Intrahepatic proliferation of ‘naive’ and ‘memory’ T cells during liver allograft rejection: primary immune response within the allograft

Abstract

Liver allograft rejection is mediated by a primary response of T lymphocytes, followed by infiltration of the graft with a mixed inflammatory reaction. Using single and double label immunocytochemistry, we examined the proliferation index and the phenotype of leukocytes on liver biopsies from 10 patients with acute rejection before and after treatment with i.v. steroids, 10 patients with chronic rejection, 10 patients without rejection posttransplant, and 15 nongrafted, nonimmunosuppressed patients. Proliferation of mononuclear leukocytes (assessed by expression of Ki-67, a nuclear antigen associated with the cell cycle) inside the allograft was a prominent feature of acute and chronic rejection and was down-regulated by steroid treatment. Leukocytes in cell cycle were located predominantly in the portal tracts at the site of the inflammatory infiltrate. The majority of 'naive' (CD45RA+) and 'memory' (CD45RO+) CD4+ T lymphocytes were also periportally distributed. In contrast, CD8+ T lymphocytes, CD57+ natural killer cells, and CD68+ macrophages were located intraparenchymally throughout the liver lobules, whereas CD20+ B lymphocytes were only present in some of the portal tracts. Predominantly CD4+ and occasionally CD8+ lymphocytes were proliferating (assessed by double staining). The proliferating CD4+ cells were of both naive (CD4+, CD45RA+) and memory (CD4+, CD45RO+) phenotypes. To our knowledge, this is the first description of proliferating naive T lymphocytes in situ in liver allografts. These findings suggest that there may be a primary immune response generated within the allograft as well as in draining lymphatic tissue. This implicates not only intrahepatic proliferation of T lymphocytes as a prominent feature of rejection, but also suggests that the liver has a special immunological status comparable to that of lymphatic tissue.