Immunomodulatory Role of Kupffer Cell in Liver Allografts

Abstract

Liver transplantation is widely used as a treatment for end-stage disease. Liver allografts seem privileged compared with other solid organ grafts for a number of reasons. Successful transplantation can be performed across major histocompatibility complex (MHC) disparities, and the is the only solid organ that, when transplanted, can protect other co-transplanted syngeneic organs from immunological tissue destruction [1]. A proportion of patients with stable function can have immunosuppression reduced or withdrawn completely [2,3]. The reasons for this liver effect are not understood. Recently, there has been interest in lymphocyte apoptosis that occurs in OLT animal models. Allograft tolerance can be readily induced in experimental animals, particularly rodents, and spontaneous tolerance of mismatched grafts occurs in some train combinations [4]. In a spontaneously tolerant murine model of transplantation, the development of tolerance was associated with a higher rate of apoptosis of cells in the portal inflammatory infiltrate [5]. Sharland et al. [6], in a rat model, also showed that tolerant animals had higher numbers of apoptotic cells; they demonstrated by double staining that these were T lymphocytes. Kupffer cells (KC), the resident macrophage population in the liver, are found within the sinusoidal lumen, adhering to the sinusoidal endothelial cells (LSEC). KC, which comprise one of major populations (20%) of the hepatic nonparenchymal cell fraction (NPC), can directly interact with passenger leukocytes and thus may play a role in immunomodulation and the induction of tolerance [7]. Following transplantation, donor KC not only migrate into the recipient lymph nodes, but also can be quickly replaced by recipient-derived monocytes [8,9]. Thus, KC are uniquely positioned for regulation of the T cell response in the liver. Our previous studies have shown that KC play an immunomodulatory role as manifested by inhibiting T lymphocyte proliferation in response to alloantigen stimulation. The purpose of this study was to quantify the effects of transplantation on KC immunomodulatory function, focusing specifically on Fas ligand (FasL) expression and their role in allo-reactive T cell apoptosis in chronic accepted and acutely rejected hepatic allografts.