Lymphangiogenesis associated with acute cellular rejection in rat liver transplantation

Lymphangiogenesis may be important for the cellular immune response in liver transplantation. In the present study, we examined lymphangiogenesis in liver allografts displaying acute cellular rejection (ACR), or long-term acceptance, or severe ACR plus antibody-mediated rejection (AMR). ACR and subsequent long-term graft acceptance developed in liver transplantations from DA to PVG rats without immunosuppression (mean survival time more than 90 days). Severe ACR and AMR developed in liver transplantations from DA to Lewis rats without immunosuppression (mean survival = 11 days). Normal DA donor livers before transplantation showed a small number of lymphatic vessels around portal veins. DA liver grafts in PVG showed ACR with lymphangiogenesis in portal areas and portal-portal bridging areas with cellular infiltration. Newly formed lymphatic vessels in ACR were characterized by proliferating endothelial cells with expression of the homeobox transcription factor PROX-1 and surrounded by discontinuous basement membranes. Thereafter, the infiltrates spontaneously disappeared, and the grafts survived more than 90 days. During the resolution of the cellular infiltration, expanded lymphatic vessels were packed with many lymphocytes. Thereafter, the number of lymphatic vessels decreased. In contrast, severe ACR and AMR in DA-to-Lewis transplantations showed lymphatic vessels disappeared with edema in the portal areas at day 11. In conclusion, lymphangiogenesis occurred during ACR. It may be involved in the resolution of ACR and reduction of inflammation. In severe ACR and AMR, lymphatic vessels were destroyed, which may be involved in persistent severe inflammation.