Kupffer cells: Another player in liver tolerance induction

A simplistic view of macrophages is that they are simply professional garbage disposers that mediate inflammation. The vital role of macrophages in cleaning up apoptotic cells and other debris is well documented. The central importance of this role could explain many observations, including the finding more than a decade ago that blockade of Kupffer cells inhibits the induction of tolerance by the liver.1 However, phenotypic diversity has been observed among macrophages, and a number of functions have been attributed to them.2 Macrophages play regulatory functions and actually can induce apoptosis during development.3 Our ongoing studies, in collaboration with R. Duane Davis, indicate that donor macrophages play a critical role in the initiation of pulmonary xenograft dysfunction, a finding that might imply a possible role for Kupffer cells in problems associated with xenografted or xenoperfused livers. In this issue, Sun et al4 provide conclusive evidence that macrophages play a role in tolerance induction in liver transplantation. Thus, liver allograft tolerance induction, a role more conventionally attributed to dendritic cells,5 is yet another example of the diverse functions carried out by macrophages. Much of the information regarding mechanisms of tolerance in the liver comes from studies with soluble antigens. The liver necessarily must be a tolerogenic organ,6,7 given its exposure to numerous foreign materials derived from the gut. It plays a key role in establishing tolerance and preventing potentially devastating inflammatory responses against both food and normal enteric bacteria. Details concerning the liver’s ability to establish tolerance for these antigens only now are being elucidated. One of the principle findings is that liver sinusoidal endothelial cells are likely important in tolerance induction.8 Like dendritic cells, sinusoidal endothelial cells in the liver process and cross-present exogenous antigens. The presentation of antigen by the sinusoidal endothelial cells results in tolerance in a manner dependent on presentation of antigen to CD8 T cells. The ability of the liver to induce tolerance to antigens found in the gut likely is associated with its immunologic privilege during transplantation. With this in mind, the results found by Sun et al4 in this issue of Liver Transplantation suggest the possibility that Kupffer cells might be involved in tolerance induction to soluble antigens of gut origin, as has been postulated.7 Conversely, work implicating liver sinusoidal endothelial cells in tolerance induction to soluble antigen suggests that the same endothelial cells may be involved in the induction of tolerance to liver allografts. Thus, the studies by Sun et al4 add to a body of knowledge obtained not only by transplant immunologists, but also by immunologists studying other aspects of tolerance induction by the liver. The studies by Sun et al4 provide another important step in what is likely a long road in elucidating the development of tolerance to liver allografts. Besides macrophages and possibly sinusoidal endothelial cells, dendritic cells likely are involved.5 Further, preliminary data would suggest that hepatocytes may be involved in tolerance induction to liver allografts.9 Interesting issues abound, including the role of donor versus recipient macrophages, the extent to which various cells may be involved, and the factors that determine tolerance versus immunity. Clearly, this field promises to be an active area of interesting study for the foreseeable future.