Research Group

  • Dr. Jiangping Wu, Principal Investigator

Location

  • Notre-Dame Hospital, Montreal, Canada

Title

  • Use of Proteosome Inhibitors to Control Rejection and to Induce Long-Term Tolerance of Organ Grafts

The proteosome is a protein complex, whose job is to degrade most of the proteins in a cell. It was considered as a “garbage collector” of cells and its role in cells was thought humble and insignificant. Our recent work shows that the function of the proteosome is tightly regulated and that it plays critical roles in controlling cell growth and death. Notably, we have found that if the activity of the proteosome is inhibited, cells that are vigorously growing will be easily killed, while cells that are not growing will be spared. This is a very interesting feature and we will take advantage of it to improve outcomes of organ transplantation.

Organ transplantation is an effective way to treat end-stage diseases of various organs. After organ transplantation, a graft will be rejected by a recipient because the immune system of the recipient recognises the graft as a foreign entity. T lymphocytes of the immune system play a major role in the graft rejection. Some T cells are specific to foreign molecules (alloantigens) of the graft and are stimulated by these molecules. These cells will start to grow and proliferate and finally cause damage to the graft, while other irrelevant T cells that might be protective against microbes remain in a resting status. If we kill the growing T cells, then we can create a hole in the immune system such that it cannot reject the graft but its protective functions against other microbes remain intact.

In this project, we will attempt to use novel proteosome inhibitors in an animal model to eliminate alloantigen-specific T cells after organ transplantation with a view to controlling graft rejection. The underlying mechanisms will be studied. Derivatives of the prototype proteosome inhibitors will also be developed to produce more effective and less toxic compounds. If the results are as expected, we will have a new category of drugs that can not only inhibit graft rejection but also induce long-term graft tolerance.

This project if a follow up of a one-year proof-of-concept study that was funded by the ROTRF in cycle II