Center for Molecular Medicine Cologne

Bock, Felix - assoc. RG 04

Local Immune Modulation in Experimental Ophthalmology

Abstract

Our research fields are the immunological microenvironment at the corneal graft area as well as the effect of immune modulatory molecules in corneal graft survival. Immune-mediated graft rejections remain the most common cause for graft failure after organ and tissue transplantation. The gold standard to inhibit the immune reaction driven corneal graft failure is the use of corticosteroids. However, this often does not work and using this immunosuppressive agent topically or systemically leads to severe side.

Figure 1

Therefore, there is a great, unmet need to develop more precise therapies to promote corneal graft survival avoiding side effects and increasing the therapeutic efficacy. Understanding the underlying immunological processes at the graft-host microenvironment will help to develop such new strategies. Reasons for corneal inflammation are manifold. We analyse different inflammatory, clinically relevant pre-conditions of the cornea regarding their cytokine profile as well as their immune cell populations and their effect on corneal graft survival. These findings will help to better understand inflammatory conditions in the cornea which also occur outside the eye like trauma, corrosion or burns and their effect on transplant immunology. Translationally, we hope to find individualized, clinically available approaches for different underlying diseases to significantly improve high risk corneal transplant survival. The microenvironment plays an important role in several immunological processes.

Figure 2

We could show that pre-incubation of donor tissue with the immune modulator soluble CD83 (sCD83) significantly improves graft survival using a high-risk corneal transplantation model. The induction of tolerogenic mechanisms in graft re- cipients was achieved by a significant upregulation of Tgfb, Foxp3, Il27, and Il10 in the transplant and an increase of regulatory dendritic cells (DCs), macrophages (Mφ), and T cells (Tregs) in eye-draining lymph nodes.
This new therapeutic concept of local graft-tolerance induction could be the seeding point for new therapeutic approaches for other tissue- and solid organ transplantations like skin- or kidney transplantations.

Clinical and Medical Relevance

Long term our aim is to establish an interdisciplinary exchange about the induction and the mechanisms of local immune tolerance between corneal transplant immunology, immune competent tissue/solid organ transplant immunology and autoimmune diseases like Sjögrens Syndrom, dry eye disease or rheumatoid arthritis where self-tolerance gets lost and impairs vision.

  • 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
  • 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. 2021 Nov 22
  • Schönberg, A., Hamdorf, M., Bock, F. Immunomodulatory Strategies Targeting Dendritic Cells to Improve Corneal Graft Survival. J Clin Med. 2020 Apr 28;9(5)
  • 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.
  • 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).
  • Willrodt AH, Salabarria AC, Schineis P, Ignatova D, Hunter MC, Vranova M, Golding-Ochsenbein AM, Sigmund E, Romagna A, Strassberger V, Fabbi M, Ferrini S, Cursiefen C, Neri D, Guenova E, Bock F*, Halin C*. ALCAM Mediates DC Migration Through Afferent Lymphatics and Promotes Allospecific Immune Reactions. Front Immunol. 10:759 (2019).
  • Bock, F., Onderka, J., Braun, G., Schneider, A.C., Hos, D., Bi, Y., Bachmann, B.O. & Cursiefen, C. Identification of Novel Endogenous Anti(lymph)angiogenic Factors in the Aqueous Humor. Invest Ophthalmol Vis Sci 57, 6554-6560 (2016).
  • Bock, F., Matthaei, M., Reinhard, T., Bohringer, D., Christoph, J., Ganslandt, T. & Cursiefen, C. High-dose subconjunctival cyclosporine a implants do not affect corneal neovascularization after high risk keratoplasty. Ophthalmology 121, 1677-1682 (2014).
  • Bock, F., Rossner, S., Onderka, J., Lechmann, M., Pallotta, M.T., Fallarino, F., Boon, L., Nicolette, C., DeBenedette, M.A., Tcherepanova, I.Y., 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 191, 1965-1975 (2013).
  • Bock, F., Maruyama, K., Regenfuss, B., Hos, D., Steven, P., Heindl, L.M. & Cursiefen, C. Novel anti(lymph)angiogenic treatment strategies for corneal and ocular surface diseases. Prog Retin Eye Res 34, 89-124 (2013).
  • 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
  • Zhang W, Schonberg A, Bock F, and 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 Technol11, 6. doi:10.1167/tvst.11.5.6.
  • Peil J, Bock F, Kiefer F, Schmidt R, Heindl LM, Cursiefen C, and Schlereth SL (2022). New Therapeutic Approaches for Conjunctival Melanoma-What We Know So Far and Where Therapy Is Potentially Heading: Focus on Lymphatic Vessels and Dendritic Cells. Int J Mol Sci23. doi:10.3390/ijms23031478.
  • 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. 2021 Nov 22
  • Hayashi T, Zhang W, Hos D, Schrittenlocher S, Nhat Hung Le V, Siebelmann S, Matthaei M, Bock F, Bachmann B, and Cursiefen C (2021). Descemet Membrane Endothelial Keratoplasty in Vascularized Eyes: Outcome and Effect on Corneal Neovascularization. Cornea40, 685-689. doi:10.1097/ICO.0000000000002502.
  • Schlereth SL, Hos D, Matthaei M, Hamrah P, Schmetterer L, O'Leary O, Ullmer C, Horstmann J, Bock F, Wacker K, Schroder H, Notara M, Haagdorens M, Nuijts R, Dunker SL, Dickman MM, Fauser S, Scholl HPN, Wheeler-Schilling T, and Cursiefen C (2021). New Technologies in Clinical Trials in Corneal Diseases and Limbal Stem Cell Deficiency: Review from the European Vision Institute Special Interest Focus Group Meeting. Ophthalmic Res64, 145-167. doi:10.1159/000509954.
  • Zhang W, Schonberg A, Hamdorf M, Georgiev T, Cursiefen C, and Bock F (2021). Preincubation of donor tissue with a VEGF cytokine trap promotes subsequent high-risk corneal transplant survival. Br J Ophthalmol. doi:10.1136/bjophthalmol-2021-319745.
  • Hadrian K, Willenborg S, Bock F, Cursiefen C, Eming SA, and Hos D (2021). Macrophage-Mediated Tissue Vascularization: Similarities and Differences Between Cornea and Skin. Front Immunol12, 667830. doi:10.3389/fimmu.2021.667830.
  • Hou Y, Bock F, Hos D, and Cursiefen C (2021). Lymphatic Trafficking in the Eye: Modulation of Lymphatic Trafficking to Promote Corneal Transplant Survival. Cells10. doi:10.3390/cells10071661.
  • Schaub F, Hou Y, Zhang W, Bock F, Hos D, Cursiefen C. Corneal Crosslinking to Regress Pathologic Corneal Neovascularization Before High-Risk Keratoplasty. Cornea. 2021 Feb 1;40(2):147-155
  • Le VNH, Hos D, Hou Y, Witt M, Barkovskiy M, Bock F, and Cursiefen C (2020a). VEGF TrapR1R2 Suspended in the Semifluorinated Alkane F6H8 Inhibits Inflammatory Corneal Hem- and Lymphangiogenesis. Translational vision science & technology 9, 15.
     
  • Le VNH, Hou Y, Bock F, and Cursiefen C (2020b). Supplemental Anti Vegf A-Therapy Prevents Rebound Neovascularisation After Fine Needle Diathermy Treatment to Regress Pathological Corneal (LYMPH)Angiogenesis. Sci Rep 10, 3908.
     
  • Salabarria AC, Koch M, Schonberg A, Zinser E, Hos D, Hamdorf M, Imhof T, Braun G, Cursiefen C, and Bock F (2020). Topical VEGF-C/D Inhibition Prevents Lymphatic Vessel Ingrowth into Cornea but Does Not Improve Corneal Graft Survival. J Clin Med 9.
     
  • Schonberg A, Hamdorf M, and Bock F (2020). Immunomodulatory Strategies Targeting Dendritic Cells to Improve Corneal Graft Survival. J Clin Med 9.
PD Dr. Felix Bock CMMC Cologne
PD Dr. Felix Bock

Clinic of General Ophthalmology

CMMC - PI - assoc. RG 04

+49 221 478 97789

+49 221 478 86465

Clinic of General Ophthalmology

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