Project Details
Projekt
Donor induced graft tolerance by sCD83 after corneal transplantation
Subject Area
Ophthalmology
Term
from 2018 to 2022
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 367339186
Immune-mediated graft rejections remain the most common cause for graft failure after organ and tissue transplantation. This holds also true for corneal transplantations. More than 40,000 transplantations of the cornea are performed per annum in North America. The early outcomes of corneal allo-transplantation are typically very good with 90% at 2 years after surgery. The situation changes dramatic if the recipient cornea is inflamed due to inflammation or transplant rejection. In this case, the one-year survival rate decreases below 50% .We and others could demonstrate that the immune reaction is triggered by the above described direct allo-sensitisation where APCs travel from the donor tissue via corneal pathological lymphatic vessels into the local draining lymph nodes of the recipient and present the foreign antigen. In contrast to the systemic suppression of the immune reaction by known immunosuppressive therapeutics (i.e. steroids, CsA, Cellsept etc.) which are used world wide to treat transplanted patients and can cause serious and long lasting side effects, an induction of graft tolerance can induce a live long, endogenous protection against graft rejection reactions. In this context we could show that the survival rate of corneal grafts in a murine so called high risk model could be improved significantly by the application of sCD83 eye drops (Bock et al., 2013). This soluble CD83 molecule is a new immune modulatory protein which does not suppress the immune system in general but induces long lasting regulatory mechanisms. The local application of sCD83 increases e.g. the regional expression of FoxP3 and reduces the transplant specific allogenic T cell response (Bock et al., J.I. 2013). Furthermore we could show that the sCD83 mediated induction of regulatory T cells only occurs in the presence of dendritic cells. In unpublished studies with transgenic mice we could show that CD83 seems to be expressed on dendriform cells in the cornea.Derived from the well known term of direct allo sensitivity the first objective of this project proposal is to analyse if sCD83 can induce a so called direct allo tolerance. We hypothesis that sCD83 induced corneal graft tolerance can be mediated directly by immune cells of the donor tissue. Using the cornea has the benefit that not only the graft but also the recipient bed can be treated locally with sCD83. Thereby the effect of sCD83 on the immune cells of the graft as well as on the immunological micro-environment of the recipient bed can be analysed. This new therapeutic concept of transplant-mediated graft-tolerance induction could be the seeding point for new therapeutic approaches for other tissue- and solid organ transplantations like skin- or kidney transplantations in which a pre-treatment of the graft by sCD83 could also lead to tolerance induction against the donor tissue and avoid live long immunosuppressive treatment of the patient.
DFG Programme
Research Grants
