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Development of compounds for the induction of tolerance following heart transplantation

Research Project
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01.01.2020
 - 31.12.2020

Heart failure is a life-threatening disease, with an estimated 25 million people being currently affected worldwide. While many factors can contribute to heart failure, one of the best treatment options for many of these would be transplantation of a healthy heart. Unfortunately, other than in the case of an identical twin, all donor hearts suffer from mismatching, resulting in high rejection rates. Moreover, even after receiving an appropriately-matched donor heart, recipients often require life-long immunosuppression. This makes them highly susceptible to opportunistic infections and spontaneous cancers. A therapy allowing mismatched heart transplantations without the need for overt immunosuppression is currently not available. Graft rejection following transplantation is mainly caused by activation of a subset of immune cells, called T cells. These cells recognize a donor organ as foreign, and therefore initiate an immune response against the graft, thereby effectively rejecting the transplanted organ. We have recently identified a hitherto unknown T cell-dependent pathway that mediates suppression of rejection following heart transplantation involving an immune cell-specific protein termed coronin 1. In recently published work (Immunity, 2019), we found that coronin 1 deletion resulted in long-term acceptance of mismatched heart allografts, in the absence of any other immunosuppressive therapy. The goal of the proposed project is to develop inhibitors of the coronin 1-dependent pathway, that may be useful for the prevention of rejection following heart allo-transplantation. The results from this project may allow the introduction of a therapy that has first of all the potential to increase the donor base by allowing heart allo-transplantation to occur between HLA-mismatched individuals. Secondly, it will allow the treatment of end-stage heart failure patients having undergone allotransplantation to avoid graft rejection. Such therapy may overcome the problems associated with overt immunosuppression including susceptibility towards infections, graft versus host disease and the development of tumors associated with conventional immunosuppression. Together the research may result in novel treatment options for patients suffering from end-stage heart disease.

Funding

Development of compounds for the induction of tolerance following heart transplantation

Foundations / Associations (GrantsTool), 01.2020-12.2020 (12)
PI : Pieters, Jean.

Members (1)

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Jean Pieters

Principal Investigator