*Purpose: Previously, in 42 cardiac allograft biopsies, we demonstrated that the presence of Foxp3+ innate and TGF- β + adaptive regulatory lymphocytes in Quilty lesions are associated with higher heart allograft acceptance. In the current study, we aimed to characterize immunomodulatory pathways associated with Quilty lesions by measuring mRNA expression.

*Methods: Endomyocardial biopsies of heart allograft from nine patients were included in this study, four with unremarkable endomyocardium (control group) and five with at least one Quilty lesion (Quilty group). No acute T-cell or antibody mediated rejection was present histologically in any of these specimens. Total RNA was extracted from formalin fixed paraffin embedded tissue. Multiplexed mRNA measurement was performed using the nCounter system (NanoString Technologies, Seattle, WA), and data were analyzed with nSolver software (NanoString Technologies, Seattle, WA).

*Results: Of 771 gene mRNA levels measured in the NanoString Transplant Immunology Panel, 274 were upregulated in the Quilty group over the control group, with approximately one third related to adaptive immunity and 5% to innate immunity. Higher levels of mRNA expression in the Quilty group were also shown in pathways for hematopoiesis (11%), cytokine (9%), chemokine (7%), cell-extracellular matrix interaction (7%), and apoptosis & cell cycle regulation (5%). More specifically, the mRNA expression of tolerance-associated immunity markers, including FoxP3, TGF-β, and CTLA4, were higher in the Quilty group (2.82, 1.42, and 3.97 fold increase, respectively, with p < 0.05). Markers of rejection-associated immunity, including IL-2 and INF-γ, although lower in the quilty group, were not statistically different.

*Conclusions: Heart allografts with Quilty lesions have dominant adaptive immunity related mRNA expression with significantly higher mRNA expression of tolerant immunity markers. These data suggest that Quilty lesions, far from passive bystanders, may serve an immunomodulatory role in cardiac allografts. The presence of intra-allograft regulatory T-lymphocyte related signaling in Quilty lesions may help to reduce the risk of rejection and foster allograft acceptance.

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