Project 1 Lymph-Transplant

Induction of corneal transplant tolerance by anti(lymph)angiogenic therapy

Summary

Corneal transplantation is the most common form of transplantation. Immune reactions are the main complication after grafting, especially when performed into pathologically hem- and lymphvascularized, so called high-risk recipient eyes. In the murine model of high-risk transplantation, partly reflecting immune competent tissue transplantations elsewhere, we could show that blockade of inflammatory lymphangiogenesis and migration of antigen presenting cells in the high-risk induction phase by systemic depletion of VEGF-A induces graft tolerance. Since in the clinic most high-risk eyes already contain lymphatic vessels prior to transplantation, we established several novel (lymph)angioregressive therapies (such as fine needle diathermy and photodynamic therapy). Using these innovative tools we validated the novel treatment concept of temporary, selective, preoperative lymphangioregression at graft site to promote subsequent graft survival. Based on these findings and since all immunomodulatory approaches in high-risk eyes so far only achieve partial (albeit significant) survival improvements, we want to develop novel improved techniques of combined antilymphangiogenesis of both donor and host and try to transfer that approach to extraocular sites. The new project has two specific aims: 1) to analyze the graft-promoting effect of local VEGF-A depletion in the donor by anti-VEGF preconditioning combined with preoperative lymphangioregression of the host and postoperative antilymphangiogenesis in both host and donor (“novel triple approach”) and 2) to translate the novel concept of antilymphangiogenic/lymphangioregressive pre-treatment of the host and donor tissue to extraocular sites, starting with tissues (skin). The results of this project will provide novel methods to improve graft survival, both in the eye but also beyond.

Project summary from the first funding period (2015-2018)

Corneal grafting (penetrating keratoplasty) is the most frequently performed transplantation worldwide. Immune reactions are the main complication after grafting into pathologically prevascularized, so called high-risk recipient eyes. We previously showed that clinically invisible lymphatic vessels play a key role in inducing corneal graft rejection and that anti(lymph)angiogenic therapy promotes graft survival in the murine model of transplantation. But the precise immunological mechanisms whereby antilymphangiogenesis promotes graft survival are only poorly understood. Our hypothesis is that the blockade of lymphangiogenesis leads to graft tolerance (rather than ignorance) due to prolonged retention and immunomodulation of antigen presenting cells in the recipient bed. Therefore, one key aim of this project is to analyse whether and when corneal antilymphangiogenic therapy leads to graft tolerance by an altered maturation status of antigen-presenting cells and/or to the induction of tolerogenic effector cells (regulatory T cells) in the absence of lymphatic vessels. Currently available anti(lymph)angiogenic therapies have the drawback that they only act on actively proliferating vessels. But most patients undergoing high-risk transplantation already have established mature pathologic corneal blood and lymphatic vessels. So far no lymphangioregressive strategies are available and the mechanisms governing lymphatic vessel maturation are not understood. Our second aim therefore is to develop strategies to regress preexisting pathologic corneal lymphatic vessels by destruction (using photodynamic therapy or diathermy) or by molecular destabilisation of the lymphatic endothelial cells. Overall this project will lead to a better understanding of the precise mechanisms whereby antilymphangiogenesis promotes transplant survival and to the development of novel strategies to regress mature lymphatic vessels in the high-risk scenario to subsequently promote graft survival.

Most recent publications of Project 1

Clahsen T, Hadrian K, Notara M, Schlereth SL, Howaldt A, Prokosch V, Volatier T, Hos D, Schroedl F, Kaser-Eichberger A, Heindl LM, Steven P, Bosch JJ, Steinkasserer A, Rokohl AC, Liu H, Mestanoglu M, Kashkar H, Schumacher B, Kiefer F, Schulte-Merker S, Matthaei M, Hou Y, Fassbender S, Jantsch J, Zhang W, Enders P, Bachmann B, Bock F, Cursiefen C. (2023)The novel role of lymphatic vessels in the pathogenesis of ocular diseases. Prog Retin Eye Res. 2023 Feb 7:101157. doi: 10.1016/j.preteyeres.2022.101157. Online ahead of print.

Zhang W, Schönberg A, Bassett F, Hadrian K, Hos D, Becker M, Bock F*, Cursiefen C* (2022) Different murine high-risk corneal transplant settings vary significantly in their (lymph)angiogenic and inflammatory cell signatures. Invest Ophthalmol Vis Sci. (2022);63(13):18. *FB and CC are senior co-authors

Zhang W, Schönberg A, Bock F*, Cursiefen C* (2022) Posttransplant VEGFR1R2 Trap Eye Drops Inhibit Corneal (Lymph)angiogenesis and Improve Corneal Allograft Survival in Eyes at High Risk of Rejection. Transl Vis Sci Technol. 11(5):6. *FB and CC are senior co-authors

Zhang W, Schönberg A, Hamdorf M, Georgiev T, Cursiefen C, Bock F. Preincubation of donor tissue with a VEGF cytokine trap promotes subsequent high-risk corneal transplant survival. Br J Ophthalmol. 2022 Nov;106(11):1617-1626

Peckert-Maier K, Schönberg A, Wild AB, Royzman D, Braun G, Stich L, Hadrian K, Tripal P, Cursiefen C, Steinkasserer A, Zinser E, Bock F. Pre-incubation of corneal donor tissue with sCD83 improves graft survival via the induction of alternatively activated macrophages and tolerogenic dendritic cells. Am J Transplant. 2022 Feb;22(2):438-454.

Schaub F, Hou Y, Zhang W, Bock F, Hos D, Cursiefen C (2021) Corneal Crosslinking to Regress Pathologic Corneal Neovascularization Before High-Risk Keratoplasty. Cornea. 40(2):147-155

Salabarria, A.C., Koch M, Schönberg A, Zinser E, Hos D, Hamdorf M, Imhof T, Braun G, Cursiefen C, Bock F. Topical VEGF-C/D Inhibition Prevents Lymphatic Vessel Ingrowth into Cornea but Does Not Improve Corneal Graft Survival.J Clin Med. 2020 Apr 28;9(5):1270.

Supplemental Anti Vegf A-Therapy Prevents Rebound Neovascularisation After Fine Needle Diathermy Treatment to Regress Pathological Corneal (LYMPH)Angiogenesis.
Le VNH, Hou Y, Bock F, Cursiefen C. Sci Rep. 2020 Mar 3;10(1):3908. doi: 10.1038/s41598-020-60705-z.

Salabarria, A.C., Braun, G., Heykants, M., Koch, M., Reuten, R., Mahabir, E., Cursiefen, C. & Bock, F. Local VEGF-A blockade modulates the microenvironment of the corneal graft bed. Am J Transplant (2019).

Bevacizumab Induces Upregulation of Keratin 3 and VEGFA in Human Limbal Epithelial Cells in Vitro.
Notara M, Lentzsch A, Clahsen T, Behboudifard S, Braun G, Cursiefen C. J Clin Med. 2019 Nov 9

Immune reactions after modern lamellar (DALK, DSAEK, DMEK) versus conventional penetrating corneal transplantation.
Hos D, Matthaei M, Bock F, Maruyama K, Notara M, Clahsen T, Hou Y, Le VNH, Salabarria AC, Horstmann J, Bachmann BO, Cursiefen C. Prog Retin Eye Res. 2019 Nov; Epub 2019 Jul 3

Risk of Corneal Graft Rejection After High-risk Keratoplasty Following Fine-needle Vessel Coagulation of Corneal Neovascularization Combined With Bevacizumab: A Pilot Study.
Hos D, Le VNH, Hellmich M, Siebelmann S, Roters S, Bachmann BO, Cursiefen C. Transplant Direct. 2019 Apr 25, 2019 May.

Tyrosinase Is a Novel Endogenous Regulator of Developmental and Inflammatory Lymphangiogenesis.
Büttner C, Clahsen T, Regenfuss B, Dreisow ML, Steiber Z, Bock F, Reis A, Cursiefen C. Am J Pathol. 2019 Feb. Epub 2018 Nov 16.

Selected Key Publications of Project 1

Clahsen T, Hadrian K, Notara M, Schlereth SL, Howaldt A, Prokosch V, Volatier T, Hos D, Schroedl F, Kaser-Eichberger A, Heindl LM, Steven P, Bosch JJ, Steinkasserer A, Rokohl AC, Liu H, Mestanoglu M, Kashkar H, Schumacher B, Kiefer F, Schulte-Merker S, Matthaei M, Hou Y, Fassbender S, Jantsch J, Zhang W, Enders P, Bachmann B, Bock F, Cursiefen C. (2023)The novel role of lymphatic vessels in the pathogenesis of ocular diseases. Prog Retin Eye Res. 2023 Feb 7:101157. doi: 10.1016/j.preteyeres.2022.101157. Online ahead of print.

Zhang W, Schönberg A, Bassett F, Hadrian K, Hos D, Becker M, Bock F*, Cursiefen C* (2022) Different murine high-risk corneal transplant settings vary significantly in their (lymph)angiogenic and inflammatory cell signatures. Invest Ophthalmol Vis Sci. (2022);63(13):18. *FB and CC are senior co-authors

Zhang W, Schönberg A, Hamdorf M, Georgiev T, Cursiefen C, Bock F. Preincubation of donor tissue with a VEGF cytokine trap promotes subsequent high-risk corneal transplant survival. Br J Ophthalmol. 2022 Nov;106(11):1617-1626

Peckert-Maier K, Schönberg A, Wild AB, Royzman D, Braun G, Stich L, Hadrian K, Tripal P, Cursiefen C, Steinkasserer A, Zinser E, Bock F. Pre-incubation of corneal donor tissue with sCD83 improves graft survival via the induction of alternatively activated macrophages and tolerogenic dendritic cells. Am J Transplant. 2022 Feb;22(2):438-454.

Hou Y, Le VNH, Clahsen T, Schneider AC, Bock F, Cursiefen C (2017) Photodynamic Therapy Leads to Time-Dependent Regression of Pathologic Corneal (Lymph) Angiogenesis and Promotes High-Risk Corneal Allograft Survival. Investigative ophthalmology & visual science 58: 5862-5869

Le VNH, Hou Y, Horstmann J, Bock F, Cursiefen C (2017) Novel Method to Detect Corneal Lymphatic Vessels In Vivo by Intrastromal Injection of Fluorescein. Cornea.[Epub ahead of print]

Hos D, Bukowiecki A, Horstmann J, Bock F, Bucher F, Heindl LM, Siebelmann S, Steven P, Dana R, Eming SA, Cursiefen C (2017) Transient Ingrowth of Lymphatic Vessels into the Physiologically Avascular Cornea Regulates Corneal Edema and Transparency. Scientific reports 7: 7227

Matthaei M, Sandhaeger H, Hermel M, Adler W, Jun AS, Cursiefen C, Heindl LM (2017) Changing Indications in Penetrating Keratoplasty: A Systematic Review of 34 Years of Global Reporting. Transplantation 101: 1387-1399

Bock F, Cursiefen C (2017) [Anti(lymph)angiogenic Strategies to Improve Corneal Graft Survival]. Klinische Monatsblatter fur Augenheilkunde 234: 674-678

Hos D, Tuac O, Schaub F, Stanzel TP, Schrittenlocher S, Hellmich M, Bachmann BO, Cursiefen C (2017) Incidence and Clinical Course of Immune Reactions after Descemet Membrane Endothelial Keratoplasty: Retrospective Analysis of 1000 Consecutive Eyes. Ophthalmology 124: 512-518

Cursiefen C, Bock F, Clahsen T, Regenfuss B, Reis A, Steven P, Heindl LM, Bosch JJ, Hos D, Eming S, Grajewski R, Heiligenhaus A, Fauser S, Austin J, Langmann T (2017) [New Therapeutic Approaches in Inflammatory Diseases of the Eye – Targeting Lymphangiogenesis and Cellular Immunity: Research Unit FOR 2240 Presents Itself]. Klinische Monatsblatter fur Augenheilkunde 234: 679-685

Hos D, Dorrie J, Schaft N, Bock F, Notara M, Kruse FE, Krautwald S, Cursiefen C, Bachmann BO (2016) Blockade of CCR7 leads to decreased dendritic cell migration to draining lymph nodes and promotes graft survival in low-risk corneal transplantation. Experimental eye research 146: 1-6

Hos D, Bucher F, Regenfuss B, Dreisow ML, Bock F, Heindl LM, Eming SA, Cursiefen C (2016) IL-10 Indirectly Regulates Corneal Lymphangiogenesis and Resolution of Inflammation via Macrophages. The American journal of pathology 186: 159-71

Hos D, Schlereth SL, Bock F, Heindl LM, Cursiefen C (2015) Antilymphangiogenic therapy to promote transplant survival and to reduce cancer metastasis: what can we learn from the eye? Seminars in cell & developmental biology 38: 117-30

More Publications of Project 1

Hamdorf M, Imhof T, Theobald SJ, Simonis A, Di Cristanziano V, Gieselmann L, Dewald F, Lehmann C., Augustin M, Klein F, Alcazar MAA, Rongisch R, Fabri M, Cursiefen C, Rybniker J, Koch M*, Bock F*. The unique ORF8 protein of SARS-CoV-2 binds to human dendritic cells and induces a cytokine storm. J. Mol. Cell Biol. 2023; Accepted. *Shared senior author

Händel A, Lüke JN, Siebelmann S, Franklin J, Roters S, Matthaei M, Bachmann BO, Cursiefen C, Hos D. Outcomes of deep anterior lamellar keratoplasty and penetrating keratoplasty in keratoconic eyes with and without previous hydrops. Graefes Arch Clin Exp Ophthalmol. 2022 Sep;260(9):2913-2923.

Schrittenlocher S, Matthaei M, Bachmann B, Cursiefen C. The Cologne-Mecklenburg-Vorpommern DMEK Donor Study (COMEDOS) – design and review of the influence of donor characteristics on Descemet membrane endothelial keratoplasty (DMEK) outcome. Graefes Arch Clin Exp Ophthalmol. 2022 Aug;260(8):2417-2426.

Mestanoglu M, Händel A, Cursiefen C, Hos D. Three-year follow-up of high-risk keratoplasty following fine-needle diathermy of corneal neovascularization combined with bevacizumab. Graefes Arch Clin Exp Ophthalmol. 2022 Jul;260(7):2383-2385.

Lin T, Quellier D, Lamb J, Voisin T, Baral P, Bock F, Schönberg A, Mirchev R, Pier G, Chiu I, Gadjeva M. Pseudomonas aeruginosa-induced nociceptor activation increases susceptibility to infection. PLoS Pathog. 2021 May 6;17(5):e1009557. doi: 10.1371/journal.ppat.1009557.

Schönberg A, Hamdorf M, Bock F. Immunomodulatory Strategies Targeting Dendritic Cells to Improve Corneal Graft Survival. J Clin Med. 2020 Apr 28;9(5):1280. doi: 10.3390/jcm9051280

Schaub F, Bachmann BO, Seyeddain O, Moussa S, Reitsamer HA, Cursiefen C. [Mid- and Longterm Experiences with the Boston-Keratoprosthesis. The Cologne and Salzburg Perspective]. Klin Monbl Augenheilkd. 2017 Jun;234(6):770-775.

Schrittenlocher S, Penier M, Schaub F, Bock F, Cursiefen C, Bachmann B. Intraocular Lens Calcifications after (Triple-) Descemet Membrane Endothelial Keratoplasty (DMEK). Am J Ophthalmol. 2017 May 5. pii: S0002-9394(17)30193-9.

Cursiefen C, Heiligenhaus A. [“Translational Research in Ophthalmology is Important!”]. Klin Monbl Augenheilkd. 2017 May;234(5):650-651.

Enders P, Holtick U, Schaub F, Tuchscherer A, Hermann MM, Scheid C, Cursiefen C, Bachmann BO. Corneal Densitometry for Quantification of Corneal Deposits in Monoclonal Gammopathies. Cornea. 2017 Apr;36(4):470-475.

Schaub F, Enders P, Bachmann BO, Heindl LM, Cursiefen C. Effect of corneal collagen crosslinking on subsequent deep anterior lamellar keratoplasty (DALK) in keratoconus. Graefes Arch Clin Exp Ophthalmol. 2017 Apr;255(4):811-816.

Lorenz K, Scheller Y, Bell K, Grus F, Ponto KA, Bock F, Cursiefen C, Flach J, Gehring M, Peto T, Silva R, Tal Y, Pfeiffer N. A prospective, randomised, placebo-controlled, double-masked, three-armed, multicentre phase II/III trial for the Study of a Topical Treatment of Ischaemic Central Retinal Vein Occlusion  to Prevent Neovascular Glaucoma – the STRONG study: study protocol for a randomised controlled trial. Trials. 2017 Mar 16;18(1):128.

Schaub F, Enders P, Roters S, Cursiefen C, Bachmann BO. Single-pass Ultrathin DSAEK (UT-DSAEK) with the SLc Expert Microkeratome(®). Acta Ophthalmol. 2017 Mar;95(2):e160-e161.

Schaub F, Enders P, Bluhm C, Bachmann BO, Cursiefen C, Heindl LM. Two-Year Course of Corneal Densitometry After Descemet Membrane Endothelial Keratoplasty. Am J Ophthalmol. 2017 Mar;175:60-67.

Schaub F, Simons HG, Enders P, Bachmann BO, Roters S, Cursiefen C, Heindl LM. [Corneal donation : Dilemma between growing demand and declining donor rate]. Ophthalmologe. 2016 Dec;113(12):1058-1065.

Schaub F, Heindl LM, Enders P, Roters S, Bachmann BO, Cursiefen C. [Deep Anterior Lamellar Keratoplasty : Experiences and results of the first 100 consecutive DALK from the University Eye Hospital of Cologne]. Ophthalmologe. 2016 Dec 21. doi: 10.1007/s00347-016-0424-4. [Epub ahead of print]

Hoerster R, Stanzel TP, Bachmann BO, Siebelmann S, Cursiefen C. Intensified Early Postoperative Topical Steroids Do Not Influence Endothelial Cell Density After Descemet Membrane Endothelial Keratoplasty Combined With Cataract Surgery (Triple-DMEK). Cornea. 2016 Nov;35(11):1396-1400.

Hoerster R, Stanzel TP, Bachmann BO, Siebelmann S, Felsch M, Cursiefen C. Intensified Topical Steroids as Prophylaxis for Macular Edema After Posterior Lamellar Keratoplasty Combined With Cataract Surgery. Am J Ophthalmol. 2016 Mar;163:174-9.

Siebelmann S, Hermann M, Dietlein T, Bachmann B, Steven P, Cursiefen C. Intraoperative Optical Coherence Tomography in Children with Anterior Segment Anomalies. Ophthalmology. 2015 Dec;122(12):2582-4.

Notara M, Refaian N, Braun G, Steven P, Bock F, Cursiefen C. Short-term uvb-irradiation leads to putative limbal stem cell damage and niche cell-mediated upregulation of macrophage recruiting cytokines. Stem Cell Res. 2015 Nov;15(3):643-54.

Heindl LM, Kaser-Eichberger A, Schlereth SL, Bock F, Regenfuss B, Reitsamer HA, McMenamin P, Lutty GA, Maruyama K, Chen L, Dana R, Kerjaschki D, Alitalo K, De Stefano ME, Junghans BM, Schroedl F, Cursiefen C. Sufficient Evidence for Lymphatics in the Developing and Adult Human Choroid? Invest Ophthalmol Vis Sci. 2015 Oct;56(11):6709-10.

Schöllhorn L, Bock F, Cursiefen C. Thrombospondin-1 as a Regulator of Corneal Inflammation and Lymphangiogenesis: Effects on Dry Eye Disease and Corneal Graft Immunology. J Ocul Pharmacol Ther. 2015 Sep;31(7):376-85.

Schaub F, Cursiefen C, Heindl LM. Retrospective Appraisal of Split-Cornea Transplantation: An Audit of 1141 Donor Corneas. JAMA Ophthalmol. 2015 Sep;133(9):1086-7.

Bucher F, Hos D, Müller-Schwefe S, Steven P, Cursiefen C, Heindl LM. Spontaneous long-term course of persistent peripheral graft detachments after Descemet’s membrane endothelial keratoplasty. Br J Ophthalmol. 2015 Jun;99(6):768-72.

Lee HS, Hos D, Blanco T, Bock F, Reyes NJ, Mathew R, Cursiefen C, Dana R, Saban DR. Involvement of corneal lymphangiogenesis in a mouse model of allergic eye disease. Invest Ophthalmol Vis Sci. 2015 May;56(5):3140-8.

Cursiefen C, Viaud E, Bock F, Geudelin B, Ferry A, Kadlecová P, Lévy M, Al Mahmood S, Colin S, Thorin E, Majo F, Frueh B, Wilhelm F, Meyer-Ter-Vehn T, Geerling G, Böhringer D, Reinhard T, Meller D, Pleyer U, Bachmann B, Seitz B. Aganirsen antisense oligonucleotide eye drops inhibit keratitis-induced corneal neovascularization and reduce need for transplantation: the I-CAN study. Ophthalmology. 2014 Sep;121(9):1683-92.

Bock F, Rössner S, Onderka J, Lechmann M, Pallotta MT, Fallarino F, Boon L, Nicolette C, DeBenedette MA, Tcherepanova IY, Grohmann U, Steinkasserer A, Cursiefen C, Zinser E. Topical application of soluble CD83 induces IDO-mediated immune modulation, increases Foxp3+ T cells, and prolongs allogeneic corneal graft survival. J Immunol. 2013 Aug 15;191(4):1965-75.

Bock F, Maruyama K, Regenfuss B, Hos D, Steven P, Heindl LM, Cursiefen C. Novel anti(lymph)angiogenic treatment strategies for corneal and ocular surface diseases. Prog Retin Eye Res. 2013 May;34:89-124.

Cursiefen C, Maruyama K, Bock F, Saban D, Sadrai Z, Lawler J, Dana R, Masli S. Thrombospondin 1 inhibits inflammatory lymphangiogenesis by CD36 ligation on monocytes. J Exp Med. 2011 May 9;208(5):1083-92.

Dietrich T*, Bock F*, Yuen D, Hos D, Bachmann BO, Zahn G, Wiegand S, Chen L, Cursiefen C. Cutting edge: lymphatic vessels, not blood vessels, primarily mediate immune rejections after transplantation. J Immunol. 2010 Jan 15;184(2):535-9. *contributed equally

Cursiefen C, Chen L, Borges LP, Jackson D, Cao J, Radziejewski C, D’Amore PA,
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