Targeting of costimulatory signaling pathways for the control of human anti-pig cellular immune responses

• Applicant: Professor Dr. Reinhard Schwinzer
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2004 to 2015
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5470814

Effective strategies for the control of human anti-pig cellular immune responses will be essential for the further development of clinical xenotransplantation. This project focuses on antibody-mediated blocking of costimulatory receptor/ligand interactions between human and pig cells in order to achieve graft-specific anergy and/or tolerance. Specific aims are: 1. Characterization of the costimulatory capacity of pig ligands. Expression vectors will be constructed containing various costimulatory ligands (e.g. CD86, CD58, CD40). The efficiency of different costimulatory pathways will be assessed by stimulating human T cells with pig cell lines transfected with individual ligands. 2. Generation of species-specific monoclonal antibodies (mAb) to those porcine ligands which deliver the strongest costimulatory signals to human T cells. 3. Evaluation of the modulatory capacity of anti-pig mAb in human T cell responses induced by (a) normal porcine tissues, (b) tissues transduced with inhibitory genes (e.g. CTLA-4-Ig, IL-10), and (c) tissues from transgenic pigs expressing human molecules which may downregulate cellular responses (e.g. HLA-E, TRAIL). The overall goal is to assess the potential of immunomodulation by anti-pig mAb alone and when combined with genetic engineering strategies developed in other projects of this joint initiative in order to control human anti-pig cellular immune responses.

• DFG Programme: Research Units
• Subproject of: FOR 535: Xenotransplantation