Lung cell transplantation for pulmonary fibrosis.
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ABSTRACT:
SUBMITTER: Milman Krentsis I
PROVIDER: S-EPMC11343030 | biostudies-literature | 2024 Aug
REPOSITORIES: biostudies-literature
Publications
Lung cell transplantation for pulmonary fibrosis.
Milman Krentsis Irit I Zheng Yangxi Y Rosen Chava C Shin Sarah Y SY Blagdon Christa C Shoshan Einav E Qi Yuan Y Wang Jing J Yadav Sandeep K SK Bachar Lustig Esther E Shetzen Elias E Dickey Burton F BF Karmouty-Quintana Harry H Reisner Yair Y
Science advances 20240823 34
Idiopathic pulmonary fibrosis is a major cause of death with few treatment options. Here, we demonstrate the therapeutic efficacy for lung fibrosis of adult lung cell transplantation using a single-cell suspension of the entire lung in two distinct mouse systems: bleomycin treatment and mice lacking telomeric repeat-binding factor 1 expression in alveolar type 2 (AT2) cells (<i>SPC-Cre TRF1<sup>fl/fl</sup></i>), spontaneously developing fibrosis. In both models, the progression of fibrosis was a ...[more]
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Project description:BackgroundIn idiopathic pulmonary fibrosis (IPF) patients, alveolar architectures are lost and gas transfer function would decline, which cannot be rescued by conventional anti-fibrotic therapy. P63+ lung basal progenitor cells are reported to have potential to repair damaged lung epithelium in animal models, which need further investigation in clinical trials.MethodsWe cloned and expanded P63+ progenitor cells from IPF patients to manufacture cell product REGEND001, which were further characterized by morphology and single-cell transcriptomic analysis. Subsequently, an open-label, dose-escalation autologous progenitor cell transplantation clinical trial was conducted. We treated 12 patients with ascending doses of cells: 0.6x, 1x, 2x and 3.3x106 cells/kg bodyweight. The primary outcome was the incidence and severity of cell therapy-related adverse events (AEs); secondary outcome included other safety and efficacy evaluations.ResultsP63+ basal progenitor cell was safe and tolerated at all doses, with no dose-limiting toxicity or cell therapy-related severe adverse events observed. Patients in three higher dose groups showed significant improvement of lung gas transfer function as well as exercise ability. Resolution of honeycomb lesion was observed in patients of higher dose groups.ConclusionsREGEND001 has high safety profile and meanwhile encourages further efficacy exploration in IPF patients.FundingNational High Level Hospital Clinical Research Funding (2022-PUMCH-B-108), National Key Research and Development Plan (2024YFA1108900, 2024YFA1108500), Jiangsu Province Science and Technology Special Project Funding (BE2023727), National Biopharmaceutical Technology Research Project Funding (NCTIB2023XB01011), Non-profit Central Research Institute Fund of Chinese Academy of Medical Science (2020-PT320-005), and Regend Therapeutics.Clinical trial numberChinese clinical trial registry: CTR20210349.
| S-EPMC11879106 | biostudies-literature
Project description:Currently, lung transplantation is the standard of care for patients with end-stage lung disease, with interstitial lung disease (ILD) being the most common reason in the recent years In the other hand, in cases where stage II and III lung cancer have been identified following lung transplantation, long-term survival outcomes are poor when compared to lung cancer patients that have not received a lung transplant because the use of immunosuppressant and the problem of rejection and infection and the treatment of recurrence and so on. However, there is no statistical difference observed in stage I (pT1N0M0) patients. In this paper we report about a patient with ILD receiving left lung transplantation in the early time. A lesion of the right lung which was considered the normal ILD tissue and without enough attention. Post-transplant it showed progress and finally the whole right lung (native lung) was occupied by the tumor. Some ground glass changes could also be found in the transplanted lung several months later. A secondary lung transplant was performed for this patient, and there has been no postoperative recurrence thus far. For lung transplant patients with high-risk factors, effective surveillance methods are required for the early detection of lung cancer.
| S-EPMC8044479 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is a distinct form of interstitial pneumonia with unknown origin and poor prognosis. Current pharmacologic treatments are limited and lung transplantation is a viable option for appropriate patients. The aim of this review was to summarize lung transplantation survival in IPF patients overall, between single (SLT) vs. bilateral lung transplantation (BLT), pre- and post Lung Allocation Score (LAS), and summarize wait-list survival.MethodsA systematic review of English-language studies published in Medline or Embase between 1990 and 2013 was performed. Eligible studies were those of observational design reporting survival post-lung transplantation or while on the wait list among IPF patients.ResultsMedian survival post-transplantation among IPF patients is estimated at 4.5 years. From ISHLT and OPTN data, one year survival ranged from 75% - 81%; 3-year: 59% - 64%; and 5-year: 47% - 53%. Post-transplant survival is lower for IPF vs. other underlying pre-transplant diagnoses. The proportion of IPF patients receiving BLT has steadily increased over the last decade and a half. Unadjusted analyses suggest improved long-term survival for BLT vs. SLT; after adjustment for patient characteristics, the differences tend to disappear. IPF patients account for the largest proportion of patients on the wait list and while wait list time has decreased, the number of transplants for IPF patients has increased over time. OPTN data show that wait list mortality is higher for IPF patients vs. other diagnoses. The proportion of IPF patients who died while awaiting transplantation ranged from 14% to 67%. While later transplant year was associated with increased survival, no significant differences were noted pre vs. post LAS implementation; however a high LAS vs low LAS was associated with decreased one-year survival.ConclusionsIPF accounts for the largest proportion of patients awaiting lung transplants, and IPF is associated with higher wait-list and post-transplant mortality vs. other diagnoses. Improved BLT vs. SLT survival may be the result of selection bias. Survival pre- vs. post LAS appears to be similar except for IPF patients with high LAS, who have lower survival compared to pre-LAS. Data on post-transplant morbidity outcomes are sparse.
| S-EPMC4151866 | biostudies-literature
Project description:BackgroundCombined pulmonary fibrosis and emphysema (CPFE) patients generally have a poorer prognosis compared to those with either pulmonary fibrosis or chronic obstructive pulmonary disease (COPD)/emphysema alone, as demonstrated by several studies. Our study aimed to identify undiagnosed CPFE cases within a lung transplantation cohort initially diagnosed with interstitial lung fibrosis or COPD/emphysema. It was hypothesized that the patient cohort might contain overlooked CPFE cases, and CPFE patients would exhibit a higher incidence of pre-transplant pulmonary hypertension and post-transplant chronic lung allograft dysfunction (CLAD).MethodsThis is a single-center, retrospective cohort study conducted at the University Hospital of Zurich, Switzerland. Expert review of pre-transplant computed tomography (CT) scans by a thoracic radiologist aimed to identify undiagnosed CPFE cases. Diagnostic criteria followed established guidelines, requiring both emphysema and pulmonary fibrosis on CT imaging. A total of 133 consecutive adult bilateral lung transplantations were performed for patients with interstitial lung disease, emphysema, or both (January 1, 2013, to December 31, 2021). A total of 113 patients could be analyzed, 20 patients were excluded because of missing data. The study analyzed pulmonary function tests, pre-transplant pulmonary hypertension screening, and CLAD staging in CPFE and non-CPFE patients. Primary outcome was the incidence of CPFE among lung transplantation candidates initially diagnosed with interstitial lung fibrosis or COPD/emphysema. Secondary outcomes were comparison of pulmonary function, diffusing capacity, invasively measured pulmonary hypertension, and CLAD stages between CPFE and non-CPFE patients.ResultsBased on pre-transplant CT scans, out of 113 patients, 12 (10.6%) were reclassified as previously undiagnosed CPFE, 49 (43.4%) as non-CPFE fibrosis, and 50 (44.2%) as non-CPFE emphysema. A solitary patient (0.9%) was classified as having both fibrosis and emphysema but did not meet the criteria of CPFE. One additional patient (n=1, 0.9%) exhibited a tree-in-bud pattern. Prior to the radiological review, none of the patients had been classified as CPFE and had instead received a radiological diagnosis of COPD, emphysema, sarcoidosis, interstitial pulmonary fibrosis (IPF) or hypersensitivity pneumonitis (HP).ConclusionsThe study confirmed undiagnosed CPFE cases in 12 (10.6%) in the lung transplantation cohort, suggesting potential underdiagnosis or misclassification. Objective analysis revealed similarities in lung function, diffusing capacity, pulmonary hypertension and CLAD between CPFE and non-CPFE groups. Further exploration is warranted to understand CPFE's diagnostic nuances and clinical implications in lung transplantation.
| S-EPMC11635263 | biostudies-literature
Project description:BackgroundCombined pulmonary fibrosis and emphysema (CPFE) is recognized as a characteristic syndrome of smoking-related interstitial lung disease that has a worse prognosis than idiopathic pulmonary fibrosis (IPF). However, outcomes after lung transplantation for CPFE have not been reported. The aim of this study is to describe the clinical features and outcomes of CPFE after lung transplantation.Research questionWhat are the clinical features and outcomes of CPFE after lung transplantation?Study design and methodsThis is a single-center retrospective cohort study of patients with CPFE and IPF who underwent lung transplantation at our center between January 2011 and December 2016. We defined CPFE as ≥10% emphysema in the upper lung fields combined with fibrosis on high-resolution CT scan. We characterized the clinical features of patients with CPFE and compared their outcomes after lung transplantation with those with IPF.ResultsTwenty-seven of 172 (16%) patients with IPF met criteria for CPFE. Severe pulmonary hypertension was present in 16 of 27 (59%) patients with CPFE. On logistic regression analysis, CPFE was significantly associated with primary graft dysfunction (PGD) grade 3 (OR, 3.14; 95% CI, 1.18-8.37; P = .02). On competing risk regression analysis, CPFE was associated with acute cellular rejection (ACR) grade ≥ A2, and chronic lung allograft dysfunction (CLAD) (hazard ratio [HR], 1.89; 95% CI, 1.10-3.25; P = .02; HR, 1.96; 95% CI, 1.02-3.77; P = .04, respectively). Five-year survival was 79.0% for the CPFE group and 75.4% for the IPF group (log-rank P = .684).InterpretationAfter transplantation, patients with CPFE were more likely to develop PGD, ACR, and CLAD compared with those with IPF. However, survival was not significantly different between the two groups.
| S-EPMC8628179 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is the most common indication for lung transplantation in North America and variants in telomere-maintenance genes are the most common identifiable cause of IPF. We reasoned that younger IPF patients are more likely to undergo lung transplantation and we hypothesized that lung transplant recipients would be enriched for individuals with telomere-mediated disease due to the earlier onset and more severe disease in these patients.MethodsIndividuals with IPF who underwent lung transplantation or were evaluated in an interstitial lung disease specialty clinic who did not undergo lung transplantation were examined. Genetic evaluation was completed via whole genome sequencing (WGS) of 426 individuals and targeted sequencing for 5 individuals. Rare variants in genes previously associated with IPF were classified using the American College of Medical Genetics guidelines. Telomere length from WGS data was measured using TelSeq software. Patient characteristics were collected via medical record review.ResultsOf 431 individuals, 149 underwent lung transplantation for IPF. The median age of diagnosis of transplanted vs non-transplanted individuals was significantly younger (60 years vs 70 years, respectively, p<0.0001). IPF lung transplant recipients (IPF-LTRs) were twice as likely to have telomere-related rare variants compared to non-transplanted individuals (24% vs 12%, respectively, p=0.0013). IPF-LTRs had shorter telomeres than non-transplanted IPF patients (p=0.0028) and >85% had telomeres below the age-adjusted mean. Post-transplant survival and CLAD were similar amongst IPF-LTRs with rare variants in telomere-maintenance genes compared to those without, as well as in those with short telomeres versus longer telomeres.ConclusionsThere is an enrichment for telomere-maintenance gene variants and short telomeres among IPF-LTRs. However, transplant outcomes of survival and CLAD do not differ by gene variants or telomere length within IPF-LTRs. Our findings support individual with telomere-mediated disease should not be excluded from lung transplantation and focusing research efforts on therapies directed toward individuals with short-telomere mediated disease.
| S-EPMC9038609 | biostudies-literature
Project description:BackgroundNutritional status is an important prognostic factor in patients with cystic fibrosis (CF) prior to lung transplantation.ObjectiveTo investigate the impact of nutritional status on pulmonary function in CF transplant recipients.MethodsAdult double lung transplanted CF patients were consecutively included. The predictive value of nutritional status on lung function - measured by spirometry - was longitudinally assessed by body composition serially evaluated by a three-compartment model bioelectrical impedance analysis (BIA) in comparison to body mass index (BMI).ResultsOverall, 147 spirometries and 147 BIAs were performed in 58 patients (59% female, median age: 30.1 years, median BMI: 19.6 kg/m2). Malnourished patients (BMI < 18.5 kg/m2; 27.6%) had a significantly reduced lung function compared to normal/overweight patients (forced expiratory volume in 1 second in percent (FEV1%pred), 57% vs 77%; p = 0.024). BMI, as well as the BIA parameters phase angle, total body water, fat free mass, body cell mass (BCM) and extracellular mass (ECM)/BCM ratio, were univariate predictors of FEV1%pred. When included in a linear mixed model, ECM/BCM ratio remained the only significant predictor of lung function (p = 0.012).ConclusionNutritional status assessed by BIA predicted lung function in CF transplant recipients. Serial BIA measurements to monitor patients' nutritional status might help to improve or maintain lung function.
| S-EPMC6137582 | biostudies-literature
Project description:BackgroundPrior studies have shown that patients with pulmonary fibrosis with mutations in the telomerase genes have a high rate of certain complications after lung transplantation. However, few studies have investigated clinical outcomes based on leukocyte telomere length.MethodsWe conducted an observational cohort study of all patients with pulmonary fibrosis who underwent lung transplantation at a single center between January 1, 2007, and December 31, 2014. Leukocyte telomere length was measured from a blood sample collected before lung transplantation, and subjects were stratified into 2 groups (telomere length <10th percentile vs ≥10th percentile). Primary outcome was post-lung transplant survival. Secondary outcomes included incidence of allograft dysfunction, non-pulmonary organ dysfunction, and infection.ResultsApproximately 32% of subjects had a telomere length <10th percentile. Telomere length <10th percentile was independently associated with worse survival (hazard ratio 10.9, 95% confidence interval 2.7-44.8, p = 0.001). Telomere length <10th percentile was also independently associated with a shorter time to onset of chronic lung allograft dysfunction (hazard ratio 6.3, 95% confidence interval 2.0-20.0, p = 0.002). Grade 3 primary graft dysfunction occurred more frequently in the <10th percentile group compared with the ≥10th percentile group (28% vs 7%; p = 0.034). There was no difference between the 2 groups in incidence of acute cellular rejection, cytopenias, infection, or renal dysfunction.ConclusionsTelomere length <10th percentile was associated with worse survival and shorter time to onset of chronic lung allograft dysfunction and thus represents a biomarker that may aid in risk stratification of patients with pulmonary fibrosis before lung transplantation.
| S-EPMC5515686 | biostudies-literature
Project description:OBJECTIVE:Lung transplantation remains the only curative treatment for end-stage lung disease, conferring a better survival for some IPF patients, but whether they should receive double lung transplantation (DLT) or single lung transplantation (SLT) is still controversial. The aim of this study was to determine which type of lung transplantation was more effective and relatively safe in IPF patients by meta-analysis. METHODS:Publications comparing overall survival (OS) or other perioperative characteristics between IPF patients undergoing SLT and DLT were selected from electronic databases. The hazard ratios (HRs) were abstracted or calculated to evaluate the survival outcome. Odds ratios (ORs) or mean differences (MDs) were used to compare the causes of death or perioperative parameters. A random-effect model was used to combine data. Heterogeneity was quantified by means of an I2 with 95% confidence interval (95% CI). The publication bias was estimated using the Eggers test with Begg's funnel plots. RESULTS:16 studies with 17,872 IPF cases who met the inclusion criteria were included in this meta-analysis. SLT was associated with declined post-transplant FEV1% (MD = -15.37, 95% CI:-22.28,-8.47; P<0.001), FVC % (MD = -12.52, 95% CI:-19.45,-5.59; P<0.001) and DLCO% (MD = -13.85, 95% CI:-20.42,-7.29; P<0.001), but no significant advantage of DLT over SLT was seen in the overall survival outcome (HR = 1.08, 95% CI: 0.91-1.29; P = 0.391). Subgroup analyses for studies of follow-up period ≥ 60 months also showed similar results (all P-values>0.05). Moreover, there was fewer deaths attributable to primary graft dysfunction in SLT recipients (OR = 0.31, 95% CI: 0.2-0.48; P<0.001), while more patients with SLT died of malignancy (OR = 3.44, 95% CI: 2.06-5.77; P<0.001). CONCLUSION:Our findings suggest that DLT was associated with better postoperative pulmonary function, but there was no difference in long-term overall survival between patients undergoing DLT and SLT. However, further high-quality and large-scale studies are needed to confirm these findings.
| S-EPMC7241801 | biostudies-literature
Project description:BackgroundIdiopathic pulmonary fibrosis (IPF) is often associated with elevations in pulmonary artery pressures. Although primary pulmonary arterial hypertension (PAH) has been associated with primary graft dysfunction (PGD), the role of secondary PAH in mediating PGD risk in patients with IPF is incompletely understood. The purpose of this study was to evaluate the relationship between mean pulmonary artery pressure (mPAP) and PGD among patients with IPF.MethodsWe performed a multicenter prospective cohort study of 126 lung transplant procedures performed for IPF between March 2002 and August 2007. The primary outcome was grade 3 PGD at 72 h after lung transplant. The mPAP was measured as the initial reading following insertion of the right-sided heart catheter during lung transplant. Multivariable logistic regression was used to adjust for confounding variables.ResultsThe mPAP for patients with PGD was 38.5 ± 16.3 mm Hg vs 29.6 ± 11.5 mm Hg for patients without PGD (mean difference, 8.9 mm Hg [95% CI, 3.6-14.2]; P = .001). The increase in odds of PGD associated with each 10-mm Hg increase in mPAP was 1.64 (95% CI, 1.18-2.26; P = .003). In multivariable models, this relationship was independent of confounding by other clinical variables, although the use of cardiopulmonary bypass partially attenuated the relationship.ConclusionsHigher mPAP in patients with IPF is associated with the development of PGD.
| S-EPMC3071272 | biostudies-literature