Can we train the body’s immune system to tolerate transplanted organs, rather than rejecting them?
That’s the question that University of Minnesota Health Cardiothoracic Surgeon Stephen Huddleston, MD, PhD, and immunology expert Marc Jenkins, PhD, are trying to answer.
Huddleston and Jenkins want to better understand how the immune system rejects transplanted organs—and are looking for ways to prevent or interrupt this process. Transplant rejection is poorly understood, and the currently available treatments have significant side effects, including decreasing the immune system’s ability to fight harmful infections. Additional research in this area has the potential to improve transplant patient outcomes. We caught up with Huddleston to learn more about transplant rejection and his research.
The body’s immune response to any infection is initially triggered by immune system cells known as CD4+ T cells. These cells detect foreign objects in the body and then “tell” other immune system cells known as B cells to produce the specific antibodies needed to fight an infection.
When a patient receives an organ transplant, the immune system often identifies the donor organ as “foreign” and targets it with T cells and antibodies made by B cells. Over time, these T cells and antibodies damage the organ, and may cause reduced organ function or organ failure. This is known as organ rejection.
Every transplant patient experiences an immune reaction to the donor organ, but whether and how organ rejection occurs varies from person to person. There are different types of rejection, including acute and chronic rejection. Acute rejection is shorter in duration and often occurs in the first few months after transplant. Chronic rejection is ongoing and may cause the donor organ to lose function over time.
To prevent rejection, transplant recipients take medications that suppress the immune system
in order to prevent it from attacking a donor organ.
Because immunosuppressant drugs affect the whole immune system, they can leave a transplant recipient vulnerable to other infections. Though some new immunosuppressant drugs have been developed that interact with T or B cells in different ways, immunosuppressant therapies have not changed much over the last several decades.
When a CD4+ T cell meets another cell carrying a foreign molecule, the two cells perform a kind of “handshake.” During this handshake, a receptor on the T cell attempts to recognize the foreign molecule carried by the other cell. If it does, that T cell activates by replicating itself over and over. These replica T cells all target that specific foreign molecule; they also trigger other parts of the immune system to respond.
Each CD4+ T cell has a unique receptor that recognizes only one type of foreign molecule carried by the other cell. At this point, we cannot distinguish between CD4+ T cells are attacking an infection or the transplanted organ. Dr. Jenkins and I are working to identify which CD4+ T cells recognize and activate against a transplanted organ, as opposed to those that are activating against harmful bacteria and viruses. Once we have isolated those T cells responsible for attacking a transplanted organ, we can study them to understand what makes them unique and how they damage the organ.
Our focus is on lung transplantation. Research on lung transplantation has lagged behind other areas because this surgery was relatively uncommon until recent years. If we can identify the exact cells that are damaging the transplanted lung, we can target those cells with our new treatments for rejection.
This has the potential to have a very significant impact. We often treat chronic rejection of transplanted lungs by performing another transplant. Unfortunately, this is a much riskier surgery. It also makes the existing donor organ shortage worse. If we can identify and target the CD4+ T cells responsible for attacking a transplanted organ, we can reduce or even prevent rejection.
Our “Holy Grail” is complete tolerance of the organ. We want the immune system to see the new organ as a normal part of the body, instead of a foreign object. If we can “teach” CD4+ T cells to accept a new organ, then we will be able to control the immune response against the organ without compromising the body’s ability to fight off other diseases. This is a very long-term goal. First, we have to find the cells, study them to gain a better understanding of their characteristics and then manipulate them. We’re on the right track, but at the early stages.
It puts a spotlight on the University of Minnesota for the unique resources that we bring to bear on healthcare in 2018. Not many medical centers have the ability to approach tough problems like this from the roots up and translate that research into clinical therapies to help our patients. For that reason, this institution is a tremendous resource for the people in Minnesota.