Warming up to a cold heart

Locally acting complement inhibitor is highly effective at healing organ injury that occurs during transplant process

by Shawn Oberrath

Cardiac transplantation is a lifeline for patients with heart failure who have exhausted all other treatment options. And while improvements have been made in the last two decades, especially with the use of immunosuppressive therapy, organ rejection remains a major risk — about one quarter of patients experience some form of rejection, which puts the patient and the new heart at risk. 

Many cases of rejection are caused by an immune reaction to the donated heart, with the patient’s fighter T cells called into action against a foe that is meant to be a friend. But another major risk factor for rejection or organ failure is the injury that can occur to the heart as part of the transplant process.

Stephen Tomlinson, Ph.D., a researcher in the Department of Microbiology and Immunology at the Medical University of South Carolina, explained that this injury, known medically as post-transplant ischemia reperfusion injury (IRI), is an unavoidable consequence of transplantation that is directly tied to the procedure itself.

Prior to a transplant operation, the donor heart must be removed from the donor and stored on ice to keep it viable while it is transported to the recipient patient. During this time, the period of “cold ischemia,” the heart has no blood flow and is also subjected to the environmental stresses of cold temperatures. When the organ is transplanted into a patient, the blood vessels are reattached and blood flow resumes by a process called reperfusion. All these stresses combine to cause some inevitable injury, or IRI. And while the organ will eventually repair the damage, the time spent in the cold can have a cascade of effects on the severity of IRI and the success of the transplant.

Tomlinson pointed to the T cell immune response as the main cause of organ rejection, and the level of this response is related to the length of the cold ischemia period and the severity of IRI. “Because of this relationship, by reducing the degree of IRI we can potentially improve transplant outcomes.”

Tomlinson and his team at MUSC recently published a paper in The Journal of Heart and Lung Transplantation to announce a potential new treatment to minimize the damage done by IRI.

It is well known that the body’s complement system — a part of the immune system that is intimately involved in inflammation — is activated after stress events, including the stresses encountered during transplantation. To lessen this response when it causes trouble in the body, researchers and biotech companies are investigating the potential of complement inhibitors to yield therapies for a variety of conditions.

Most complement inhibitors that are currently available or in clinical development affect the body systemically and thus can influence healthy complement-mediated processes as well as the intended targets, sometimes creating unwanted side effects. In contrast, in Tomlinson’s lab the approach focuses on a very specific target in the injured donor organ.

In an organ subjected to ischemia and reperfusion, cell surface molecules called neoepitopes become exposed, and these injury-specific neoepitopes bind preexisting antibodies in the blood that then activate the complement system.

By building a drug that targets these neoepitopes and affects only damaged tissue, Tomlinson and his colleagues aim to decrease the severity of IRI without affecting the overall immune system. This is extremely important for transplant recipients, who are already immunosuppressed and thus more vulnerable to infections and autoimmune disorders, against which complement plays a protective role.

In the new study, they created a test treatment that uses a targeting antibody called C2 combined with a human complement inhibitor called CR1 to reduce the effects of IRI in a mouse model of cardiac transplant. They compared the new targeted inhibitor to an untargeted counterpart and examined the effectiveness and safety of both.

The results were clear. “We could use half the dose of the targeted drug to protect transplanted hearts against IRI,” said Tomlinson. “But the really important thing is that there was no effect on systemic complement activity.”

This means that the targeted treatment has specific effects in the transplanted heart but will not decrease the immune system’s overall ability to fight infection.

The new study demonstrates the promise of a locally targeted treatment for IRI that can protect against organ injury without harming the overall immune system. In fact, the researchers found that the targeted treatment had no effect on susceptibility to infection, whereas the untargeted inhibitor significantly increased susceptibility to infection.

More development and research are needed before this type of complement inhibitor will be ready for human patients, but there is certainly hope for a new and effective way to avoid the harm of IRI in vulnerable patients receiving a new heart and a new lease on life.