Associated Principal Investigator, Chairman Department of Ophthalmology, University Hospital of Cologne
Corneal opacities are the second most common cause of blindness worldwide. Corneal transplantation is the main therapeutic procedure against corneal transparency loss. Immunological rejection remains the main reason for graft failure worldwide. The risk of an immune reaction depends decisively on the preoperative initial situation of the recipient: if this is, as in the normal case, free of vessels and low in inflammation ("corneal angiogenic and immune privilege“), rejection reactions are rare both in the mouse model of corneal transplantation and in the patient. However, if pathological inflammation or neovascularization of the cornea is present, the risk of rejection increases to more than 50% ("high-risk situation“). This concerns especially patients in so-called "lower middle-income countries“ (LMIC).
Our research: We could show that pathological blood vessels and even more clinically invisible pathological lymphatic vessels sprouting into the cornea are crucial for the increased risk of rejections after corneal transplantation. Targeted blockade of corneal lymphangiogenesis or lymphangioregression preoperatively reduced graft survival in the well-characterized mouse model of corneal transplantation. Lymphangioregressive approaches include, as described by us for the first time, the destruction of lymphatic vessels by UVA-light-associated crosslinking, via photodynamic therapy or monopolar vascular cauterization. Here, further molecular experimental but also translational clinical studies are needed to translate this concept of temporary perioperative lymphangioregression to improve graft survival into the clinic.
Our successes: The team was not only able to identify invisible pathologic corneal lymphatics as a crucial risk factor for the occurrence of immune reactions after transplantation in the mouse model, but also to establish the new therapeutic concept of modulating corneal lymphangiogenesis to improve graft survival. This was successful not only in animal models, but also in first pilot studies in patients. Currently, a prospective randomized BMBF-funded study is ongoing to test the concept of preoperative temporary locoregional lymphangioregression to improve graft survival in pathologically vascularized high-risk eyes.
Our objectives: The goal of the research group is to further characterize the molecular mechanisms leading to loss of corneal angiogenic and lymphangiogenic privilege and pathologic inflammatory response in the cornea, to optimize drug-based and also physical strategies for lymphatic regression in high-risk eyes, and ultimately to further develop personalized and disease-specific modulation of lymphangiogenesis and inflammatory cells (antigen presenting cells) in the cornea to improve graft survival in high-risk eyes. This is currently supported by our DFG RU 2240 (www.for2240.de).
Our methods and techniques: The team works with a wide range of molecular, cell biology, protein biochemical and also animal models. We have established a wide variety of animal models for high-risk corneal transplant situations (aniridia, chemical burn, injury, infectious keratitis, etc.). Furthermore, the team has expertise in conducting clinical trials (from first-in-men to phase I – III), in the supervision of clinical studies and in the field of image analysis. Here, there is a dedicated reading center in the eye clinic for quantification of pathological blood vessels in the cornea. Several phase II-IV studies were supervised here.
Figure 1: Preexisting pathologic corneal blood and even more so lymphatic vessels determine the fate of a corneal transplant.
Figure 2: Temporary pretransplant lymphangioregression at the recipient site promotes corneal graft survival after subsequent transplantation in high-risk eyes.