Photo Credit: iStock.com/KS Kim

Research shows that small extracellular vesicles shed by donor heart cells and circulating T cells provide a precise readout of heart transplant rejection.

Although routine endomyocardial biopsy remains the gold standard for grading acute cellular rejection (ACR) after heart transplantation, new research published in Transplantation has shown that small extracellular vesicles (sEVs) shed by donor heart cells and circulating T cells provide a precise, minimally invasive readout of rejection.

“T cells are constantly surveilling their environment, looking for infections and other things that are ‘non-self,’” explained study principal investigator Prashanth Vallabhajosyula, MD, MPH, of Yale School of Medicine, in a news release. “They see the transplanted heart as non-self, so they mount an attack.”

Distinct Molecular Shifts Signal Danger

In a longitudinal pilot study, the researchers collected 70 paired blood samples and biopsies from 12 recipients during the first 120 postoperative days. They isolated donor-derived sEVs with anti-human leukocyte antigens (HLA) I beads and probed for cardiac troponin T (cTnT) protein and messenger ribonucleic acid (mRNA), while anti-cluster of differentiation 3 beads captured T-cell sEVs enriched for cluster of differentiation 4, cluster of differentiation 8, T-cell receptor proteins, and microRNAs (mRNAs) let-7i, 101b, and 21a.

According to study results, eleven episodes of moderate ACR occurred in six patients (incidence 15.7%). Compared with grade 0/1 biopsies, donor-heart sEV cTnT protein and mRNA fell markedly (P<0.001), whereas T-cell sEV protein and miRNA cargoes rose (all P<0.001). These shifts were detectable as early as day 5 post-transplant; ten of the eleven episodes presented within 38 days, a timeframe in which commercial blood tests typically fail, according to the authors.

Monitoring Treatment Success

By escalating immunosuppression, the researchers reversed both clinical rejection and sEV signatures. Donor-heart cTnT mRNA and miR-21a tracked treatment response with Spearman coefficients of 0.87 and 0.85, respectively.

“Not only can we detect rejection, but our investigation also suggests that we can use our exosome platform to potentially monitor the efficacy of treatment of rejection,” Vallabhajosyula stated. The authors noted that the platform also identified one case of antibody-mediated rejection by analyzing B-cell sEVs, highlighting its versatility.

Toward Safer Transplant Care

“This is the first time that we’ve had a noninvasive method to delineate between the different types of rejection that may occur within the heart,” noted study co-author Sounok Sen, MD, of Yale School of Medicine.

According to the researchers, a larger validation study involving more than 100 patients is underway to refine diagnostic thresholds and assess long-term prognostic value. They noted that, if confirmed, sEV profiling could significantly reduce the need for repeat biopsies, lower procedural complications, and enable clinicians to adjust therapy earlier, ultimately improving outcomes for heart transplant recipients.