Chronic Rejection of Cardiac Allografts is Associated with Increased Lymphatic Flow and Cellular Trafficking

Background -Cardiac transplantation is an excellent treatment for end-stage heart disease. However, rejection of the donor graft, particularly by chronic rejection leading to cardiac allograft vasculopathy, remains a major cause of graft loss. The lymphatic system plays a crucial role in the alloimmune response, facilitating trafficking of antigen presenting cells (APCs) to draining lymph nodes (dLN). The encounter of APCs with T lymphocytes in secondary lymphoid organs is essential for the initiation of alloimmunity. Donor lymphatic vessels are not anastomosed to that of the recipient during transplantation. The pathophysiology of lymphatic disruption is unknown and whether this disruption enhances or hinders the alloimmune responses is unclear. Although histological analysis of lymphatic vessels in donor grafts can yield information on the structure of the lymphatics, the function, however, following cardiac transplantation is poorly understood. Methods -Using Single photon emission computed tomography/CT (SPECT/CT) lymphoscintigraphy, we quantified the lymphatic flow index (LFI) following heterotrophic cardiac transplantation in a murine model of chronic rejection. Results -Ten weeks following transplantation of a minor antigen (HY) gender-mismatched heart graft, the LFI was significantly increased compared with gender-matched controls. Furthermore, the enhanced LFI correlated with an increase in donor cells in the mediastinal dLN; increased lymphatic vessel area; and graft infiltration of CD4(+), CD8(+) T-cells and CD68(+) macrophages. Conclusions -Chronic rejection results in increased lymphatic flow from the donor graft to dLNs, which may be a factor in promoting cellular trafficking, alloimmunity, and cardiac allograft vasculopathy.