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Gerckens/Mümmler Lab

Lung Transplantation: Therapeutic Immunology

Lung transplantation is a life-saving treatment option for patients with the most severe lung diseases. The aim of our working group - led jointly by the doctors Dr. Michael Gerckens and Dr. Carlo Mümmler - is to improve outcomes after lung transplantation. The two group leaders bring their extensive experience in clinical and scientific research to this initiative and pursue an innovative management concept that integrates clinical and scientific tasks. The group works in close cooperation with the Hospital of the University of Munich (KUM).

This integration of clinical practice and scientific research across this research focus facilitates a better understanding of lung transplant function and the development of new therapeutic approaches in order to - hopefully - significantly improve the quality of life and survival of patients after lung transplants.

Lung transplantation is a life-saving treatment option for patients with the most severe lung diseases. The aim of our working group - led jointly by the doctors Dr. Michael Gerckens and Dr. Carlo Mümmler - is to improve outcomes after lung transplantation. The two group leaders bring their extensive experience in clinical and scientific research to this initiative and pursue an innovative management concept that integrates clinical and scientific tasks. The group works in close cooperation with the Hospital of the University of Munich (KUM).

This integration of clinical practice and scientific research across this research focus facilitates a better understanding of lung transplant function and the development of new therapeutic approaches in order to - hopefully - significantly improve the quality of life and survival of patients after lung transplants.

Chronic lung allograft dysfunction

Unfortunately, long-term survival rates and long-term prognosis after lung transplantation remain unsatisfactory compared to other organ transplants. This is due to a variety of complications associated with patients' immunosuppression and concomitant therapies after lung transplantation. These include various types of lung transplant failure.

A central concern of the research efforts is to characterize chronic lung allograft dysfunction (CLAD), a serious complication characterized by a progressive loss of lung function after an initial stable plateau, in more detail in order to derive new therapeutic options. In addition, the group is investigating different types of transplanted lung dysfunction, such as primary graft dysfunction (PGD) or baseline lung allograft dysfunction (BLAD). Humoral and acute rejection are also significant challenges that greatly influence survival and prognosis after lung transplantation.

Picture right: Digitalized bronchoalveolar lavage cytospin for further automated analysis

Pleural effusions and their causes

Another important area of ​​research is the study of pleural effusions, which occur as a complication of lung disease and other diseases. Pleural effusions are accumulations of fluid between the pleural sheets that may result from dysfunction of the pulmonary or cardiovascular systems or from other causes such as malignancies or immunological events. In lung transplant recipients, we observe a previously unknown form of lymphocyte-rich pleural effusions, which influence survival and morbidity after lung transplantation and the cause of which is also being investigated by the research group.

Technological innovations: Automated analysis of bronchoalveolar lavage

A central concern of the working group is the automated analysis of bronchoalveolar lavage (BAL), an important diagnostic tool in lung diseases and transplantation processes. Bronchoalveolar lavage can be obtained through bronchoscopy with lung lavage and provides valuable information about the immunological conditions in the lungs. The working group is researching how machine learning and artificial intelligence can be used to improve and simplify these analyses. The aim is to develop a clinically usable tool that makes the analysis of lung fluid more efficient and precise.

Picture right: Digitalized bronchoalveolar lavage cytospin for further automated analysis

Scientists at Gerckens/Mümmler Lab

Bilousov_Oleksandr_Portrait

Oleksandr Bilousov

MD candidate
Portrait Michael Gerckens LHI

Dr. Michael Gerckens

Group Leader / Clinician Scientist
Khmelovska_Daria_Portrait

Daria Khmelovska

MD candidate

Dr. Linjohn Kurz

Postdoc
Mümmler_Carlo_Portrait

Dr. Carlo Mümmler

Group Leader / Clinician Scientist
Richard_Alexander_Portrait

Alexander Richard

Statistician / Research assistant
Siddiqui_Aorchie_Portrait

Aorchie Siddiqui

MSc. candidate

Publications

2024, Wissenschaftlicher Artikel in Transplantation

Characterization of baseline lung allograft dysfunction in single lung transplant recipients.

BACKGROUND: Baseline lung allograft dysfunction (BLAD) is characterized by the failure to achieve normal baseline lung function after double lung transplantation (DLTX) and is associated with a high risk of mortality. In single lung transplant (SLTX) recipients, however, cutoff values and associated factors have not been explored. Here, we aimed to define BLAD in SLTX recipients, investigate its impact on allograft survival, and identify potential risk factors for BLAD in SLTX recipients. METHODS: We performed a retrospective, single-center analysis of the LTX cohort of LMU Munich between 2010 and 2018. In accordance with DLTX cutoffs, BLAD in SLTX recipients was defined as failure to achieve percentage of forced expiratory volume in 1 s and percentage of forced vital capacity of >60% on 2 consecutive tests >3 wk apart. Survival analysis and regression analysis for potential predictors of BLAD were performed. RESULTS: In a cohort of 141 SLTX recipients, 43% of patients met BLAD criteria. SLTX recipients with BLAD demonstrated impaired survival. Native lung hyperinflation was associated with BLAD in obstructive disease, whereas donor/recipient lung size mismatch was associated with BLAD in both obstructive and restrictive underlying diseases. Pulmonary function testing at 3 mo after lung transplantation predicted normal baseline lung function in SLTX recipients with obstructive lung disease. CONCLUSIONS: BLAD in SLTX recipients is as relevant as in DLTX recipients and should generally be considered in the follow-up of LTX recipients. Risk factors for BLAD differed between underlying obstructive and restrictive lung disease. A better understanding of associated factors may help in the development of preventive strategies.

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2024, Wissenschaftlicher Artikel in Thorax

COPD basal cells are primed towards secretory to multiciliated cell imbalance driving increased resilience to environmental stressors.

INTRODUCTION: Environmental pollutants injure the mucociliary elevator, thereby provoking disease progression in chronic obstructive pulmonary disease (COPD). Epithelial resilience mechanisms to environmental nanoparticles in health and disease are poorly characterised. METHODS: We delineated the impact of prevalent pollutants such as carbon and zinc oxide nanoparticles, on cellular function and progeny in primary human bronchial epithelial cells (pHBECs) from end-stage COPD (COPD-IV, n=4), early disease (COPD-II, n=3) and pulmonary healthy individuals (n=4). After nanoparticle exposure of pHBECs at air-liquid interface, cell cultures were characterised by functional assays, transcriptome and protein analysis, complemented by single-cell analysis in serial samples of pHBEC cultures focusing on basal cell differentiation. RESULTS: COPD-IV was characterised by a prosecretory phenotype (twofold increase in MUC5AC+) at the expense of the multiciliated epithelium (threefold reduction in Ac-Tub+), resulting in an increased resilience towards particle-induced cell damage (fivefold reduction in transepithelial electrical resistance), as exemplified by environmentally abundant doses of zinc oxide nanoparticles. Exposure of COPD-II cultures to cigarette smoke extract provoked the COPD-IV characteristic, prosecretory phenotype. Time-resolved single-cell transcriptomics revealed an underlying COPD-IV unique basal cell state characterised by a twofold increase in KRT5+ (P=0.018) and LAMB3+ (P=0.050) expression, as well as a significant activation of Wnt-specific (P=0.014) and Notch-specific (P=0.021) genes, especially in precursors of suprabasal and secretory cells. CONCLUSION: We identified COPD stage-specific gene alterations in basal cells that affect the cellular composition of the bronchial elevator and may control disease-specific epithelial resilience mechanisms in response to environmental nanoparticles. The identified phenomena likely inform treatment and prevention strategies.

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2024, Wissenschaftlicher Artikel in European Respiratory Journal

Sfrp1 inhibits lung fibroblast invasion during transition to injury induced myofibroblasts.

BACKGROUND: Fibroblast to myofibroblast conversion is a major driver of tissue remodeling in organ fibrosis. Distinct lineages of fibroblasts support homeostatic tissue niche functions, yet, their specific activation states and phenotypic trajectories during injury and repair have remained unclear. METHODS: We combined spatial transcriptomics, multiplexed immunostainings, longitudinal single-cell RNA-seq and genetic lineage tracing to study fibroblast fates during mouse lung regeneration. Our findings were validated in IPF patient tissues in situ as well as in cell differentiation and invasion assays using patient lung fibroblasts. Cell differentiation and invasion assays established a function of SFRP1 in regulating human lung fibroblast invasion in response to TGFβ1. MEASUREMENTS AND MAIN RESULTS: We discovered a transitional fibroblast state characterized by high Sfrp1 expression, derived from both Tcf21-Cre lineage positive and negative cells. Sfrp1+ cells appeared early after injury in peribronchiolar, adventitial and alveolar locations and preceded the emergence of myofibroblasts. We identified lineage specific paracrine signals and inferred converging transcriptional trajectories towards Sfrp1+ transitional fibroblasts and Cthrc1+ myofibroblasts. TGFβ1 downregulated SFRP1 in non-invasive transitional cells and induced their switch to an invasive CTHRC1+ myofibroblast identity. Finally, using loss of function studies we showed that SFRP1 modulates TGFβ1 induced fibroblast invasion and RHOA pathway activity. CONCLUSIONS: Our study reveals the convergence of spatially and transcriptionally distinct fibroblast lineages into transcriptionally uniform myofibroblasts and identifies SFRP1 as a modulator of TGFβ1 driven fibroblast phenotypes in fibrogenesis. These findings are relevant in the context of therapeutic interventions that aim at limiting or reversing fibroblast foci formation.

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2023, Wissenschaftlicher Artikel in Science Translational Medicine

Ex vivo tissue perturbations coupled to single-cell RNA-seq reveal multilineage cell circuit dynamics in human lung fibrogenesis.

Pulmonary fibrosis develops as a consequence of failed regeneration after injury. Analyzing mechanisms of regeneration and fibrogenesis directly in human tissue has been hampered by the lack of organotypic models and analytical techniques. In this work, we coupled ex vivo cytokine and drug perturbations of human precision-cut lung slices (hPCLS) with single-cell RNA sequencing and induced a multilineage circuit of fibrogenic cell states in hPCLS. We showed that these cell states were highly similar to the in vivo cell circuit in a multicohort lung cell atlas from patients with pulmonary fibrosis. Using micro-CT-staged patient tissues, we characterized the appearance and interaction of myofibroblasts, an ectopic endothelial cell state, and basaloid epithelial cells in the thickened alveolar septum of early-stage lung fibrosis. Induction of these states in the hPCLS model provided evidence that the basaloid cell state was derived from alveolar type 2 cells, whereas the ectopic endothelial cell state emerged from capillary cell plasticity. Cell-cell communication routes in patients were largely conserved in hPCLS, and antifibrotic drug treatments showed highly cell type-specific effects. Our work provides an experimental framework for perturbational single-cell genomics directly in human lung tissue that enables analysis of tissue homeostasis, regeneration, and pathology. We further demonstrate that hPCLS offer an avenue for scalable, high-resolution drug testing to accelerate antifibrotic drug development and translation.

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2023, Wissenschaftlicher Artikel in BMC Surgery

Preoperative risk factors predict perioperative allogenic blood transfusion in patients undergoing primary lung cancer resections: a retrospective cohort study from a high-volume thoracic surgery center.

BACKGROUND: Our study aimed to identify preoperative predictors for perioperative allogenic blood transfusion (ABT) in patients undergoing major lung cancer resections in order to improve the perioperative management of patients at risk for ABT. METHODS: Patients admitted between 2014 and 2016 in a high-volume thoracic surgery clinic were retrospectively evaluated in a cohort study based on a control group without ABT and the ABT group requiring packed red blood cell units within 15 days postoperatively until discharge. The association of ABT with clinically established parameters (sex, preoperative anemia, liver and coagulation function, blood groups, multilobar resections) was analyzed by contingency tables, receiver operating characteristics (ROC) and logistic regression analysis, taking into account potential covariates. RESULTS: 60 out of 529 patients (11.3%) required ABT. N1 and non-T1 tumors, thoracotomy approach, multilobar resections, thoracic wall resections and Rhesus negativity were more frequent in the ABT group. In multivariable analyses, female sex, preoperative anemia, multilobar resections, as well as serum alanine-aminotransferase levels, thrombocyte counts and Rhesus negativity were identified as independent predictors of ABT, being associated with OR (95% Confidence interval, p-value) of 2.44 (1.23-4.88, p = 0.0112), 18.16 (8.73-37.78, p < 0.0001), 5.79 (2.50-13.38, p < 0.0001), 3.98 (1.73-9.16, p = 0.0012), 2.04 (1.04-4.02, p = 0.0390) and 2.84 (1.23-6.59, p = 0.0150), respectively. CONCLUSIONS: In patients undergoing major lung cancer resections, multiple independent risk factors for perioperative ABT apart from preoperative anemia and multilobar resections were identified. Assessment of these predictors might help to identify high risk patients preoperatively and to improve the strategies that reduce perioperative ABT.

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2022, Wissenschaftlicher Artikel in The journal of allergy and clinical immunology. In practice

Overall response to anti-IL5/anti-IL5Rα treatment in severe asthma does not depend on initial bronchodilator responsiveness.

BACKGROUND: Positive bronchodilator responsiveness (BDR) (ΔFEV1≥+200ml and ≥+12%) after inhalation of short-acting beta-agonist (SABA) has been an inclusion criterion in licensing trials of anti-IL5/anti-IL5Rα biologics in severe asthma. However, in clinical practice patients with severe uncontrolled asthma frequently show a negative BDR. OBJECTIVE: To investigate whether the response to anti-IL5/anti-IL5Rα therapies differs between patients with positive and negative BDR at baseline. METHODS: Retrospective multicenter analysis of treatment outcomes in patients with severe asthma receiving anti-IL5/anti-IL5Rα stratified for baseline BDR. RESULTS: Of 133 patients included, 37 had a positive and 96 had a negative BDR at baseline. Following anti-IL5/anti-IL5Rα treatment FEV1 improved significantly in both groups compared to baseline (p<0.0001), with no significant difference between patients with positive and negative BDR (ΔFEV1 +493ml vs +306ml, p=0.06). FVC increased (ΔFVC: +85ml vs +650ml, p<0.01) and RV decreased (ΔRV +113ml vs -307ml, p<0.01) significantly in patients with negative BDR. Median annualized exacerbations (0 vs 0; p=0.7), reduction of exacerbation rate (Δexacerbations: 0 vs -2, p=0.07), continuous oral corticosteroid (OCS) use (Δpatients on OCS: -35% vs -39%, p=0.99) and improvement of asthma control test (ACT) score (ΔACT: 6 vs 5, p=0.7) were similar in both groups. Multivariate logistic regression analysis showed no significant correlations of positive vs negative BDR with response parameters. CONCLUSIONS: Both groups improved following treatment with similar responses concerning reduction of OCS therapy, exacerbations and improvement of symptom control. Pulmonary function also improved in both groups during anti-IL5/anti-IL5Rα treatment, with differences in response patterns noted.

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Contact

Portrait Michael Gerckens LHI

Dr. Michael Gerckens

Group Leader / Clinician Scientist

Contact

Mümmler_Carlo_Portrait

Dr. Carlo Mümmler

Group Leader / Clinician Scientist