Personalized Lymphvascular- and Immunomodulation in High Risk Corneal Transplantation (Joined Project AG Cursiefen/AG Bock within DFG RU 2240; 2015-2023)

The healthy cornea is the “windscreen” of the eye. Pathologic insults like chemical or thermal burns, hypoxia, transplant rejection or trauma lead to blindness and to a so called “high risk situation” with increased rejection rates after subsequent corneal transplantation.

All these insults cause different immunological tissue responses. We could e.g. show that a suture induced inflammation causes the ingrowth of both blood and lymphatic vessels whereas corneal trauma only causes an isolated lymphangiogenic response. Trauma and burns induce primarily an innate immune response whereas corneal grafts induce adaptive, allospecific immunity.  

Nonetheless, irrespective of the underlying cause, so far corticosteroids have remained the mainstay of immunomodulatory therapy after i.e. high risk penetrating corneal transplantation, but only 50% of the rejection episodes respond to that treatment.

Personalized medicine, already approaching clinical routine in oncology, has not conquered ophthalmology yet. 

Recently, we could show that the different types of corneal injury caused significantly different hem- and lymphangiogenic responses. Furthermore, the infiltration of corneal macrophages, dendritic cells, neutrophils, and MHC II+ cells varied significantly in different high-risk settings. In conclusion, the murine high-risk settings caused by different underlying pathologies varied significantly in their (lymph)angiogenic and inflammatory cell patterns. (Zhang W, Schönberg A, Bassett F, Hadrian K, Hos D, Becker M, Bock F*, Cursiefen C.*Different Murine High-Risk Corneal Transplant Settings Vary Significantly in Their (Lymph)angiogenic and Inflammatory Cell Signatures. Invest Ophthalmol Vis Sci. 2022).

Our data demonstrate that different “immune- and lymphvascular signatures” indeed exist and that they depend on the underlying injury. These signatures may need specific and disease-oriented novel therapeutic approaches to promote graft survival, i.e. customized immune modulatory and lymphangioregressive approaches.

Corneal Crosslinking and Fine-needle diathermy as (Lymph)Angioregressive treatments to improve graft survival (DFG Cu 47/12-1; 15-1; 2023-2025)

Besides pharmacological strategies, we and others have identified lymphangioregressive (and immunodampening) strategies to prepare the high-risk recipient bed for future transplantations (Clahsen et al., PRER, Prog Retin Eye Res. 2023 Feb 7:101157. doi: 10.1016/j.preteyeres.2022.101157). Besides FND (fine needle diathermy) and PDT (photodynamic therapy; [25], UVA-light based Corneal Crosslinking (CXL) was shown to not only regress pathologic corneal blood and lymphatic vessels [26], but to also induce reduction of corneal antigen presenting cells (APCs) and most importantly to promote subsequent graft survival after high-risk transplantation [26]. In fact, all three approaches led to temporary regression of pathologic corneal blood and lymphatic vessels as well as alteration/depletion of corneal resident APCs before transplantation. Subsequently, they promoted graft survival in the murine high-risk model. Preliminary clinical data from patients undergoing high-risk transplantation suggest that UVA-based corneal crosslinking also regresses pathologic corneal neovascularization in patients [19]. Even more so, a retrospective mono-centric pilot study on pre-transplantation FND in high-risk patients demonstrated good tolerability and relatively good subsequent corneal graft survival [22]. Whether the beneficial effect on graft survival is due to (lymph)angioregression, depletion and alteration of APCs or both remains unclear.

The phenomenon of UV-light mediated alteration of APCs is well known e.g. from UVB irradiation of the skin [27] and previous studies of UVB effects in experimental cornea studies. It is still unknown what the optimal strategy is to down regulate the immune response and regress lymphangiogenesis in high-risk recipient beds and whether that varies between different underlying diseases.

BMBF-funded pilot clinical trial - UV light-mediated corneal crosslinking as a (lymph)angioregressive pretreatment to improve graft survival after subsequent high-risk corneal transplantation (2023-2027)

Based on the above mentioned data, the BMBF-funded prospective randomized multi-center trial CrossCornealVision testing pre-transplantation UVA-based CXL as a new method to promote high-risk 

Recently, UV-based corneal crosslinking (CXL) using Riboflavin as photosensitizer, a technique used in the clinic to stabilize corneas, was shown to also destroy corneal vessels both experimentally and in pilot clinical data. In the CrossCornealVision Study we test the novel concept of “(lymph)angioregressive preconditioning” of high-risk eyes using CXL to promote graft survival in a prospective, randomised multicenter exploratory clinical trial. Prior to high-risk transplantation, patients are randomised into CXL or no pretreatment (control). Then, incidence of graft rejection episodes and safety are evaluated. This will be the first improvement to promote graft survival in high-risk transplants for decades, and will significantly improve vision and quality of life in patients suffering from corneal blindness and help designing a later confirmatory trial.

Targeting the osmosensitive transcription factor NFAT5 in acute and chronic corneal edema: ZMMK Projekt (2023-2025): Dr. Karina Hadrian, PD Dr. Deniz Hos, Prof. Cursiefen, Claus

The cornea is the transparent avascular outer barrier and major refractive element of the eye. Loss of corneal transparency, e.g. due to dysfunction of corneal endothelial cells resulting in corneal swelling (edema), leads to corneal blindness and is the second most common cause for blindness worldwide. The only possible treatment so far is corneal transplantation, resulting in more than a million people suffering from corneal blindness due to shortage of donor corneas worldwide. Due to shortage of tissue donors, only 1 in 70 patients can be cured. Thus, non-surgical approaches to reduce corneal edema would be of great therapeutic value to treat corneal blindness. In this context, we recently discovered a novel suppressive role for the osmosensitive transcription factor nuclear factor of activated T cells 5 (NFAT5; or tonicity-responsive enhancer binding protein; TonEBP) in corneal edema resorption, thereby identifying a novel potential therapeutic target to non-surgically combat edema-induced corneal blindness. Aim of this work is to translate these findings into a clinically applicable direction by therapeutically modulating NFAT5 in the cornea in mouse models of acute and chronic corneal edema. Furthermore, this study will investigate the impact of modulating NFAT5 on graft survival after corneal transplantation.