Antigen-specific modulation of T cell alloreactivity by MHC derived peptides and their analogues to induce T cell tolerance after allogeneic transplantation
Project management at the University of Würzburg:
Our goal in the D-2 project, is the development of strategies for the antigen-specific prevention of allograft rejection. The immune response caused by the MHC-incompatible organ leads to loss of allograft function. MHC peptides, produced from foreign or allo-MHC-molecules during antigen processing, play an important part in stimulating the activation of alloreactive CD4+ T cells. These cells activated by the pathway of indirect alloantigen recognition are crucial for the pathogenesis of both acute and chronic rejection; two immune reactions occurring at different times following transplantation. The helper T-cells are the basis of a possible immunomodulating, T cell tolerance-inducing concept, because over their cytokines, they control the two pathways of the adaptive immune reaction: the cellular and the humoral pathway. For the future, we anticipate significant clinical alternatives to the present immunosuppression and the resulting serious side effects for the patients, such as infections and the induction of malignancies.In the D-2 project, part of the IZKF section D "Transplantation", we are pursuing strategies to prevent these misguided immune reactions based on MHC-peptides. In such a peptide therapy, we apply modified immunodominant peptides to prevent T cell transmitted rejection. Hereby, we are aiming to establish peptide analogues or "altered peptide ligands" (APLs) from an immunodominant allo-MHC peptide by exchanging individual amino acids. From the viewpoint of transplantation immunology, it would be very appealing to induce allogen-specific regulator T cells with such APLs; which would then be used in vivo to prevent the immune response to the graft. Parallel to this experimental work, we would like to develop an in vitro detection system for monitoring the immune status of transplanted patients based on our own extensive experience with immune-dominant MHC-peptides. This system could be established as a more sensitive and efficient alternative to the existing system, and would also make possible the further examination of the importance of allo-MHC peptides in clinical graft rejection.
Projekt period: from 05.1999 to 04.2004