[Anti(lymph)angiogenic Strategies to Improve Corneal Graft Survival]

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.