Project

Discipline

lung transplantation; chronic rejection; magnetic resonance imaging

Lead
Die Magnetresonanz-Tomographie wird zum Nachweis der chronischen Abstossungsreaktion nach Lungentransplantation eingesetzt, um diese in einem frühen, noch behandelbaren Stadium zu erkennen.
Lay summary
Inhalt und Zielsetzung des Forschungsprojektes: Die chronische Abstossungsreaktion ist die häufigste Komplikation nach Lungentransplantation und wesentlich für die eingeschränkte Lebenserwartung dieser Patienten verantwortlich. Innerhalb von 3 Jahren kommt es bei mehr als 70% der Patienten nach Lungentransplantation zu Vernarbungen mit Verlegung der kleinen Atemwege, welche zu einer irreversiblen Zerstörung des Transplantats führen. In der klinischen Routine wird in der Regel die hochaufgelöste Computer-Tomographie verwendet um Komplikationen nach Lungentransplantation nachzuweisen. Jedoch sind die durch Computer-Tomographie erhobenen Befunde oft unspezifisch, so dass es sehr schwierig ist, Lungeninfekte von der chronischen Abstossungsreaktion zu unterscheiden. Die Magnetresonanz-Tomographie ist eine Methode, bei der unterschiedliche Kontraste eingesetzt werden, um  Informationen über den Aufbau und die Funktion des Gewebes zu erhalten ohne schädliche ionisierende Strahlung anwenden zu müssen. Das Ziel dieses Projektes ist die Entwicklung und Erprobung von Techniken der Magnetresonanz-Tomographie zur Beurteilung der Belüftung (Ventilation) und einer möglichen Vernarbung (Fibrose) des Lungengewebes nach Transplantation in einem Mausmodell. Wissenschaftlicher und gesellschaftlicher Kontext: Die zu entwickelnde Technik soll es erlauben, eine chronische Lungentransplantatabstossung in einem frühen, noch behandelbaren Stadium zu entdecken und so die Überlebenszeit nach Lungentransplantation zu verlängern.

Direct link to Lay Summary

Last update: 11.03.2013

Number	Title	Start	Funding scheme

Background: In spite of remarkable progress in prevention and treatment of acute pulmonary rejection, the phenomenon of chronic allograft rejection (CR) still constitutes the major obstacle on the way to unlimited graft acceptance after lung transplantation (Tx). Within three years post-Tx, more than 70% of all lung allografts develop fibro-obliterative remodeling of small airways, leading to a progressive and irreversible deterioration of the transplant. The pathological hallmark of pulmonary CR is bronchiolitis obliterans (BO), an inflammatory fibro-proliferative process, resulting in an obstruction of small bronchioles. Once BO is emerging, current therapy cannot reverse the impeding deterioration of graft function. High-resolved computed tomography (HR-CT) is most frequently used for the assessment of complications after lung Tx providing high sensitivity for the detection of pulmonary pathological patterns. However, the imaging findings are non-specific thus rendering CR not distinguishable from other diseases. Bronchoscopic biopsy is the mainstay for diagnosis of BO but is often inconclusive due to a patchy distribution of CR lesions. Moreover, BO diagnosis is made at a stage when current therapeutics are not effective anymore. To overcome these obstacles, we aim here to develop a technique of magnetic resonance imaging (MRI) that characterizes and detects early CR lesions on the basis of a validated CR model of orthotopic mouse single lung transplantation.Working hypothesis: we propose a suitable protocol for MRI of the lung capable to detect and monitor CR with similar sensitivity to HR-CT but higher specificity without applying ionizing irradiation. The detection of CR changes implies the possibility to beneficially modulate the progress of CR at an early stage of the disease.Specific Aims: Based on the orthotopic lung Tx model in mice established at our institution, we will here employ a validated CR mouse model and develop a suitable MRI technique to target the following aims: (a) implementation of the CR mouse model, (b) introduction of a HR-CT gold standard of the mouse lung using a microcomputer-tomograph (micro-CT), (c) quantification of pulmonary ventilation using MRI, (d) quantification of fibrosis of small airways using MRI, and (e) modulation of CR by blocking IL-17A/F and correlation of the dynamics using the established MRI protocol. Experimental Design and Methods: For aim (a), n=6 mice will be transplanted between the minor histoincompatible strains C57BL/10?C57BL/6 and histologically evaluated at day 7, 14, 21, 28, and 35, when CR reliably develops as described. Syngeneic Tx between C57BL/6?C57BL/6 mice will serve as controls. Micro-CT imaging will serve as a gold standard for subprojects (c), (d), and (e). Recently developed ultra-short echo-time (UTE) sequences allow for lung imaging at high static magnetic field strength. Ventilation information will be obtained from the measurement of the T2* decay of the transverse magnetization which is influenced by the magnetic susceptibility of the breathing gas. For subgoal (c), a measurement protocol applying UTE sequences for T2* quantification during normoxic and hyperoxic conditions will be implemented. In subgoal (d), magnetization transfer imaging with UTE will be used to quantify pulmonary fibrosis. After final establishing of the MRI protocols, mice developing CR will undergo MRI using the established protocols and will be correlated to HR-CT using micro-CT. Once the correlation between CR and corresponding MRI results are established, the progress of CR development will be monitored by blocking IL-17A/F. Expected Value of the Proposed Project: We propose a reproducible approach for the in-vivo studying of CR in lung Tx using new MRI techniques. This measure will allow for an early detection of the pathological changes at the level of small airways during the course of BO. It will serve as a standardized in vivo monitoring tool for the control of CR in order to be able to detect and beneficially influence the progress of this detrimental disease at an early time point.