic stem cell transplantation
Journal of Pediatric Intensive Care, 2015Co-Authors: Orly R Klein, Kenneth R CookeAbstract:Non-infectious lung injury following hematopoietic stem cell transplant may be driven by either immune or non-immune pathways of inflammation. Common alloimmune lung complications include Idiopathic Pneumonia Syndrome (IPS), transfusion related lung injury, diffuse alveolar hemorrhage, and peri-engraftment respiratory distress Syndrome, with both diffuse alveolar hemorrhage and peri-engraftment respiratory distress Syndrome existing as subsets of IPS when infection is absent. This review will discuss the definitions, risk factors, and pathogeneses of IPS and highlight the diagnostic work-up and novel approaches to treatment.
-
human biomarker discovery and predictive models for disease progression for Idiopathic Pneumonia Syndrome following allogeneic stem cell transplantation
Molecular & Cellular Proteomics, 2012Co-Authors: Daniela Schlatzer, Vincent T Ho, Jeaneudes J Dazard, Rob M Ewing, Serguei Ilchenko, Sara E Tomcheko, Gregory Yanik, Mark R Chance, Kenneth R CookeAbstract:Allogeneic hematopoietic stem cell transplantation (SCT) is the only curative therapy for many malignant and nonmalignant conditions. Idiopathic Pneumonia Syndrome (IPS) is a frequently fatal complication that limits successful outcomes. Preclinical models suggest that IPS represents an immune mediated attack on the lung involving elements of both the adaptive and the innate immune system. However, the etiology of IPS in humans is less well understood. To explore the disease pathway and uncover potential biomarkers of disease, we performed two separate label-free, proteomics experiments defining the plasma protein profiles of allogeneic SCT patients with IPS. Samples obtained from SCT recipients without complications served as controls. The initial discovery study, intended to explore the disease pathway in humans, identified a set of 81 IPS-associated proteins. These data revealed similarities between the known IPS pathways in mice and the condition in humans, in particular in the acute phase response. In addition, pattern recognition pathways were judged to be significant as a function of development of IPS, and from this pathway we chose the lipopolysaccaharide-binding protein (LBP) protein as a candidate molecular diagnostic for IPS, and verified its increase as a function of disease using an ELISA assay. In a separately designed study, we identified protein-based classifiers that could predict, at day 0 of SCT, patients who: 1) progress to IPS and 2) respond to cytokine neutralization therapy. Using cross-validation strategies, we built highly predictive classifier models of both disease progression and therapeutic response. In sum, data generated in this report confirm previous clinical and experimental findings, provide new insights into the pathophysiology of IPS, identify potential molecular classifiers of the condition, and uncover a set of markers potentially of interest for patient stratification as a basis for individualized therapy.
-
an official american thoracic society research statement noninfectious lung injury after hematopoietic stem cell transplantation Idiopathic Pneumonia Syndrome
American Journal of Respiratory and Critical Care Medicine, 2011Co-Authors: Angela Panoskaltsismortari, Rodney J Folz, Matthias Griese, David K Madtes, John A Belperio, Imad Y Haddad, Kenneth R CookeAbstract:Rationale: Acute lung dysfunction of noninfectious etiology, known as Idiopathic Pneumonia Syndrome (IPS), is a severe complication following hematopoietic stem cell transplantation (HSCT). Several mouse models have been recently developed to determine the underlying causes of IPS. A cohesive interpretation of experimental data and their relationship to the findings of clinical research studies in humans is needed to better understand the basis for current and future clinical trials for the prevention/treatment of IPS.Objectives: Our goal was to perform a comprehensive review of the preclinical (i.e., murine models) and clinical research on IPS.Methods: An ATS committee performed PubMed and OVID searches for published, peer-reviewed articles using the keywords “Idiopathic Pneumonia Syndrome” or “lung injury” or “pulmonary complications” AND “bone marrow transplant” or “hematopoietic stem cell transplant.” No specific inclusion or exclusion criteria were determined a priori for this review.Measurements and...
-
response etanercept for Idiopathic Pneumonia Syndrome
Blood, 2009Co-Authors: Gregory A Yanik, Kenneth R CookeAbstract:Response: We appreciate Dr Frangoul's comments regarding long-term survival of the patients reported in our article.[1][1] Idiopathic Pneumonia Syndrome (IPS) remains a leading cause of treatment-related mortality, with one-month mortality rates approaching 80%. The goal of our study was to
James L M Ferrara - One of the best experts on this subject based on the ideXlab platform.
-
the impact of soluble tumor necrosis factor receptor etanercept on the treatment of Idiopathic Pneumonia Syndrome after allogeneic hematopoietic stem cell transplantation
Blood, 2008Co-Authors: Gregory A Yanik, Joseph R Custer, John E Levine, Vincent T Ho, Eric S White, Thomas M Braun, Joseph H Antin, Joel Whitfield, Dawn Jones, James L M FerraraAbstract:Idiopathic Pneumonia Syndrome (IPS) refers to a diffuse, noninfectious, acute lung injury after hematopoietic stem cell transplantation. Historically, IPS is associated with respiratory failure and mortality rates exceeding 50%. Preclinical studies have implicated tumor necrosis factor-α as an important effector molecule in the development of disease. We studied the tumor necrosis factor-α inhibitor, etanercept, combined with corticosteroids in treating 15 patients (median age, 18 years; range, 1-60 years) with IPS. Eight of 15 patients required mechanical ventilation at therapy onset. Etanercept was administered subcutaneously at a dose of 0.4 mg/kg (maximum 25 mg) twice weekly, for a maximum of 8 doses. Therapy was well tolerated with no infectious pulmonary complications noted. Ten of 15 patients had a complete response, defined as the ability to discontinue supplemental oxygen support during study therapy. The median time to complete response was 7 days (range, 3-18 days), with a day 28 survival of 73%. IPS onset was associated with elevations of several inflammatory proteins in the bronchoalveolar lavage fluid and plasma, and response to therapy correlated with reductions in pulmonary and systemic inflammation. The combination of etanercept and corticosteroids is safe and is associated with high response rates and improved survival in patients with IPS.
-
survival following etanercept therapy for the treatment of Idiopathic Pneumonia Syndrome post allogeneic stem cell transplantation
Blood, 2004Co-Authors: Gregory A Yanik, James L M Ferrara, J Uberti, John E Levine, Vincent T Ho, Joseph H Antin, Kenneth R CookeAbstract:Pulmonary complications, both infectious and non-infectious, significantly contribute to mortality following allogeneic bone marrow transplantation (BMT). In the acute setting, a diffuse non-infectious process termed Idiopathic Pneumonia Syndrome (IPS) may occur. Clinically, IPS is associated with a rapid progression to respiratory failure and mortality rates of 50 – 70%. Historically, we have noted a 9.0% incidence of IPS at our center, with a median survival of only 14 days following its onset. Etanercept, a soluble tumor necrosis factor (TNF) receptor, consists of two soluble p75 TNF receptors fused to the Fc portion of a human IgG1. A trial examining etanercept in the treatment of IPS following allogeneic BMT was undertaken. Fifteen patients (median 18 yrs, range 1 – 60 yrs), each meeting the diagnostic criteria for IPS were enrolled. Broncho-alveolar lavage (BAL) specimen were obtained pre and post therapy, undergoing analysis for both infectious pathogens (viral, bacterial, fungal, PCP, AFB) and for a panel of inflammatory cytokine markers, including TNFa and TNFR1. Patients in whom the pre-therapy BAL was positive for a potential pathogen (by specific stain or culture) were ineligible for therapy. Etanercept was administered subcutaneously at a dose of 0.4 mg/kg (maximum dose 25 mg) twice weekly, for a maximum of 8 doses. All patients required supplemental oxygen at therapy onset, with seven patients requiring mechanical ventilation. Etanercept therapy was initiated a median of 17 days (range 11–87 days) post transplant. All patients received corticosteroids (2 mgkg/day) x 7 days, which were then tapered as clinically indicated. RESULTS: Nine of 15 patients had a complete response, defined as the ability to completely withdraw from supplemental oxygen support within 28 days of initiation of etanercept therapy. In responders, the median time to complete response was 7 days (range 3–18 days). The median survival was extended from 14 days (historical controls) to 67 days (range 3–822) in treated patients. Survival at day 28 and day 56 (following the first etanercept dose) was 73% and 60% respectively. The duration of mechanical ventilation required prior to therapy onset had a significant impact on survival. Patients requiring 48 hours prior to study entry. Overall, therapy was well tolerated. Two episodes of bacteremia, without sepsis, were noted during therapy, . No infectious pulmonary complications were noted. Three patients died while on therapy, from progressive pulmonary or organ dysfunction. Post therapy BAL fluid analysis noted significant reductions in all inflammatory cytokines tested, including TNFa, TNFR1, sCD14, LBP and MCP-1, when compared to pre-therapy BAL values. CONCLUSION: The addition of etanercept to corticosteroids for the treatment of IPS post allogeneic BMT may improve survival, with minimal toxicity. Moreover, the timing of such intervention may have a significant impact on overall outcome. A phase III trial, investigating the efficacy of etanercept in treating IPS is now being considered.
-
a role for tumor necrosis factor α mediated endothelial apoptosis in the development of experimental Idiopathic Pneumonia Syndrome
Transplantation, 2004Co-Authors: Armin Gerbitz, James L M Ferrara, Lester Kobzik, Gerhard C Hildebrandt, Krystyna M Olkiewicz, Nicole E Willmarth, Brian J Nickoloff, Gunther Eissner, Ernst Holler, Kenneth R CookeAbstract:BACKGROUND: Idiopathic Pneumonia Syndrome (IPS) is a frequent and often fatal complication of allogeneic bone marrow transplantation (BMT). We have previously shown that experimental IPS is associated with alloreactive donor T cells and the inflammatory mediators TNF-alpha and lipopolysaccharide. Both TNF-alpha and lipopolysaccharide are known contributors to endothelial injury. Although damage to vascular endothelia has been associated with other complications after BMT, its relationship to lung injury has not been explored. METHODS: We used a well-established murine BMT system, in which lung injury and graft-versus-host disease are induced by minor histocompatibility antigenic differences between donor and host, and the DNA terminal transferase nick-end labeling (TUNEL) procedure to evaluate whether significant pulmonary vascular endothelial cell (EC) apoptosis is present during the development of IPS. RESULTS: Our data demonstrate that pulmonary histopathology after allogeneic BMT is accompanied by significant EC apoptosis and the appearance of activated caspase 3. Further evaluation reveals that EC injury coincides with the onset of pulmonary pathology, is associated with elevations in bronchoalveolar lavage fluid tumor necrosis factor (TNF)-alpha levels, and is accompanied by evidence for EC activation. Administration of a soluble TNF-alpha binding protein (recombinant human TNF-alpha receptor:Fc) from week 4 to week 6 after allogeneic BMT significantly reduces EC apoptosis and lung histopathology observed in this setting. CONCLUSIONS: EC damage mediated by TNF-alpha is directly linked to the development of experimental IPS. Methods that protect or maintain the integrity of the pulmonary vascular endothelium may therefore prove effective in reducing the severity of lung injury after BMT.
-
etanercept enbrel administration for Idiopathic Pneumonia Syndrome after allogeneic hematopoietic stem cell transplantation
Biology of Blood and Marrow Transplantation, 2002Co-Authors: Gregory A Yanik, James L M Ferrara, Beth A Hellerstedt, Joseph R Custer, Raymond J Hutchinson, Deborah Kwon, J Uberti, Kenneth R CookeAbstract:Abstract Acute pulmonary dysfunction remains a frequent and severe complication of hematopoietic stem cell transplantation (SCT). Almost half of the pulmonary insults that occur in this seating are noninfectious in origin and are referred to as Idiopathic Pneumonia Syndrome (IPS). In this series of 3 patients, etanercept (Enbrel; Immunex, Seattle, WA), a soluble, dimeric tumor necrosis factor alpha-binding protein, was administered to 3 consecutive pediatric allogeneic BMT recipients with IPS. The administration of etanercept, in combination with standard immunosuppressive therapy, was well tolerated and associated with significant improvements in pulmonary dysfunction within the first week of therapy. These data suggest that etanercept may represent a safe, non-cross-reactive, therapeutic option for patients with IPS and that clinical trials studying etanercept for this indication are warranted. Biol Blood Marrow Transplant 2002;8(7):395-400.
-
hyporesponsiveness of donor cells to lipopolysaccharide stimulation reduces the severity of experimental Idiopathic Pneumonia Syndrome potential role for a gut lung axis of inflammation
Journal of Immunology, 2000Co-Authors: Kenneth R Cooke, Geoffrey R Hill, Armin Gerbitz, Joanne P Brewer, Thomas R Martin, Lester Kobzik, James M. Crawford, James L M FerraraAbstract:Idiopathic Pneumonia Syndrome (IPS) is a major complication of allogeneic bone marrow transplantation (BMT). We have shown that experimental IPS is associated with increased levels of LPS and TNF-α in the bronchoalveolar lavage (BAL) fluid. We hypothesized that the deleterious effects of these inflammatory mediators in the lung may be linked to gut injury that develops after BMT. To test this hypothesis, we used mouse strains that differ in their sensitivity to LPS as donors in an experimental BMT model. Lethally irradiated C3FeB6F 1 hosts received BMT from either LPS-sensitive or LPS-resistant donors. Five weeks after BMT, LPS-resistant BMT recipients had significantly less lung injury compared with recipients of LPS-sensitive BMT. This effect was associated with reductions in TNF-α secretion (both in vitro and in vivo), BAL fluid LPS levels, and intestinal injury. The relationship between TNF-α, gut toxicity, and lung injury was examined further by direct cytokine blockade in vivo; systemic neutralization of TNF-α resulted in a significant reduction in gut histopathology, BAL fluid LPS levels, and pulmonary dysfunction compared with control-treated animals. We conclude that donor resistance to endotoxin reduces IPS in this model by decreasing the translocation of LPS across the intestinal border and systemic and pulmonary TNF-α production. These data demonstrate a potential etiologic link between gut and lung damage after BMT and suggest that methods that reduce inflammatory responses to LPS, and specifically, those that protect the integrity of the gut mucosa, may be effective in reducing IPS after BMT.
Gregory A Yanik - One of the best experts on this subject based on the ideXlab platform.
-
tnf receptor inhibitor therapy for the treatment of children with Idiopathic Pneumonia Syndrome a joint pediatric blood and marrow transplant consortium and children s oncology group study asct0521
Biology of Blood and Marrow Transplantation, 2015Co-Authors: Gregory A Yanik, Stephan A Grupp, Michael A Pulsipher, John E Levine, Kirk R Schultz, Donna A Wall, Bryan Langholz, Christopher C Dvorak, Keith Alangaden, Rakesh K GoyalAbstract:Abstract Idiopathic Pneumonia Syndrome (IPS) is an acute, noninfectious lung disorder associated with high morbidity and mortality after hematopoietic cell transplantation. Previous studies have suggested a role for TNFα in the pathogenesis of IPS. We report a multicenter phase II trial investigating a soluble TNF-binding protein, etanercept (Enbrel, Amgen, Thousand Oaks, CA), for the treatment of pediatric patients with IPS. Eligible patients were P = .01). Overall survival at 28 days and 1 year after therapy were 89% (95% confidence interval [CI], 70% to 96%) and 63% (95% CI, 42% to 79%), respectively. Plasma levels of proinflammatory cytokines were significantly increased at onset of therapy, subsequently decreasing in responding patients. The addition of etanercept to high-dose corticosteroids was associated with high response rates and survival in children with IPS.
-
randomized double blind placebo controlled trial of soluble tumor necrosis factor receptor enbrel etanercept for the treatment of Idiopathic Pneumonia Syndrome after allogeneic stem cell transplantation blood and marrow transplant clinical trials net
Biology of Blood and Marrow Transplantation, 2014Co-Authors: Gregory A Yanik, Daniel J. Weisdorf, Vincent T Ho, Mary M Horowitz, Brent R Logan, Robert J Soiffer, Shelly L Carter, Juan Wu, John R Wingard, Nancy DifronzoAbstract:Abstract Idiopathic Pneumonia Syndrome (IPS) is a diffuse, noninfectious lung injury that occurs acutely after allogeneic hematopoietic cell transplantation (HCT). IPS-related mortality has been historically high (>50%) despite treatment with systemic corticosteroids and supportive care measures. We have now examined the role of tumor necrosis factor inhibition in a randomized, double-blind, placebo-controlled trial of corticosteroids with etanercept or placebo. Thirty-four subjects (≥18 years) with IPS after HCT were randomized to receive methylprednisolone (2 mg/kg/day) plus etanercept (0.4 mg/kg twice weekly × 4 weeks; n = 16) or placebo (n = 18). No active infections and a pathogen-negative bronchoscopy were required at study entry. Response (alive, with complete discontinuation of supplemental oxygen support) and overall survival were examined. This study, originally planned to accrue 120 patients, was terminated prematurely due to slow accrual. In the limited number of patients examined, there were no differences in response rates at day 28 of study. Ten of 16 patients (62.5% [95% confidence interval {CI}, 35.4% to 84.8%]) receiving etanercept and 12 of 18 patients (66.7% [95% CI, 41.0% to 86.7%]) receiving placebo met the day 28 response definition ( P = 1.00). The median survival was 170 days (95% CI, 11 to 362) with etanercept versus 64 days (95% CI, 26 to 209) with placebo ( P = .51). Among responders, the median time to discontinuation of supplemental oxygen was 9 days (etanercept) versus 7 days (placebo). Therapy was well tolerated, with 1 toxicity-related death from infectious Pneumonia in the placebo arm. The treatment of IPS with corticosteroids in adult HCT recipients was associated with high early response rates (>60%) compared with historical reports, with poor overall survival. The addition of etanercept did not lead to further increases in response, although the sample size of this truncated trial preclude a definitive conclusion.
-
response etanercept for Idiopathic Pneumonia Syndrome
Blood, 2009Co-Authors: Gregory A Yanik, Kenneth R CookeAbstract:Response: We appreciate Dr Frangoul's comments regarding long-term survival of the patients reported in our article.[1][1] Idiopathic Pneumonia Syndrome (IPS) remains a leading cause of treatment-related mortality, with one-month mortality rates approaching 80%. The goal of our study was to
-
the impact of soluble tumor necrosis factor receptor etanercept on the treatment of Idiopathic Pneumonia Syndrome after allogeneic hematopoietic stem cell transplantation
Blood, 2008Co-Authors: Gregory A Yanik, Joseph R Custer, John E Levine, Vincent T Ho, Eric S White, Thomas M Braun, Joseph H Antin, Joel Whitfield, Dawn Jones, James L M FerraraAbstract:Idiopathic Pneumonia Syndrome (IPS) refers to a diffuse, noninfectious, acute lung injury after hematopoietic stem cell transplantation. Historically, IPS is associated with respiratory failure and mortality rates exceeding 50%. Preclinical studies have implicated tumor necrosis factor-α as an important effector molecule in the development of disease. We studied the tumor necrosis factor-α inhibitor, etanercept, combined with corticosteroids in treating 15 patients (median age, 18 years; range, 1-60 years) with IPS. Eight of 15 patients required mechanical ventilation at therapy onset. Etanercept was administered subcutaneously at a dose of 0.4 mg/kg (maximum 25 mg) twice weekly, for a maximum of 8 doses. Therapy was well tolerated with no infectious pulmonary complications noted. Ten of 15 patients had a complete response, defined as the ability to discontinue supplemental oxygen support during study therapy. The median time to complete response was 7 days (range, 3-18 days), with a day 28 survival of 73%. IPS onset was associated with elevations of several inflammatory proteins in the bronchoalveolar lavage fluid and plasma, and response to therapy correlated with reductions in pulmonary and systemic inflammation. The combination of etanercept and corticosteroids is safe and is associated with high response rates and improved survival in patients with IPS.
-
survival following etanercept therapy for the treatment of Idiopathic Pneumonia Syndrome post allogeneic stem cell transplantation
Blood, 2004Co-Authors: Gregory A Yanik, James L M Ferrara, J Uberti, John E Levine, Vincent T Ho, Joseph H Antin, Kenneth R CookeAbstract:Pulmonary complications, both infectious and non-infectious, significantly contribute to mortality following allogeneic bone marrow transplantation (BMT). In the acute setting, a diffuse non-infectious process termed Idiopathic Pneumonia Syndrome (IPS) may occur. Clinically, IPS is associated with a rapid progression to respiratory failure and mortality rates of 50 – 70%. Historically, we have noted a 9.0% incidence of IPS at our center, with a median survival of only 14 days following its onset. Etanercept, a soluble tumor necrosis factor (TNF) receptor, consists of two soluble p75 TNF receptors fused to the Fc portion of a human IgG1. A trial examining etanercept in the treatment of IPS following allogeneic BMT was undertaken. Fifteen patients (median 18 yrs, range 1 – 60 yrs), each meeting the diagnostic criteria for IPS were enrolled. Broncho-alveolar lavage (BAL) specimen were obtained pre and post therapy, undergoing analysis for both infectious pathogens (viral, bacterial, fungal, PCP, AFB) and for a panel of inflammatory cytokine markers, including TNFa and TNFR1. Patients in whom the pre-therapy BAL was positive for a potential pathogen (by specific stain or culture) were ineligible for therapy. Etanercept was administered subcutaneously at a dose of 0.4 mg/kg (maximum dose 25 mg) twice weekly, for a maximum of 8 doses. All patients required supplemental oxygen at therapy onset, with seven patients requiring mechanical ventilation. Etanercept therapy was initiated a median of 17 days (range 11–87 days) post transplant. All patients received corticosteroids (2 mgkg/day) x 7 days, which were then tapered as clinically indicated. RESULTS: Nine of 15 patients had a complete response, defined as the ability to completely withdraw from supplemental oxygen support within 28 days of initiation of etanercept therapy. In responders, the median time to complete response was 7 days (range 3–18 days). The median survival was extended from 14 days (historical controls) to 67 days (range 3–822) in treated patients. Survival at day 28 and day 56 (following the first etanercept dose) was 73% and 60% respectively. The duration of mechanical ventilation required prior to therapy onset had a significant impact on survival. Patients requiring 48 hours prior to study entry. Overall, therapy was well tolerated. Two episodes of bacteremia, without sepsis, were noted during therapy, . No infectious pulmonary complications were noted. Three patients died while on therapy, from progressive pulmonary or organ dysfunction. Post therapy BAL fluid analysis noted significant reductions in all inflammatory cytokines tested, including TNFa, TNFR1, sCD14, LBP and MCP-1, when compared to pre-therapy BAL values. CONCLUSION: The addition of etanercept to corticosteroids for the treatment of IPS post allogeneic BMT may improve survival, with minimal toxicity. Moreover, the timing of such intervention may have a significant impact on overall outcome. A phase III trial, investigating the efficacy of etanercept in treating IPS is now being considered.
Gerhard C Hildebrandt - One of the best experts on this subject based on the ideXlab platform.
-
a role for tnf receptor type ii in leukocyte infiltration into the lung during experimental Idiopathic Pneumonia Syndrome
Biology of Blood and Marrow Transplantation, 2008Co-Authors: Kenneth R Cooke, Gerhard C Hildebrandt, Krystyna M Olkiewicz, Leigh A Corrion, Shawn G Clouthier, Elizabeth PierceAbstract:Abstract Idiopathic Pneumonia Syndrome (IPS) is a frequently fatal complication following allogeneic stem cell transplantation (allo-SCT). Experimental models have revealed that TNF-α contributes to pulmonary vascular endothelial cell (EC) apoptosis, and modulates the infiltration of donor leukocytes into the lung parenchyma. The inflammatory effects of TNF-α are mediated by signaling through the type I (TNFRI) or type II (TNFRII) TNF receptors. We investigated the relative contribution of TNFRI and TNFRII to leukocyte infiltration into the lung following allo-SCT by using established murine models. Wild-type (wt) B6 mice or B6 animals deficient in either TNFRI or TNFRII were lethally irradiated and received SCT from allogeneic (LP/J) or syngeneic (B6) donors. At week 5 following SCT, the severity of IPS was significantly reduced in TNFRII−/− recipients compared to wt controls, but no effect was observed in TNFRI−/− animals. Bronchoalveolar lavage fluid (BALF) levels of RANTES and pulmonary ICAM-1 expression in TNFRII−/− recipients were also reduced, and correlated with a reduction of CD8 + cells in the lung. Pulmonary inflammation was also decreased in TNFRII−/− mice using an isolated MHC class I disparate model (bm1 → B6), and in bm1 wt mice transplanted with B6 TNF-α−/− donor cells. Collectively, these data demonstrate a role for TNF-α signaling through TNFRII in leukocyte infiltration into the lung following allo-SCT, and suggest that disruption of the TNF-α:TNFRII pathway may be an effective tool to prevent or treat IPS.
-
The lung's friend, the gut's foe
Blood, 2007Co-Authors: Gerhard C HildebrandtAbstract:In this issue of Blood , Burman and colleagues provide a detailed experimental study of the ambiguous role of IFNγ in GVHD target-organ pathophysiology. The development of severe interstitial pneumonitis, characteristic of Idiopathic Pneumonia Syndrome (IPS) as a form of acute graft-versus-host
-
donor t cell production of rantes significantly contributes to the development of Idiopathic Pneumonia Syndrome after allogeneic stem cell transplantation
Blood, 2005Co-Authors: Gerhard C Hildebrandt, Krystyna M Olkiewicz, Leigh A Corrion, Shawn G Clouthier, Sung Choi, Jonathan S Serody, Kenneth R CookeAbstract:Idiopathic Pneumonia Syndrome (IPS) is a major cause of mortality following allogeneic stem cell transplantation (allo-SCT). Clinical and experimental data support a role for conditioning-induced inflammation and alloreactive T-cell responses in IPS pathophysiology, but the mechanisms by which donor leukocytes are ultimately recruited to the lung are not fully understood. RANTES is a chemokine ligand that is up-regulated during inflammation and promotes the recruitment of T cells and macrophages to sites of tissue damage. Using a lethally irradiated murine SCT model (B6 → B6D2F1), we evaluated the role of donor leukocyte–derived RANTES in the development of IPS. Pulmonary mRNA and protein levels of RANTES were significantly elevated in allo-SCT recipients compared to syngeneic controls and were associated with enhanced mRNA expression of CCR5 and CCR1 and with inflammatory cell infiltration into the lung. Allo-SCT with RANTES-/- donor cells significantly decreased IPS and improved survival. Combinations of allogeneic wild-type or RANTES-/- bone marrow with wild-type or RANTES-/- T cells demonstrated that the expression of RANTES by donor T cells was critical to the development of lung injury after SCT. These data reveal that donor T cells can help regulate leukocyte recruitment to the lung after allo-SCT and provide a possible mechanism through which inflammation engendered by SCT conditioning regimens is linked to allo-specific T-cell responses during the development of IPS.
-
a role for cd54 intercellular adhesion molecule 1 in leukocyte recruitment to the lung during the development of experimental Idiopathic Pneumonia Syndrome
Transplantation, 2005Co-Authors: Armin Gerbitz, Gerhard C Hildebrandt, Krystyna M Olkiewicz, Nicole E Willmarth, Debra L Williams, Gunther Eissner, Patricia Ewing, Andrea Wilke, Reinhard Andreesen, Ernst HollerAbstract:BACKGROUND: Idiopathic Pneumonia Syndrome (IPS) is a frequently fatal complication of allogeneic bone marrow transplantation (BMT). IPS is associated with elevated bronchoalveolar lavage (BAL) fluid levels of tumor necrosis factor-alpha and lipopolysaccharide, both of which are potent activators of endothelial cells (ECs). EC expression of the adhesion molecule CD54 (intercellular adhesion molecule [ICAM]-1) has been shown to be a major regulator of pulmonary inflammation in various experimental models. METHODS: Using a well-established murine BMT system in which lung injury and graft-versus-host disease (GvHD) are induced by minor histocompatibility antigenic differences between donor and host, the RNase Protection Assay, mice deficient in ICAM-1 expression, and a monoclonal blocking antibody to ICAM, we evaluated the role of the pulmonary vascular expression of CD54 in the development of IPS. RESULTS: Enhanced pulmonary vascular expression of ICAM-1 coincided with the development of IPS. When ICAM-1 -/- mice were used as allogeneic BMT recipients, IPS severity (measured by lung histopathology, BAL cellularity, and cytokine expression) was significantly reduced compared with wild-type controls. Similar results were also observed when wild-type recipients were treated with a monoclonal blocking antibody to ICAM-1. Surprisingly, ICAM-1 had differential effects on leukocyte infiltration into GvHD target organs; ICAM-1 deficiency had no impact on intestinal histopathology, whereas ICAM-1-/- BMT recipients had significantly enhanced hepatic injury. CONCLUSIONS: These data demonstrate that although the expression of ICAM-1 is critical for the development of IPS, different mechanisms of leukocyte recruitment are operative in other GvHD target organs.
-
a role for tumor necrosis factor α mediated endothelial apoptosis in the development of experimental Idiopathic Pneumonia Syndrome
Transplantation, 2004Co-Authors: Armin Gerbitz, James L M Ferrara, Lester Kobzik, Gerhard C Hildebrandt, Krystyna M Olkiewicz, Nicole E Willmarth, Brian J Nickoloff, Gunther Eissner, Ernst Holler, Kenneth R CookeAbstract:BACKGROUND: Idiopathic Pneumonia Syndrome (IPS) is a frequent and often fatal complication of allogeneic bone marrow transplantation (BMT). We have previously shown that experimental IPS is associated with alloreactive donor T cells and the inflammatory mediators TNF-alpha and lipopolysaccharide. Both TNF-alpha and lipopolysaccharide are known contributors to endothelial injury. Although damage to vascular endothelia has been associated with other complications after BMT, its relationship to lung injury has not been explored. METHODS: We used a well-established murine BMT system, in which lung injury and graft-versus-host disease are induced by minor histocompatibility antigenic differences between donor and host, and the DNA terminal transferase nick-end labeling (TUNEL) procedure to evaluate whether significant pulmonary vascular endothelial cell (EC) apoptosis is present during the development of IPS. RESULTS: Our data demonstrate that pulmonary histopathology after allogeneic BMT is accompanied by significant EC apoptosis and the appearance of activated caspase 3. Further evaluation reveals that EC injury coincides with the onset of pulmonary pathology, is associated with elevations in bronchoalveolar lavage fluid tumor necrosis factor (TNF)-alpha levels, and is accompanied by evidence for EC activation. Administration of a soluble TNF-alpha binding protein (recombinant human TNF-alpha receptor:Fc) from week 4 to week 6 after allogeneic BMT significantly reduces EC apoptosis and lung histopathology observed in this setting. CONCLUSIONS: EC damage mediated by TNF-alpha is directly linked to the development of experimental IPS. Methods that protect or maintain the integrity of the pulmonary vascular endothelium may therefore prove effective in reducing the severity of lung injury after BMT.
Lester Kobzik - One of the best experts on this subject based on the ideXlab platform.
-
a role for tumor necrosis factor α mediated endothelial apoptosis in the development of experimental Idiopathic Pneumonia Syndrome
Transplantation, 2004Co-Authors: Armin Gerbitz, James L M Ferrara, Lester Kobzik, Gerhard C Hildebrandt, Krystyna M Olkiewicz, Nicole E Willmarth, Brian J Nickoloff, Gunther Eissner, Ernst Holler, Kenneth R CookeAbstract:BACKGROUND: Idiopathic Pneumonia Syndrome (IPS) is a frequent and often fatal complication of allogeneic bone marrow transplantation (BMT). We have previously shown that experimental IPS is associated with alloreactive donor T cells and the inflammatory mediators TNF-alpha and lipopolysaccharide. Both TNF-alpha and lipopolysaccharide are known contributors to endothelial injury. Although damage to vascular endothelia has been associated with other complications after BMT, its relationship to lung injury has not been explored. METHODS: We used a well-established murine BMT system, in which lung injury and graft-versus-host disease are induced by minor histocompatibility antigenic differences between donor and host, and the DNA terminal transferase nick-end labeling (TUNEL) procedure to evaluate whether significant pulmonary vascular endothelial cell (EC) apoptosis is present during the development of IPS. RESULTS: Our data demonstrate that pulmonary histopathology after allogeneic BMT is accompanied by significant EC apoptosis and the appearance of activated caspase 3. Further evaluation reveals that EC injury coincides with the onset of pulmonary pathology, is associated with elevations in bronchoalveolar lavage fluid tumor necrosis factor (TNF)-alpha levels, and is accompanied by evidence for EC activation. Administration of a soluble TNF-alpha binding protein (recombinant human TNF-alpha receptor:Fc) from week 4 to week 6 after allogeneic BMT significantly reduces EC apoptosis and lung histopathology observed in this setting. CONCLUSIONS: EC damage mediated by TNF-alpha is directly linked to the development of experimental IPS. Methods that protect or maintain the integrity of the pulmonary vascular endothelium may therefore prove effective in reducing the severity of lung injury after BMT.
-
hyporesponsiveness of donor cells to lipopolysaccharide stimulation reduces the severity of experimental Idiopathic Pneumonia Syndrome potential role for a gut lung axis of inflammation
Journal of Immunology, 2000Co-Authors: Kenneth R Cooke, Geoffrey R Hill, Armin Gerbitz, Joanne P Brewer, Thomas R Martin, Lester Kobzik, James M. Crawford, James L M FerraraAbstract:Idiopathic Pneumonia Syndrome (IPS) is a major complication of allogeneic bone marrow transplantation (BMT). We have shown that experimental IPS is associated with increased levels of LPS and TNF-α in the bronchoalveolar lavage (BAL) fluid. We hypothesized that the deleterious effects of these inflammatory mediators in the lung may be linked to gut injury that develops after BMT. To test this hypothesis, we used mouse strains that differ in their sensitivity to LPS as donors in an experimental BMT model. Lethally irradiated C3FeB6F 1 hosts received BMT from either LPS-sensitive or LPS-resistant donors. Five weeks after BMT, LPS-resistant BMT recipients had significantly less lung injury compared with recipients of LPS-sensitive BMT. This effect was associated with reductions in TNF-α secretion (both in vitro and in vivo), BAL fluid LPS levels, and intestinal injury. The relationship between TNF-α, gut toxicity, and lung injury was examined further by direct cytokine blockade in vivo; systemic neutralization of TNF-α resulted in a significant reduction in gut histopathology, BAL fluid LPS levels, and pulmonary dysfunction compared with control-treated animals. We conclude that donor resistance to endotoxin reduces IPS in this model by decreasing the translocation of LPS across the intestinal border and systemic and pulmonary TNF-α production. These data demonstrate a potential etiologic link between gut and lung damage after BMT and suggest that methods that reduce inflammatory responses to LPS, and specifically, those that protect the integrity of the gut mucosa, may be effective in reducing IPS after BMT.
-
tumor necrosis factor alpha neutralization reduces lung injury after experimental allogeneic bone marrow transplantation
Transplantation, 2000Co-Authors: Kenneth R Cooke, Geoffrey R Hill, Armin Gerbitz, Joanne P Brewer, Thomas R Martin, Lester Kobzik, James M. Crawford, James L M FerraraAbstract:Background, Idiopathic Pneumonia Syndrome (IPS) is a frequent and potentially fatal complication of bone marrow transplantation (BR;TT), We have previously shown that experimental TPS is associated with increased levels of lipopolysaccaride (LPS) and tumor necrosis factor-alpha (TNF alpha) in the bronchoalveolar lavage (BAL) fluid, and that administration of LPS to animals with extensive graft versus host exacerbated underlying lung injury (Blood 1996; 88: 3230).
-
an experimental model of Idiopathic Pneumonia Syndrome after bone marrow transplantation i the roles of minor h antigens and endotoxin
Blood, 1996Co-Authors: Kenneth R Cooke, Joanne P Brewer, Thomas R Martin, Lester Kobzik, James M. Crawford, John Delmonte, James L M FerraraAbstract:Idiopathic Pneumonia Syndrome (IPS) refers to diffuse, non-infectious Pneumonia that occurs after allogeneic bone marrow transplantation (BMT). We have developed a model of IPS using a well-characterized murine BMT system (B10.BR-->CBA) in which lung injury after BMT can be induced by minor histocompatibility (H) antigenic differences between donor and host. Lung pathology and broncho-alveolar lavage (BAL) fluid were analyzed in transplant recipients before and after both syngeneic and allogeneic BMT. At 2 weeks after BMT, no specific pathologic abnormalities were noted; at 6 weeks, both pneumonitis and mononuclear cell infiltration around vessels and bronchioles were observed only in mice receiving allogeneic BMT. This injury was associated with elevated BAL fluid levels of endotoxin (lipopolysaccharide [LPS]), neutrophils, and tumor necrosis factor alpha. No pathologic organisms were isolated from the respiratory tract of any animal. We also tested the role of endotoxin in the development of this injury. Injection of LPS 6 weeks after transplantation caused profound lung injury only in mice with moderate graft-versus-host disease; dramatic increases in BAL neutrophils and tumor necrosis factor alpha were observed, with alveolar hemorrhage occurring in 4 of 12 of these mice but in no other group. We conclude that (1) this murine BMT system is a potentially useful model of clinical IPS; (2) minor H differences between donor and recipient can be important stimuli in the pathogenesis of IPS; and (3) endotoxin in BAL fluid is associated with lung injury, and excess endotoxin can cause the development of alveolar hemorrhage in this model.
-
the roles of alloreactivity and endotoxin in an experimental model of Idiopathic Pneumonia Syndrome after bone marrow transplantation 909
Pediatric Research, 1996Co-Authors: Kenneth R Cooke, Thomas R Martin, Lester Kobzik, Joanne Brewer, John Delmonte, J L M FerraraAbstract:THE ROLES OF ALLOREACTIVITY AND ENDOTOXIN IN AN EXPERIMENTAL MODEL OF Idiopathic Pneumonia Syndrome AFTER BONE MARROW TRANSPLANTATION. • 909
