Project N1 Ocular GvHD

Lymph- and hemangiogenesis in ocular graft-versus-host disease

Summary as new project of second funding period:

Ocular graft-versus-host disease (ocular GvHD) is a potentially sight-threatening disease that occurs in 60-80 % of patients following allogeneic hematopoetic stem cell transplantation (aHSCT). Whereas acute ocular GvHD is rare and onsets within the first months after aHSCT, chronic ocular GvHD is frequent and onsets during or after reduction of systemic immunosuppression. The latter leads to severe dry-eye disease and destruction of lacrimal gland, Meibomian glands and conjunctival scarring. In systemic GvHD it has been shown experimentally that hem- and lymphangiogenesis play a role in the pathogenesis of disease and anti(lymph)angiogenic therapy has been demonstrated to reduce severity of GvHD and mortality. This project will investigate the role of hem- and lymphangiogenesis in acute and chronic GvHD mouse models to test the hypothesis that systemic but also topical anti(lymph)angiogenic substances may reduce ocular GvHD. Besides morphometric investigations, molecular analyses, detailed histology and intravital imaging techniques are applied. Furthermore using non-invasive imaging techniques in patients undergoing aHSCT, it is prospectively investigated, whether lymphatic and blood vessel morphology correlate with ocular GvHD activity. Overall the project investigates potential disease mechanisms in ocular GvHD that are very likely to play a key role and that have the potential to serve as therapeutic and diagnostic targets hereby filling an actual gap in clinical care of patients with ocular GvHD. In detail this project aims to answer the fundamental question if lymph- and hemangiogenesis is augmented during ocular GvHD, and in the following if a targeted inhibition of lymph- and/or hemangiogenesis reduces or even prevents ocular GvHD.

Selected Key Publications of Project N1

Steven P, Bock F, Huettmann G, Cursiefen C (2011) Intravital two-photon microscopy of cellular dynamics in corneal lymphatic vessels. PLoS One 6(10): e26253. IF 4.41

Siebelmann S*, Gehlsen U*, Huettmann G, Koop N, Boelke T, Gebert A, Stern ME, Niederkorn JY, Steven P (2013) Development, alteration and real time dynamics of conjunctiva associated lymphoid tissue. PLoS One 8(12): e82355. IF 3.73

Gehlsen U, Szaszak M, Gebert A, Koop N, Huettmann G, Steven P (2014) Non- Invasive Multi-Dimensional Two-Photon Microscopy enables optical fingerprinting (TPOF) of immune cells. JBiophotonics 8(6): 466-479. IF 4.447

Engel L, Wittig S, Bock F, Sauerbier L, Scheid C, Holtick U, Chemnitz J.M., Hallek M, Cursiefen C, Steven P. (2015) Meibography and Meibomian Gland Measurements in ocular Graft-versus host
Disease. Bone Marrow Transpl 50(7): 961-7. IF 3.466

Steven P, Scherer D, Krösser S, Beckert M, Cursiefen C, Kaercher T. (2015) Semifluorinated Alkane Eye Drops for Treatment of Dry Eye Disease-A Prospective, Multicenter Noninterventional Study. J Ocul Pharmacol Ther. (8): 498-503. IF 1.470

Tahmaz V, Gehlsen U, Sauerbier L, Holtick U, Engel L, Radojska S, Petrescu-Jipa V, Scheid C,Hallek M, Gathof B, Cursiefen C, Steven P (2016) Treatment of severe chronic ocular graftversus-host disease using 100% autologous serum eye drops from a sealed manufacturings ystem: a retrospective cohort study. Br J Ophthalmol 0:1-5 (Epub). IF 3.036

Gehlsen U, Braun T, Notara M, Krösser S, Steven P. (2017) A semifluorinated alkane (F4H5) asnovel carrier for cyclosporine A: a promising therapeutic and prophylactic option for topical treatment of dry eye. Graefes Arch Clin Exp Ophthalmol. 255(4): 767-775. IF 1.991

Steven P, Braun T, Krösser S, Gehlsen U. (2017) Influence of Aging on Severity and Anti-Inflammatory Treatment of Experimental Dry Eye Disease. Klin Monbl Augenheilkd. 234(5):662-669. IF 0.669

Steven P, Augustin A J, Geerling G, Kaercher T, Kretz F, Kunert K, Menzel-Severing J, Schrage N, Schrems W, Krösser S, Beckert M, Messmer EM (2017) Semifluorinated alkane eye drops for treatment of dry eye disease due to Meibomian gland disease. J Ocul Pharmacol Ther. Sep 18 IF 1.679

Osae AE, Gehlsen U, Horstmann J, Siebelmann S, Stern ME, Kumah DB, Steven P (2017) Epidemiology of dry eye disease in Africa: The sparse information, gaps and opportunities. Ocul Surf. 15(2): 159-168. IF 4.477