This is a typical near-infrared fluorescence image of lymphatics in the lower leg of a subject with lymphedema. Credit: John Rasmussen

The human lymphatic system is an important but poorly understood circulatory system consisting of tiny vessels spread throughout the body. This “drainage” network helps guard against infections and prevents swelling, which occasionally happens when disease or trauma interrupts normal lymphatic function. Chronic swelling is the hallmark of a painful, incurable condition known as lymphedema, which often occurs after cancer therapy and can leave the limbs and other body parts disfigured for life.

Detecting lymphedema early, before swelling occurs, would lead to better outcomes for patients, but the major barrier preventing early diagnosis is the lack of high-resolution imaging techniques that can resolve these tiny vessels. Recently, a team of researchers at The University of Texas Health Science Center at Houston (UTHealth) Medical School has developed a new technology that can non-invasively image the human lymphatic system (also known as “lymphatics”). A fluorescent dye and commercially-available laser diode and military-grade night vision devices are used to visualize the lymphatic capillaries.

Clinically, the device promises dramatic improvements in patient care because it allows even tiny lymph vessels to be imaged, and it can quantitatively measure fluid flow throughout the lymphatic system—two types of measurements that are impossible with today’s technology.

At CLEO: 2014, being held June 8-13 in San Jose, California, USA, UTHealth scientist John Rasmussen will describe how they have taken this technology, which they call near-infrared fluorescence lymphatic imaging (NIRFLI), from bench-top development to various clinical applications.

“We feel that the ability to see the lymphatics will provide opportunities to revolutionize lymphatic care,” Rasmussen said.

This is a typical near-infrared fluorescence image of healthy lymphatics in the lower arm. Credit: John Rasmussen

Why the Human Lymphatic System is Hard to Image

The major problem with lymphatic imaging is that the small lymphatic vessels are filled with lymph, a clear liquid that lacks the natural contrast needed to show up on instruments like CT scanners or MRIs. While one might think about injecting dyes or other contrast “agents” into the lymphatic vessels to make them more visible, the vessels are very difficult to find and are most often too small to insert a needle.

An existing technology, called lymphoscintigraphy, can take images of the lymphatic system following injection of a radioactive compound into or below the skin. However, lymphoscintigraphy typically takes 20-45 minutes to acquire a single grainy picture, and can only image the largest lymphatic vessels or trunks. The smaller vessels, which make up the bulk of the lymphatic system, are invisible to lymphoscintigraphy. In addition because of the long acquisition times, it cannot capture the real-time flow of fluid in the system.

To acquire images of the lymphatics, NIRFLI uses indocyanine green dye, which is injected in tiny amounts into the skin of a patient. The dye is absorbed into the lymphatics and when illuminated by the laser diode, it emits a fluorescent light, which the device amplifies with a military-grade image intensifier—the main component in night vision goggles—and then captures with a commercial CCD digital camera.

The image intensifier enables the small lymphatic vessels to be visualized, and by taking sequences of such images, they can produce movies showing flow within the lymphatics. Rasmussen said that the most immediate promise of NIRFLI will be to diagnose and monitor the treatment of lymphedema and may also help surgeons identify and remove lymph nodes into which cancer tumors drain.

“From these images and movies, we can identify abnormal lymphatic structure and function in a variety of diseases and disorders in which the lymphatics play a role,” Rasmussen said. “I think we have barely scratched the surface of what is possible.”

More information: Presentation AM1P.1, titled “Clinical Translation and Discovery with Near-infrared Fluorescence Lymphatic Imaging,” will take place Monday, June 9, at 8 a.m. in the Willow Glen I – III Room of the San Jose Marriott.

Read more at: http://phys.org/news/2014-06-lasers-night-vision-technology-imaging-hidden.html#jCp

http://www.medstand.com/neue-funktion-fur-einen-botenstoff  

ETH Zürich Assistent Professor Cornelia Halin und ihre Kollegen haben eine neue Funktion des bekannten Messenger-Protein Interleukin-7 entdeckt: es erleichtert den Abfluss von Lymphflüssigkeit aus dem Gewebe. In Zukunft wollen die Wissenschaftler untersuchen, ob dieses Molekül verwendet werden könnten, zu verhindern oder zu behandeln Lymphödem werden.

Das Molekül Interleukin-7 (IL-7) ist ein wichtiger Immunbotenstoff Protein, das eine ausreichende Zahl von T-Zellen vorhanden sind, im Körper für die Immunabwehr gewährleistet. Forscher der ETH Zürich haben nun gezeigt, dass IL-7 eine weitere wichtige Funktion hat: es verbessert die Funktion der Entwässerung Lymphgefäßen, die Flüssigkeit zu sammeln, die von Blutgefäßen in das Körpergewebe durchgesickert und senden es an die Blutbahn. In Zukunft könnte diese Erkenntnis nützlich werden für Lymphödem-Patienten, deren Lymphdrainage nicht richtig funktioniert, was in Flüssigkeitsansammlung und Gewebe Schwellung.
Die Veranlagung zu Lymphödem entwickeln kann, einerseits erblich bedingt sein. Auf der anderen Seite, Lymphödem tritt häufig in der Zeit nach einer Tumor-Chirurgie. Bei primären Tumoren chirurgisch herausgeschnitten werden Tumor-Lymphknoten oft als gut, entfernt, da sie möglicherweise Tumorzelle Metastasen enthalten. Im Verlauf eines solchen chirurgischen Eingriffen wird das lymphatische Gewebe beschädigt. Als Ergebnis kann Gewebeflüssigkeit oft nicht mehr ordnungsgemäß entleert werden, was zum Auftreten von lymphedema in 20 bis 30 Prozent der Patienten.
Keine medikamentöse Behandlung noch
Derzeit sind die einzigen Behandlungsoptionen für Lymphödem-Patienten tragen Kompressionsstrümpfe und unterziehen manuelle Lymphdrainage durch einen medizinischen Masseur.”In IL-7, wir haben ein Molekül und einen Mechanismus für die Verbesserung der Lymphdrainage, die möglicherweise sein könnte für Lymphödem-Therapie nützlich entdeckt”, sagt der Leiter der Studie Cornelia Halin, Assistant Professor of Drug Discovery Technologies.
In ihrer Studie fanden die Forscher, dass IL-7 durch die sogenannte Endothelzellen, die das lymphatische Behälterwand bilden erzeugt wird. Diese Zellen exprimieren auch die Rezeptoren, die spezifisch IL-7 basiert auf dem Schloss-und-Schlüssel-Prinzip. “Obwohl wir nicht formal bewiesen haben, so weit gehen wir davon aus, dass die lymphatischen Endothelzellen den Botenstoff produzieren, so dass sie ihre eigene Funktion direkt beeinflussen können”, sagt Halin. Bisher ist IL-7 eine von nur wenigen Molekülen, die identifiziert wurden, um Lymphdrainage unterstützt. Vor ein paar Jahren entdeckten Forscher, dass die anderen endogenen Wachstumsfaktor VEGF-C könnte auch ein interessantes Molekül in dieser Hinsicht sein.

Erkenntnisse aus einem Tiermodell
Halin und Kollegen gezeigt, die Drainage-tragende Funktion von IL-7, indem Drainage Experimente in Mäusen injiziert, wo sie eine blaue, Albumin-bindenden Farbstoff in das Ohr Haut der Mäuse. Bemerkenswert ist, dass Albumin ein endogenes Protein, das kann nur von dem Gewebe transportiert werden über die Lymphgefäße. Durch die Quantifizierung der Farbstoff, der in dem Gewebe einen Tag nach der Injektion blieb, waren die Forscher in der Lage, festzustellen, wie gut die Lymphdrainage in diesen Versuchstieren gearbeitet.
Bei der Durchführung dieses Experiment bei Mäusen fehlt ein funktionierendes IL-7 Rezeptors, beobachteten sie, dass diese Mäuse konnten nur halb so viel Farbstoff aus ihrer Haut zu entfernen Ohr im Vergleich zu Mäusen mit einem funktionierenden IL-7-Rezeptor.Im Gegensatz dazu stellten sie eine deutliche Steigerung der lymphatische Drainage in Mäusen mit erhöhter IL-7-Produktion. Schließlich wird in einem dritten Experiment sie IL-7 Proteins, modifizierten, gesunde Mäuse verabreicht und beobachtet, dass diese therapeutischen Behandlung zur Verbesserung Lymphabstrombereich Funktion geführt.
Bereits bei Patienten getestet
Die Wissenschaftler planen nun, ähnliche Experimente in Mäusen, in denen Lymphgefäße chirurgisch zerstört durchzuführen, ähnlich der Situation bei Patienten nach einer Krebsoperation gefunden. Hier würden die Forscher gerne testen, ob die Behandlung mit IL-7 könnte helfen, Lymphödem oder ob IL-7 könnte sogar verabreicht, um bestehenden Lymphödem reduzieren verhindern.
Das langfristige Ziel ist es, das Potenzial eines IL-7-basierte Medikamente für Lymphödem zu erkunden. Bemerkenswert ist, dass IL-7 bereits in klinischen Studien getestet, wenn auch für verschiedene Indikationen: wegen seiner immun-stimulierende Aktivität auf T-Zellen, IL-7 wird derzeit bei Patienten mit Immunschwäche Krankheiten wie HIV oder Hepatitis-Infektionen getestet, haben oder die Knochenmark-Transplantationen unterzogen.

Science

New function for a messenger molecule

ETH Zurich Assistant Professor Cornelia Halin and her colleagues have discovered a new function of the well-known messenger protein interleukin-7: it facilitates the drainage of lymph fluid from tissues. In the future, the scientists plan to investigate whether this molecule could be used to prevent or treat lymphedema.

The molecule interleukin-7 (IL-7) is an important immune messenger protein which ensures that a sufficient number of T cells are present in our body for immune defence. Researchers from ETH Zurich have now demonstrated that IL-7 has another important function: it enhances the drainage function of lymphatic vessels, which collect fluid that has leaked out of blood vessels into the body tissue and return it to the bloodstream. In the future, this finding could become useful for lymphedema patients, whose lymphatic drainage system does not work properly, resulting in fluid accumulation and tissue swelling.

The predisposition to develop lymphedema may, on one hand, be hereditary. On the other hand, lymphedema often occurs in the aftermath of a tumour surgery. When primary tumours are surgically excised, tumour-draining lymph nodes are often removed as well, as they may contain tumour cell metastases. In the course of such surgical interventions, the lymphatic tissue is damaged. As a result, tissue fluid can often no longer be drained properly, leading to the occurrence of lymphedema in 20 to 30 per cent of patients.

No drug treatment yet

Currently, the only treatment options for lymphedema patients are wearing compression garments and undergoing manual lymph drainage by a medical massage therapist. “In IL-7, we have discovered a molecule and a mechanism for enhancing lymphatic drainage which could potentially be useful for lymphedema therapy,” says the head of the study Cornelia Halin, Assistant Professor of Drug Discovery Technologies.

In their study, the researchers found that IL-7 is produced by the so-called endothelial cells, which form the lymphatic vessel wall. These cells also express the receptors that specifically recognise IL-7 based on the lock-and-key principle. “Although we have not formally proven it so far, we assume that the lymphatic endothelial cells produce the messenger substance so that it can affect their own function directly,” says Halin. So far, IL-7 is one out of only few molecules that have been identified to support lymphatic drainage. A few years ago, other researchers discovered that the endogenous growth factor VEGF-C might also be an interesting molecule in this regard.

Insights from an animal model

Halin and her colleagues demonstrated the drainage-supporting function of IL-7 by performing drainage experiments in mice where they injected a blue, albumin-binding dye into the ear skin of the mice. Notably, albumin is an endogenous protein, which can only be transported out of the tissue via the lymphatic vessels. By quantifying the dye that remained in the tissue one day after the injection, the researchers were able to determine how well the lymphatic drainage worked in these laboratory animals.

When performing this experiment in mice lacking a functioning IL-7 receptor, they observed that these mice were only able to remove half as much dye from their ear skin in comparison with mice possessing a functional IL-7 receptor. By contrast, they observed a considerable increase in lymphatic drainage in mice with increased IL-7 production. Finally, in a third experiment, they administered IL-7 protein to unmodified, healthy mice and observed that this therapeutic treatment led to an improvement of lymphatic drainage function.

Already tested in patients

The scientists are now planning to conduct similar experiments in mice in which lymphatic vessels have been surgically destroyed, similarly to the situation found in patients after cancer surgery. Here, the researchers would like to test whether treatment with IL-7 could help to prevent lymphedema or whether IL-7 could even be administered in order to reduce existing lymphedema.

The long-term goal is to explore the potential of an IL-7-based medication for lymphedema. Notably, IL-7 is already being tested in clinical trials, albeit for different indications: because of its immune-stimulatory activity on T cells, IL-7 is currently being tested in patients with immunodeficiency diseases, such as HIV, or hepatitis infections, or who have undergone bone-marrow transplantations.

Literature reference

Iolyeva M, Aebischer D et al.: Interleukin-7 is produced by afferent lymphatic vessels and supports lymphatic drainage. Blood, 2013, published ahead of print, doi: 10.1182/blood-2013-01-478073