Novel Blood Test Detects Rejection After Lung Transplant

A simple blood test could one day replace invasive biopsies for detecting acute cellular rejection (ACR) after lung transplantation, a recent American Journal of Transplantation study finds.

Across solid organ transplants, lung transplants have among the highest rates of ACR. Patients generally undergo multiple surgical biopsies to continuously monitor for rejection. This procedure can be associated with significant complications including bleeding or abnormal air leakage in the chest cavity.

Now, researchers have discovered a novel biomarker that could help minimize these risks and ease the burden for patients. Cells release tiny packages of biological molecules called small extracellular vesicles (sEVs) that transfer information and enable communication with one another. The team found that sEVs from immune cells called T cells provide a reliable window into early ACR processes.

“We could very well be on our way to having a novel blood test that can replace or minimize having to do biopsies for lung transplant monitoring,” says Prashanth Vallabhajosyula, MD, professor of surgery (cardiac) and the study’s co-principal investigator.

Vallabhajosyula focuses on the pathophysiology of ACR. His ongoing research has shown that some processes driving rejection are similar across organ types. Last year, his team developed a new blood test that used T cell sEVs as a biomarker to successfully detect ACR following heart transplantation. They hypothesized that a similar platform could also be used to detect ACR in the lung.

Historically, it has been challenging for scientists to develop a noninvasive test for ACR because a blood sample contains sEVs from every type of cell. “You can imagine that the extracellular vesicles from a single cell type represents less than 1% of the total extracellular vesicle content in the blood,” Vallabhajosyula says.

To address this problem, his team developed a novel technology capable of extracting extracellular vesicles in the blood and enriching those originating from T cells. T cells are the primary drivers of ACR, and they undergo changes after becoming activated during rejection. Using their new technology, the researchers explored whether the sEVs released into the blood by T cells also underwent measurable changes.

First, they studied mouse models of lung transplantation. Seven days after lung transplant, the scientists compared the profiles of circulating sEVs from animals who experienced ACR and those that did not. Deviations in sEV profiles in ACR models correlated with changes in the lung tissue associated with rejection.

Next, they tested their technology on 20 patients who underwent bilateral lung transplantation, looking at blood samples from one, three, and 30 days after the procedure. They found that sEVs from patients who experienced ACR underwent similar changes to those seen in the animal models.

“The signals were dramatically different between those two groups,” Vallabhajosyula says. “This is our first validation in humans that our T cell sEV data correlated perfectly with the biopsy data.”

Lung transplants are associated with some of the poorest long-term survival rates of any solid organ transplant. Half of patients who receive a heart transplant will live over 10 years. On the other hand, approximately 60% of patients post-lung transplant will survive five years. Low survival rates are due in large part to patients experiencing chronic organ rejection, resulting in the accumulation of scar tissue in the lungs. There are currently no effective medical treatments for patients who experience this.

ACR episodes increase one’s risk of developing chronic rejection. The researchers are hopeful that the ability to catch and treat ACR earlier could improve long-term survival.

“Globally there’s a need for better diagnostics in transplant patients that allow us to intervene earlier when less damage is done to the organ, which we believe predisposes patients to chronic rejection,” says Daniel Kreisel, MD, PhD, the G. Alexander Patterson MD / Mid-America Transplant Endowed Distinguished Chair in Lung Transplantation and surgical director of lung transplantation at Washington University School of Medicine and the study’s co-principal investigator.

They are looking forward to testing their technology in a larger cohort of patients over a longer period of time. “Now that we have these very promising results, we plan to do a long-term analysis to see how well our platform performs in comparison to the gold standard, which is still biopsies,” Vallabhajosyula says. “And to see if we can actually have a blood test that can address this major clinical gap in this space.”