Notch-1 Inhibition Promotes Immune Regulation in Transplantation Via Regulatory T Cell-Dependent Mechanisms.

BACKGROUND: Transplantation is the treatment of choice for many patients with end-stage organ disease. Despite advances in immunosuppression, long-term outcomes remain suboptimal, hampered by drug toxicity and immune-mediated injury, the leading cause of late graft loss. The development of therapies that promote regulation while suppressing effector immunity is imperative to improve graft survival and minimize conventional immunosuppression. Notch signaling is a highly conserved pathway pivotal to T-cell differentiation and function, rendering it a target of interest in efforts to manipulate T cell-mediated immunity. METHODS: We investigated the pattern of Notch-1 expression in effector and regulatory T cells (Tregs) in both murine and human recipients of a solid-organ transplant. Using a selective human anti-Notch-1 antibody (aNotch-1), we examined the effect of Notch-1 receptor inhibition in full major histocompatibility complex-mismatch murine cardiac and lung transplant models, and in a humanized skin transplant model. On the basis of our findings, we further used a genetic approach to investigate the effect of selective Notch-1 inhibition in Tregs. RESULTS: We observed an increased proportion of Tregs expressing surface and intracellular (activated) Notch-1 in comparison with conventional T cells, both in mice with transplants and in the peripheral blood of patients with transplants. In the murine cardiac transplant model, peritransplant administration of aNotch-1 (days 0, 2, 4, 6, 8, and 10) significantly prolonged allograft survival in comparison with immunoglobulin G-treated controls. Similarly, aNotch-1 treatment improved both histological and functional outcomes in the murine lung transplant model. The use of aNotch-1 resulted in a reduced proportion of both splenic and intragraft conventional T cells, while increasing the proportion of Tregs. Furthermore, Tregs isolated from aNotch-1-treated mice showed enhanced suppressive function on a per-cell basis, confirmed with selective Notch-1 deletion in Tregs (Foxp3EGFPCreNotch1fl/fl). Notch-1 blockade inhibited the mammalian target of rapamycin pathway and increased the phosphorylation of STAT5 (signal transducer and activator of transcription 5) in murine Tregs. Notch-1low Tregs isolated from human peripheral blood exhibited more potent suppressive capacity than Notch-1high Tregs. Last, the combination of aNotch-1 with costimulation blockade induced long-term tolerance in a cardiac transplant model, and this tolerance was dependent on CTLA-4 (cytotoxic T-lymphocyte-associated antigen-4) signaling. CONCLUSIONS: Our data reveal a promising, clinically relevant approach for immune modulation in transplantation by selectively targeting Notch-1.

Treating the Airway Consequences of Cystic Fibrosis Transmembrane Conductance Regulator Dysfunction.

In cystic fibrosis (CF), absent or dysfunctional CF transmembrane conductance regulator (CFTR) on the surface of airway epithelial cells causes abnormal mucociliary clearance, leading to chronic endobronchial infection and inflammation, in turn resulting in life-shortening progressive obstructive lung disease and structural airway damage. Fortunately, CF-specific therapies have been developed that improve lung function and reduce pulmonary exacerbations, contributing significantly to improved survival over the past 4 decades. Therapies not originally developed for CF, such as bronchodilators and corticosteroids, are also widely used by people living with CF. Therapies to be reviewed in this article include mucolytics, airway surface liquid hydrators, anti-inflammatory medications, bronchodilators, inhaled and oral antibiotics, and airway clearance techniques. Determining which therapies to utilize can be challenging, as there is variable evidence for each treatment, differing national guidelines, few head-to-head studies, potential for drug-drug interactions, and synergistic toxicities, as well as issues with burden of care. In this review, we summarize the mechanism of action and available evidence, and compare national guidelines for each major medication used to treat the airway consequences of CFTR dysfunction.

Evaluation of the line probe assay for the rapid detection of bacterial meningitis pathogens in cerebrospinal fluid samples from children.

BACKGROUND: The aim of this study is to compare the diagnostic performance of the line probe assay (LPA) with conventional multiplex polymerase chain reaction (PCR) for Streptococcus pneumoniae as well as real-time PCR for Neisseria meningitidis and Haemophilus influenzae type b (Hib) in cerebrospinal fluid (CSF) samples from children during the multicenter national surveillance of bacterial meningitis between the years 2006 and 2009 in Turkey. RESULTS: During the study period 1460 subjects were enrolled and among them 841 (57%) met the criteria for probable bacterial meningitis. The mean age of subjects was 51 ± 47 months (range, 1-212 months). We performed the line probe assay in 751 (89%) CSF samples of 841 probable bacterial meningitis cases, of whom 431 (57%) were negative, 127 (17%) were positive for S. pneumoniae, 53 (7%) were positive for H. influenzae type b, and 41 (5%) were positive for N. meningitidis. The LPA was positive in 19 of 23 (82%) S. pneumoniae samples, 4 of 6 (67%) N. meningitidis samples and 2 of 2 (100%) Hib samples in CSF culture-positive cases. The specificity of the LPA for all of S. pneumoniae, H. influenzae type b, and N. meningitidis was 88% (95% CI: 85-91%), when using the standard PCR as a reference. The specificity of LPA for each of S. pneumoniae, H. influenzae type b, and N. meningitidis was 93% (95% CI: 89-95%), 96% (95% CI: 94-98%), and 99% (95% CI: 97-99%), respectively. For all of S. pneumoniae, H. influenzae type b and N. meningitidis the sensitivity of the LPA was 76% (95% CI: 70-82%) and for each of S. pneumoniae, H. influenzae type b and N. meningitidis was 72% (95% CI:63-79%), 88% (95% CI: 73-95%), and 81% (95% CI:67-92%), respectively. CONCLUSIONS: The LPA assay can be used to detect common bacterial meningitis pathogens in CSF samples, but the assay requires further improvement.

Diversity, Equity, and Inclusion in the Pediatric Pulmonary Workforce: An Official American Thoracic Society Workshop Report.

Despite growing recognition of the need for increased diversity among students, trainees, and faculty in health care, the medical workforce still lacks adequate representation from groups historically underrepresented in medicine (URiM). The subspecialty field of pediatric pulmonology is no exception. Although there have been efforts to address issues of diversity, equity, and inclusion (DEI) in our own field, gaps persist. To address these gaps, the members of the Diversity, Equity, and Inclusion Advisory Group (DEI-AG) of the American Thoracic Society Pediatrics Assembly created and distributed a Needs Assessment Survey in the United States and Canada to better understand the racial and ethnic demographics of the pediatric pulmonary workforce and to learn more about successes, gaps, and opportunities to enhance how we recruit, train, and retain a diverse workforce. The DEI-AG leadership cochairs convened a workshop to review the findings of the DEI Needs Assessment Survey and to develop strategies to improve the recruitment and retention of URiM fellows and faculty. This Official ATS Workshop Report aims to identify barriers and opportunities for recruitment, training, and career development within the field of pediatric pulmonology. Additionally, we offer useful strategies and resources to improve the recruitment of URiM residents, the mentorship of trainees and junior faculty, and the career development of URiM faculty in academic centers. This Workshop Report is an important first deliverable by the DEI-AG. We hope that this work, originating from within the Pediatrics Assembly, will serve as a model for other Assemblies, disciplines across the ATS, and other fields in Pediatrics.

Diagnosing latent tuberculosis infection in haemodialysis patients: T-cell based assay (T-SPOT.TB) or tuberculin skin test?

BACKGROUND: The international guidelines recommend screening haemodialysis (HD) patients for latent tuberculosis infection (LTBI). The aim of this study is to compare the diagnostic utility of tuberculin skin test (TST) with an interferon-γ-based assay (T-SPOT.TB) for the diagnosis of LTBI in HD patients. METHODS: A total of 411 patients [233 male (57%), mean age 56±16 years] in five HD centres were prospectively tested by TST and T-SPOT.TB assays. A total of 302 patients (75%) had Bacillus Calmette-Guerin vaccination scar. RESULTS: LTBI was detected in 39 and 61% of patients by one-step TST and T-SPOT.TB, respectively. The booster phenomenon determined additional 60 (25%) LTBI among 243 patients. Overall, 218 (53%) patients showed a positive reaction to TST after performing the two-step TST. Among 250 one-step TST negative patients T-SPOT.TB assay was positive in 118 (47%). Of 158 patients with a positive one-step TST, T-SPOT.TB was negative in 34 (22%). On the other hand, T-SPOT.TB was negative in 16 (27%) of boosted patients. T-SPOT.TB was negative in 50 (23%) of overall TST-positive patients and positive in 71 (39%) of TST negative ones. Multivariate logistic regression analysis revealed that male gender was independently associated with positive T-SPOT.TB, and positive T-SPOT.TB was inversely associated with the presence of BCG vaccine scar, serum albumin level and HD duration. Annual conversion rates were 12 and 32% for TST and T-SPOT.TB tests, respectively. CONCLUSION: Usage of T-SPOT.TB in HD patients with negative TST may enhance diagnosis of LTBI.

C-reactive protein is an independent predictor for carotid artery intima-media thickness progression in asymptomatic younger adults (from the Bogalusa Heart Study).

BACKGROUND: Conflicting information exists regarding the association between hsCRP and the progression of early stages of atherosclerosis. The purpose of the study was to investigate the association of high sensitiviy c-reactive protein (hsCRP) along with major cardiovascular (CV) risk factors on early carotid atherosclerosis progression in a large, population-based cohort study. METHODS: The study cohort included 839 young adults (aged 24 to 43 years, 70% white, 42% men) enrolled in Bogalusa Heart Study, who in 2001-2002 attended baseline examination with measurements of CV risk factors. Progression of carotid artery intima-media thickness (IMT) was assessed during a mean follow-up of 2.4 years. RESULTS: Carotid artery IMT progression rates were as follows: composite carotid artery = 9.2 ± 52 µm/y, common carotid artery = 0.0 ± 51 µm/y, carotid bulb = 8.8 ± 103 µm/y, and internal carotid artery = 18.9 ± 81 µm/y. Elevated baseline hsCRP, reflecting an inflammatory state, showed independent association with composite carotid artery IMT progression. Increased age, systolic blood pressure, fasting glucose, LDL cholesterol, and current smoking were other risk associates of carotid artery IMT progression in young adults, indicating an underlying burden on the CV system by multiple risk factors. CONCLUSION: In this population-based study, we observed independent categorical association of increased hsCRP with carotid artery IMT progression in young adults. This study underlines the importance of assesssing hsCRP levels along with smoking and traditional CV risk factor profiles in asymptomatic young adults.

Acute hyperglycaemia in cystic fibrosis pulmonary exacerbations.

Background: Hyperglycaemia may contribute to failure to recover from pulmonary exacerbations in cystic fibrosis (CF). We aimed to evaluate the prevalence and mechanism of hyperglycaemia during and post-exacerbations. Methods: Nine paediatric CF patients, not on insulin, hospitalized for intravenous antibiotics, underwent an oral glucose tolerance test (OGTT) and continuous glucose monitoring (CGM) upon admission (visit 1) and an OGTT 2 weeks (visit 2) and 6 weeks to 12 months later when at stable baseline (visit 3). Insulin and glucose levels were measured before, 30, 60 and 120 min after glucose ingestion during OGTT. Hyperglycaemia on OGTT was defined according to the American Diabetes Association criteria as abnormal OGTT or consistent with diabetes. Hyperglycaemia on CGM was defined as CGM time above 140 mg/dL > 4.5%. Results: At visit 1, 8/9 patients had hyperglycaemia on both CGM and OGTT (2 diabetes and 6 abnormal OGTT). At visit 2, 5/8 had hyperglycaemia (all abnormal OGTT). At visit 3, (median (IQR) time since visit 1, 4.9 (3.8-6.3) months), 5/7 had hyperglycaemia (2 diabetes and 3 abnormal OGTT). At visits 1, 2 and 3, respectively, mean (SD) 2-hour OGTT glucose was 175.8 (42.3), 146.3 (31.9) and 176.9 (51.7) mg/dL. CGM time above 140 mg/dL at visit 1 was 25.3% (16.9). Insulin AUC decreased from visit 2 (median (IQR) 5449 (3321-8123) mcIU-min/mL) to visit 3 (3234 (2913-3680) mcIU-min/mL). Conclusion: Hyperglycaemia is prevalent during paediatric CF exacerbations; it appears to improve with exacerbation treatment but to worsen later in association with decreased insulin secretion.

From Theory to Patient Care: A Model for the Development, Adaptation, and Testing of Psychosocial Interventions for Patients With Serious Illness.

Psychosocial and supportive care interventions are a cornerstone of palliative care science, yet there is little published guidance regarding how to develop, test, adapt, and ultimately disseminate evidence-based interventions. Our objective was to describe the application of a single intervention-development model in multiple populations of patients with serious illness. Specifically, we use the "Promoting Resilience in Stress Management" (PRISM) intervention as an exemplar for how the Obesity Related Behavioral Intervention Trials (ORBIT) intervention-development model may be applied to: 1) create an initial palliative care intervention; 2) adapt an existing intervention for a new patient-population; 3) expand an existing intervention to include new content; and, 4) consider dissemination and implementation of a research-proven intervention. We began by identifying key psychological and social science theories and translating them a testable clinical hypothesis. Next, we conducted observational studies and randomized trials to design, refine, and standardize PRISM within unique patient-populations. We moved backwards in the ORBIT model when necessary to adapt or expand PRISM content and delivery-strategies to meet patient-reported needs. Finally, we began to explore PRISM's effectiveness using Dissemination and Implementation research methods. Key lessons include the need to ground intervention-development in evidence-based theory; involve patient, clinician, and other stakeholders at every phase of development; "meet patients where they are at" with flexible delivery strategies; invest in the time to find the right scientific premise and the right intervention content; and, perhaps most importantly, involve an interdisciplinary research team.

Resilience in adolescents and young adults with cystic fibrosis: A pilot feasibility study of the promoting resilience in stress management intervention.

BACKGROUND: Disease burden in cystic fibrosis (CF) impacts quality of life, distress, and treatment adherence. The promoting resilience in stress management (PRISM), is a brief patient-focused intervention to promote resilience in adolescents and young adults (AYAs), which may mitigate the negative outcomes, and is proven to be feasible and acceptable in other diseases. OBJECTIVE: Our aim was to test the feasibility and acceptability of PRISM among AYAs with CF in addition to collecting pilot data regarding patient-reported resilience, distress, and quality of life. METHODS: Eligible English speaking, 12 to 21 year patients admitted to the hospital were enrolled. We defined feasibility as 80% completion of all sessions. Acceptability was defined qualitatively based on feedback about timing, content and delivery of intervention. As an exploratory aim, questionnaires measuring resilience (Connor-Davidson resilience scale), distress (Kessler-6 scale), and disease-specific health-related quality of life (CF questionnaire-revised [CFQ-R]) were given at baseline and postintervention. RESULTS: 10 out of 17 (59%) patients consented to participate. Eight were Caucasian, eight female with age range 13 to 20 years (median: 18). Nine completed all PRISM sessions with universally positive feedback. Health perception and respiratory domain scores of the CFQ-R improved (47.2-65.1; 95% confidence interval [CI], 2.6-35.6; 50.9-61.9; 95% CI, 1.7-19.9, respectively), however in the setting of inpatient exacerbation treatment it would be hard to attribute these changes to PRISM. CONCLUSION: PRISM was feasible and highly acceptable among AYAs with CF. Future research is needed to test the efficacy of PRISM among a larger group of patients with CF in a multicenter trial.

Highlights from the 2019 North American Cystic Fibrosis Conference.

This review briefly summarizes presentations in several major topic areas at the conference: pathophysiology and basic science of cystic fibrosis lung disease, clinical trials, clinical quality improvement, microbiology and treatment of infection, and transition, advanced lung disease and transplant, mental health and psychosocial concerns. The review is intended to highlight several areas and is not a comprehensive summary of the conference. Citations from the conference are by the first author and abstract number or symposium number, as designated in the supplement.

Highlights from the 2018 North American cystic fibrosis conference.

The 32nd annual North American Cystic Fibrosis Conference was held in Denver, CO on Oct. 18 to 20, 2018. This review highlights presentations in several topic areas, including the pathophysiology and basic science of cystic fibrosis lung disease, clinical trials, clinical care, and quality improvement. Citations from the conference are by first author and abstract or symposium number, as designated in the previously published supplement.

Comparison of positive tuberculin skin test with an interferon-gamma-based assay in unexposed children.

A false-positive tuberculin skin test (TST) may be a result of T-cell sensitivity due to Bacille Calmette-Guerin (BCG) vaccination or exposure to non-tuberculous mycobacteria, thus leading to unnecessary isoniazid preventive therapy, especially in low-risk populations. Unlike TST, T-SPOT.TB is not confounded by BCG vaccination or exposure to most of the other non-tuberculous mycobacteria, because this assay is based on enumeration of interferon-gamma-secreting T cells in response to Mycobacterium tuberculosis-specific antigens. We compared the TST with T-SPOT.TB with respect to different TST cut-off points in healthy unexposed BCG-vaccinated schoolchildren. A total of 209 children between 6 and 10 years of age with a TST induration of 0 (n = 50), 10 - 14 (n = 45), 15 - 19 (n = 95) and > or =20 mm (n = 19) were enrolled. Among TST-positive subjects, only 26 (23%) were positive with T-SPOT.TB, and T-SPOT.TB was positive in 4, 7, 20 and 42% of children with TST indurations of 0, 10 - 14, 15 - 19 and > or =20 mm, respectively. We suggest that confirmation of a positive TST by the interferon-gamma-based test would reduce unnecessary preventive therapy significantly in healthy unexposed BCG-vaccinated children.

Hickman Catheter-Related Bacteremia with Kluyvera cryocrescens: a Case Report.

This report describes a 2-year-old child with neuroectodermal tumor presenting with febrile neutropenia. Blood cultures drawn from the peripheral vein and Hickman catheter revealed Kluyvera cryocrescens growth. The Hickman catheter was removed and the patient was successfully treated with cefepime and amikacin. Isolation of Kluyvera spp. from clinical specimens is rare. This saprophyte microorganism may cause serious central venous catheter infections, especially in immunosuppressed patients. Clinicians should be aware of its virulence and resistance to many antibiotics.

Highlights from the 2017 North American Cystic Fibrosis Conference.

The 31st annual North American Cystic Fibrosis Conference (NACFC) was held in Indianapolis, IN on November 2-4, 2017. Abstracts of presentations from the conference were published in a supplement to Pediatric Pulmonology [2017; Pediatr Pulmonol Suppl. 52: S1-S776]. The current review summarizes several major topic areas addressed at the conference: the pathophysiology and basic science of cystic fibrosis (CF) lung disease, clinical trials, clinical management issues, and quality improvement (QI). In this review, we describe emerging concepts in several areas of CF research and care.

The effect of recurrent tonsillitis and adenotonsillectomy on growth in childhood.

OBJECTIVE: Tonsil and adenoid hypertrophy may cause recurrent tonsillitis and upper airway obstruction in children. A reduced dietary intake and failure to gain weight is frequently reported by parents of children with a history of recurrent acute tonsillitis and adenotonsiller hypertrophy. The purpose of this prospective study was to evaluate whether surgical treatment of adenotonsillar hypertrophy affects the circulating concentrations of insulin-like growth factor-1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) along with IGF-1 SDS and IGFBP-3 SDS's adjusted to age which are more important in evaluating growth in childhood. METHODS: Thirty-eight prepubertal children 24 boys and 14 girls participated in this study. The mean age at surgery was 6.66+/-1.84 years (range 4-10 years). Weight, height, IGF-1 and IGFBP-3 levels and standard deviation scores were evaluated before and 12-18 months after adenotonsillectomy (T&A). RESULTS: The number of infections in a year reduced from 8.6+/-4.4 to 0.37+/-0.68 after operation. The mean weight standard deviation score (SDS) increased significantly after T&A (p<0.01). The mean IGFBP-3 level increased from 1912+/-511.5 to 2989+/-1125ng/ml (p<0.001) and IGFBP-3 SDS increased from -3.0+/-0.58 SDS to -1.96+/-1.27 SDS (p: 0.001). However, the mean serum IGF-1 level increased from 80.3+/-48.5 to 116.8+/-105.9ng/ml (p: 0.135), and IGF-1 SDS increased from -1.36+/-0.51 SDS to -1.31+/-1.14 SDS (p: 0.701), which were both not statistically significant. CONCLUSIONS: We have demonstrated postoperative weight gain and significant increase in IGFBP-3 concentrations and IGFBP-3 SDS, accompanying significant decrease in the number of tonsillitis episodes after adenotonsillectomy.

Outcomes of mechanical support in a pediatric lung transplant center.

Pediatric lung transplantation is a lifesaving option for patients with end stage lung disease, although the scarcity of suitable donor organs results in long wait times and increased waitlist mortality. Many pediatric centers consider mechanical ventilatory support, such as long-term invasive ventilation and ECMO, a contraindication to lung transplantation. We hypothesized that current survival rates and outcomes for patients on mechanical ventilatory support in the pre-transplant period were not remarkably different. In our retrospective analysis we included patients between the ages of 0-21 years listed for lung transplantation from deceased donors between 2007 and 2014 at our institution. One-year survival outcomes were compared between three groups of patients: (i) patients bridged to transplant on ECMO (n = 6, 1-year survival = 67%); (ii) patients needing mechanical ventilation (either through endotracheal intubation or tracheostomy) but not ECMO (n = 12, 1-year survival = 75%); and (iii) patients who did not need endotracheal ventilation, tracheostomy, or ECMO (n = 25, 1-year survival = 88%). Comparison of outcomes of transplanted patients between these three groups were not statistically different in terms of successful hospital discharge and 1-year survival rates (P > 0.05). We believe that "bridging" the end-stage lung disease patient with long-term mechanical ventilation and/or ECMO support is a reasonable option in selected patients until suitable donors become available. Pediatr Pulmonol. 2017;52:360-366. © 2016 Wiley Periodicals, Inc.

Postoperative keratitis due to Paecilomyces: a rare pediatric case.

Fungal infections like Paecilomyces keratitis have emerged in childhood recently. The diagnosis and treatment of Paecilomyces keratitis is difficult and the outcome is usually poor. Corneal culture should be performed on fungal media such as Sabouraud glucose neopeptone agar (SDA) as soon as possible for diagnosis. We report a rare case of Paecilomyces keratitis in an immunocompetent child, which was unresponsive to amphotericin B. The case was managed by a multidisciplinary approach involving the departments of ophthalmology, microbiology and pediatric infectious diseases. We want to draw attention once again that fungal keratitis caused by unusual agents are increasing. Physicians should consider fungal causes of keratitis, in patients with some predisposing factors like ocular surgery and prolonged use of topical corticosteroids.

Cerebral complications in diabetic ketoacidosis.

Although much is known about diabetic ketoacidosis (DKA) and its treatment, the pathology of cerebral complications in patients who develop ketoacidosis is not yet well understood. In this article, we discuss the cerebral complications due to DKA by presenting two cases who were admitted with severe DKA and who both developed early and severe neurological complications.

Recurrent Candida albicans Ventriculitis Treated with Intraventricular Liposomal Amphotericin B.

Central nervous system (CNS) infection with Candida is rare but significant because of its high morbidity and mortality. When present, it is commonly seen among immunocompromised and hospitalized patients. Herein, we describe a case of a four-year-old boy with acute lymphoblastic leukemia (ALL) who experienced recurrent Candida albicans meningitis. The patient was treated successfully with intravenous liposomal amphotericin B at first attack, but 25 days after discharge he was readmitted to hospital with symptoms of meningitis. Candida albicans was grown in CFS culture again and cranial magnetic resonance imaging (MRI) showed ventriculitis. We administered liposomal amphotericin B both intravenously and intraventricularly and favorable result was achieved without any adverse effects. Intraventricular amphotericin B may be considered for the treatment of recurrent CNS Candida infections in addition to intravenous administration.

Therapeutic lymphangiogenesis ameliorates established acute lung allograft rejection.

Lung transplantation is the only viable option for patients suffering from otherwise incurable end-stage pulmonary diseases such as chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis. Despite aggressive immunosuppression, acute rejection of the lung allograft occurs in over half of transplant recipients, and the factors that promote lung acceptance are poorly understood. The contribution of lymphatic vessels to transplant pathophysiology remains controversial, and data that directly address the exact roles of lymphatic vessels in lung allograft function and survival are limited. Here, we have shown that there is a marked decline in the density of lymphatic vessels, accompanied by accumulation of low-MW hyaluronan (HA) in mouse orthotopic allografts undergoing rejection. We found that stimulation of lymphangiogenesis with VEGF-C156S, a mutant form of VEGF-C with selective VEGFR-3 binding, alleviates an established rejection response and improves clearance of HA from the lung allograft. Longitudinal analysis of transbronchial biopsies from human lung transplant recipients demonstrated an association between resolution of acute lung rejection and decreased HA in the graft tissue. Taken together, these results indicate that lymphatic vessel formation after lung transplantation mediates HA drainage and suggest that treatments to stimulate lymphangiogenesis have promise for improving graft outcomes.