Beyond Histocompatibility: Donor Tissue Immune States and Their Role in Heart Transplantation

Heart transplantation transfers not only donor alloantigens and functional myocardium but also a pre-existing tissue environment shaped by resident immune, vascular, stromal, and parenchymal populations. This review examines the hypothesis that the biological state of donor tissue influences subsequent recipient immunity and contributes to heterogeneity in allograft outcomes. Donor-resident macrophages, endothelial cells, fibroblasts, extracellular matrix, and tissue-resident lymphocytes constitute an immunologically active myocardial niche that encounters ischemia-reperfusion injury and recipient immune effectors immediately after implantation. Experimental and human studies demonstrate the dynamic coexistence and replacement of donor- and recipient-derived immune populations, with recipient cells acquiring phenotypes within the graft microenvironment. We distinguish transient donor-tissue activation from genuine tissue immune memory, which would require persistence of an exposure-induced molecular or functional state and an altered response to a subsequent challenge. Potential mechanisms include trained innate immunity, epigenetic and metabolic reprogramming, endothelial inflammatory memory, and persistent stromal-immune interactions. We propose that allograft biology be investigated at the level of the donor-recipient immune pair and outline longitudinal single-cell, spatial, and cell-of-origin approaches to test this concept in human heart transplantation.