Core signature of rejection-associated cytokines and chemokines in endomyocardial biopsies after heart transplantation

Background: Rejection remains a limiting factor for survival after heart
transplantation (HTx), and predictive biomarkers are still missing. Therefore, we
aimed to define the cytokine/chemokine microenvironment in endomyocardial
biopsies (EMB) and plasma after HTx and to identify patterns that reflect ischemia/
reperfusion injury as well as allograft rejection. Therefore, we hypothesize distinct
cytokine/chemokine patterns in heart biopsies with histopathologically proven
rejection compared with the microenvironment in unsuspicious biopsies.
Methods: EMB (n = 181; n = 52 patients) and peripheral blood samples (n = 147;
n = 52 patients) were obtained between 6 days and 5 years after HTx. 50 immune
proteins in EMB tissue lysates and plasma were quantified, and concentrations
were compared between EMB with and without histopathologically defined
acute rejection (AR), and correlation analyses between tissue and plasma
were performed.
Results: Regarding rejection status, distinct cytokine/chemokine patterns were
identified with significantly higher concentrations of CCL4, CXCL9, and
CXCL10 in EMB with acute rejection (p < 0.001). In addition, we identified
individual long-term dynamics of patients after HTx associated with rejection.
Elevated chemokine concentrations were also detected in EMB of patients
with donor-specific antibodies (DSAs). Moreover, significantly different patterns
were observed between heart tissue and plasma without direct correlations.
Conclusion: A core signature was defined for EMB with histopathologically
proven AR, consisting of high concentrations of CXCL9, CXCL10, CCL3, and
CCL4. This EMB chemokine signature was clearly distinct from plasma
samples, arguing for a local protein microenvironment associated with AR.
Further research is also needed with the help of AI to translate the different
approaches for the detection and prediction of AR into clinical practice.