Lymphatic neoangiogenesis in human kidney transplants is associated with immunologically active lymphocytic infiltrates

Renal transplant rejection is caused by a lymphocyterich inflammatory infiltrate that attacks cortical tubules and endothelial cells. immunosupressive therapy reduces the number of infiltrating cells; however, their exit routes are not known. Here a >50-fold increase of lymphatic vessel density over normal kidneys in grafts with nodular mononuclear infiltrates is demonstrated by immunohistochemistry on human remal transplant biopsie susing antibodies to the lymphatic enclothelial inarker protein podoplanin. Nodular infiltrates are constantly associated with newly formed, Ki-67-expressing lymphatic vessels and contain the entire repertoire of T and B lymphocytes to provide specific cellular and hurnoral alloantigenic immune responses, including Ki-67(+) CD4(+) and CD8(+) T lymphocytes, S100(+) dendritic cells, and Ki-67(+) CD20(+) B lymphocytes and lambda- and kappa-chain-expressing plasmacytoid cells. Numerous chemokine receptor CCR7(+) cells within the nodular infiltrates seemed to be attracted by secondary lymphatic chemokine (SLC/CCL21) that is produced and released by lymphatic enclothelial cells in a complex with podoplanin. From these results, it is speculated that lymphatic neoangiogenesis not only contributes to the export of the rejection infiltrate but also is involved in the maintenance of a potentially detrimental alloreactive immune response in renal transplants and provides a novel therapeutic target.