While immunosuppressants have improved organ transplantation outcomes, immune-mediated rejection remains a major challenge. Calcineurin inhibitors such as tacrolimus (FK-506) prevent acute rejection but cause nephrotoxicity, hypertension, and other adverse effects that contribute to transplant vasculopathy. This study evaluated the effects of soluble programmed death-ligand 1 (PD-L1) alone and combined with FK-506 on graft survival and immune modulation in a heterotopic heart transplantation model. BALB/c mice served as donors and C57BL/6 mice as recipients, and animals were assigned to four groups: control, FK-506 alone, soluble PD-L1 alone, and combination therapy. Graft survival, flow cytometry, interferon-γ (IFN-γ) levels, and histological analyses were performed. The combination therapy group showed the longest median survival (45 days) compared with FK-506 alone (24 days; P = 0.039). Histological analysis revealed reduced cardiac vasculopathy and perivascular infiltration in the combination group, with a significant increase in FOXP3 + regulatory T cells (P < 0.001) and elevated LAG-3 expression in CD8 + T cells in the PD-L1 group. Soluble PD-L1 alone had limited impact, but combined with FK-506, it significantly improved graft survival, likely through modulation of immune cell populations. This combination may offer a promising approach to enhance immunosuppressive strategies in organ transplantation.
Yun et al. (2026) studied this question.