Shortages of organs for patients who are awaiting a transplant are widespread, with over 100,000 people in the United States currently on the transplant waitlist. This is only one reason that it is critical to develop ways to ensure that a transplant recipient’s immune system does not trigger rejection of the donor organ. With a new one-year, $40,000 grant from the Alternatives Research & Development Foundation, Division of Transplantation Assistant Professor Matthew Brown, PhD will be developing a test to better detect endarteritis, an inflammatory condition associated with rejection of a transplanted kidney.
“Clinicians urgently need biomarkers that can serve as an early warning sign for when the immune system is gearing up to reject a transplanted organ,” explained Brown. “If they can diagnose it early enough, they may be able to identify ways to effectively thwart rejection and save the organ. This will reduce the need for re-transplantation due to organ loss, and it will ultimately save or extend the lives of kidney transplant patients worldwide.”
Brown’s research relies on a specific type of stem cell, called induced pluripotent stem cells (iPSCs), to provide a model for evaluating rejection and tolerance of transplanted organs.
“iPSCs are a special kind of stem cell made from adults; we can use them to make almost any type of cell in the body,” explained Brown. “For this study, we’ll be using iPSCs that have been programmed to develop into endothelial cells, which are the main type of cell than lines the blood vessels that feed our organs. We’ll add peripheral blood mononuclear cells, or PBMCs, which are the immune cells that drive transplant rejection. We can then study how the two types of cells interact – for example, how the genes of endothelial cells respond to immune attack – by using a technique called single cell RNA sequencing.”
Using previously collected blood samples of human patients, Brown’s team plans to take iPSC-induced endothelial cells from an organ donor and expose them to iPSC-induced PBMCs from an organ recipient who is not well-matched to the donor. At a cellular level, this will replicate what happens when an organ recipient’s immune system triggers rejection of a donor organ. The team will then analyze the cells’ genome to identify biomarkers of this rejection process. From there, they can develop an assay that is sensitive to these biomarkers.
“By developing a test that can diagnose transplant rejection, we can contribute to lasting improvements in the health and well-being of kidney transplant recipients,” said Brown. “We’re also excited that this line of research could open up new avenues of using iPSCs to model and study organ transplant outcomes. Importantly, this project does not involve use of any research animals or animal products – it’s entirely human-focused. We’re hopeful that that will increase the likelihood that our findings will one day benefit UW transplant patients. I’m enormously grateful to the Alternatives Research & Development Foundation for their support.”