Antihämangiogene/antilymphangiogene Strategien zur Verbesserung des Transplantatüberlebens nach Keratoplastik

Zusammenfassung

Die Hornhauttransplantation (Keratoplastik) ist die weltweit am häufigsten durchgeführte Form der Transplantation. Eine Abstoßungsreaktion gegen das Transplantat ist die Hauptkomplikation, die nach der Transplantation in einem schon vaskularisierten, sogenanntem „Hochrisiko“-Empfängerauge auftritt. Unsere Arbeitsgruppe konnte zeigen, dass klinisch unsichtbare Lymphgefäße eine entscheidende Rolle bei der Induktion einer Abstoßungsreaktion gegen das Hornhauttransplantat spielen und dass anti(lymph)angiogene Therapien im Mausmodell der Keratoplastik das Transplantatüberleben deutlich verbessern können. Die zugrunde liegenden Mechanismen, welche das Transplantatüberleben durch antilymphangiogene Therapien verbessern, sind bis heute allerdings nur sehr wenig verstanden. Wir gehen davon aus, dass die Blockade der Lymphgefäßaussprossung zu einer Toleranz (und nicht zu einer einfachen Ignoranz) des Transplantats führt, in dem die antigenpräsentierenden Zellen länger in der Hornhaut festgehalten werden und es dadurch zu einer Immunmodulation dieser Zellen kommt. Daher ist ein wichtiges Ziel unseres Projekts, herauszufinden, ob und wann es durch eine korneale antilymphangiogene Therapie zu einer Transplantattoleranz kommt. Wir nehmen an, dass antigenpräsentierende Zellen durch die Therapie einen veränderten Reifegrad erlangen und sich vermehrt tolerogene Effektorzellen (regulatorische T-Zellen, Tregs) in Abwesenheit von lymphatischen Gefäßen entwickeln. Bisherige anti(lymph)angiogene Therapien haben den Nachteil, dass sie vor allem auf aktiv wachsende Gefäße wirken. Die meisten Patienten, die eine Hochrisikokeratoplastik erhalten, stellen sich meist mit bereits etablierten, maturen Blut- und Lymphgefäßen vor. Derzeit sind keine lymphgefäßregredierenden Strategien vorhanden und die Mechanismen, welche die Reifung der Lymphgefäße regulieren, sind weitestgehend unbekannt. Daher ist es unser 2. Ziel, neue Strategien zur Regression bestehender, pathologischer Lymphgefäße in der Hornhaut zu entwickeln. Hierbei testen wir sowohl destruktive Strategien wie die photodynamische Therapie und die Diathermie als auch Strategien zur molekularen Destabilisierung des Lymphgefäßendothels aus. Unser Projekt identifiziert also die präzisen Mechanismen, mit denen antilymphangiogene Therapien das Transplantatüberleben verbessern, und wir entwickeln neue Strategien, um mature Lymphgefäße im Hochrisikosetting zurückzudrängen.

Abstract

Corneal transplantation (keratoplasty) is the most frequently performed form of transplantation worldwide. A rejection reaction against the transplant is the main complication occurring after transplantation in an already vascularized, so-called “high-risk” recipient eye. Our group has shown that clinically invisible lymphatic vessels play a crucial role in the induction of a rejection reaction against the corneal graft, and that anti-(lymph)angiogenic therapies in the mouse model of keratoplasty can significantly improve transplant survival. The underlying mechanisms, which improve transplant survival through anti-lymphangiogenic therapies have not been well understood. We assume that the blockade of lymph vessel sprouting leads to a tolerance (and not to a simple ignorance) of the transplant, in which the antigen-presenting cells are held longer in the cornea and, thus, an immunomodulation of these cells occurs. Therefore, an important goal of our project is to find out whether and when transplant tolerance comes from a corneal anti-lymphangiogenic therapy. We assume that the antigen-presenting cells will have a different maturity level and that more tolerogenic effector cells (regulatory T cells, Tregs) develop in the absence of lymphatic vessels. Current anti(lymph)angiogenic therapies have the disadvantage that they are primarily effective on actively growing vessels. Most patients who receive high-risk keratoplasty often present in the clinic with already established, mature corneal blood and lymphatic vessels. At present, there are no lymph vessel regressing strategies, and the mechanisms regulating the maturation of the lymphatics are largely unknown. Therefore, our second goal is to develop new strategies for the regression of existing, pathological lymphatic vessels in the cornea. We are testing both destructive strategies, such as photodynamic therapy and diathermy as well as strategies for the molecular destabilization of the lymph vessel endothelium. Thus, our project identifies the precise mechanisms by which anti-lymphangiogenic therapies improve transplant survival, and we are developing new strategies to push back mature lymphatics in the high-risk setting.

Schlüsselwörter

Transplantation - Kornea - Toleranz - Regression

Key words

transplantation - cornea - tolerance induction - vessel regression

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