SFB 738 - Research Project B9

Inflammation and Fibrogenesis in Early Lesions of Chronic Lung Allograft Dysfunction

"Our ultimate goal is to identify the molecular mechanisms of CLAD to identify targets for therapeutic intervention."

Danny Jonigk - principal investigator

Our Vision

The major limitation of survival following lung transplantation (LuTx) remains chronic lung allograft dysfunction (CLAD), the morphological hallmark of which is obliterative remodeling of the small airways (OAR) specifically termed bronchiolitis obliterans (BO). OAR represents a focal event which frequently escapes histological detection by transbronchial biopsy. Therefore lung function tests are used clinically as surrogate markers for patient monitoring, which are unspecific and rather insensitive, though. The initial lesion which develops into OAR has not been defined yet. Based on a review of >200 whole lung graft explants / autopsy specimens, we hypothesize that OAR is preceded by inflammatory foci of yet unknown cellular composition and localization and that in the initiating inflammatory foci classically activated macrophages and regulatory T-cells as well as the local microbiome play decisive roles as necessary co-factors. In recent work we analyzed fibrosis associated regulatory pathways using a customized mini array system (Fluid Card, ABI) and could demonstrate a differential expression of fibrosis-associated genes in OAR. Moreover we could show the potential value of a subset of genes including thrombospondin, MMP1, BMP4, SMAD 1 and IL6 to diagnose and predict BO even in morphologically inconspicuous transplant biopsies. We are convinced that a in correlative analysis of disease morphology with spatial gene expression will enable us to identify therapeutic targets and make a difference in the prognosis for our patients.

Our Goals

To further address the pathogenesis of OAR, we want to identify the transition zone between normal and remodeled airways by a novel tissue sample preparation technique for 3D imaging (e. g. SLOT or light sheet microscopy), enabling a comprehensive reconstruction of lung parenchyma. These areas will be serially cut and subjected to an analysis of fibrosis associated genes and tissue based in-situ assays for the immunolocalization of B- T- NK-cells and macrophages in addition to bacterial 16s ribosomal RNA (rRNA) in-situ analysis. Using specially designed software overlays of conventional morphology and in-situ techniques will allow a topographic mapping of the early OAR lesions and the inflammatory infiltrate as well as the microbiome.

Principal Investigators Project B9

Prof. Dr. med. Danny Jonigk

Institut für Pathologie
Medizinische Hochschule Hannover
Carl-Neuberg-Str.1
30625 Hannover
Tel.: +49 511 532-4490

Jonigk.Danny@mh-hannover.de

Dr. med. Florian Länger

Institut für Pathologie
Medizinische Hochschule Hannover
Carl-Neuberg-Str.1
30625 Hannover
Tel.: +49 511 532-4477

Laenger.Florian@mh-hannover.de

Staff Project B9

Dr. rer. nat. Mark Kühnel

Dr. med. Lavinia Mägel

Dr. med. Peter Braubach

Kristin Teiken

Annette Müller Brechlin

Christina Fiedler

Regina Engelhardt

Denise Kühl