gets, it is possible that human intrahepatic biliary epithelial The intrahepatic biliary epithelium is susceptible to cells (HIBEC) play an active role in the intrahepatic immune extensive T-cell-mediated damage during primary biliresponse. 7 ary cirrhosis, primary sclerosing cholangitis, and he-Cells that express class II major histocompatibility compatic allograft rejection. During these processes, human plex (MHC) antigens have the potential to interact with and intrahepatic biliary epithelial cells (HIBEC) become acto activate antigen-specific T cells that express the CD4 activated and express high levels of the lymphocyte adhecessory molecule. Immunocytochemical studies have shown sion molecules, intercellular adhesion molecule-1 that the intrahepatic biliary epithelium expresses class II (ICAM-1) and lymphocyte-associated antigen (LFA)-3, MHC antigens during inflammation. 8,9 In vitro studies have and of class II MHC antigens. It follows that activated
shown that HIBEC can be induced to express high levels of HIBEC may also play a direct role in the activation of antigen-specific CD4 / T lymphocytes. The capacity of class II MHC antigens by proinflammatory cytokines such class II MHC antigen-expressing HIBEC to present antias interferon gamma (IFN-g). 10,11 HIBEC can also express gen and induce specific proliferation of CD4 / T cells was adhesion molecules such as intercellular adhesion moleculeexamined in this study. Lines of purified HIBEC were 1 (ICAM-1; CD54) and lymphocyte function-associated antiactivated by culture with the proinflammatory cytogen (LFA)-3 (CD58), which stabilize conjugation with lymkines interferon gamma (IFN-g) and tumor necrosis facphocytes by interaction with LFA-1 (CD18/CD11a) and CD2, tor a and were mixed in coculture with allogeneic CD4 / respectively. It follows that HIBEC may be capable of pre- T cells. The result of interaction between these cells was senting antigen to liver-infiltrating CD4 / lymphocytes and of assessed by measurement of lymphoproliferation and initiating or maintaining an intrahepatic immune response.
IL-2 production. Class II MHC antigen-expressing HI-
Activation of antigen-specific CD4 / helper T cells is a pre-BEC failed to induce either lymphoproliferation or IL-2 requisite for the development of cell-mediated immune proproduction. However, both of these parameters of T-cell cesses. However, it is clear that stimulation of the T-cell antiactivation were positive in cocultures when a costimulagen receptor alone provides inadequate stimulation for tion signal was delivered to T cells by adding bivalent complete lymphocyte activation. This process can only occur anti-CD28 antibodies. The antigen-specific activation of if the lymphocyte simultaneously receives a second or ''cothese T cells was further enhanced by the addition of a stimulatory'' signal. 12 Furthermore, it has been demonstrated cross-linking secondary antibody that caused CD28 rethat efficient activation of CD4 / T cells can only occur if both ceptor aggregation. The failure of cytokine-stimulated the antigen-specific primary signal and the costimulatory sig-HIBEC to induce T-cell activation is consistent with the nal are provided by the same target cell. 13 It is generally observation that HIBEC do not express the costimulaaccepted that interaction between members of the B7 family tory CD28 ligands B7-1 or B7-2 at either mRNA or protein on hematogenous antigen-presenting cells and the CD28 relevels. It may be concluded that HIBEC are unlikely to ceptor on T lymphocytes causes transduction of a costimulaplay a direct role in activation of antigen-specific CD4 / tory signal, which is important for primary T-cell activation. 14 T lymphocytes within the inflamed liver. (HEPATOLOGY However, our previous studies have shown that cultured 1996;24:561-567.)
HIBEC do not express B7 molecules, even after stimulation by proinflammatory cytokines. 15 Human intrahepatic bile ducts are a major target for im-It is clear that stimulation of additional accessory receptors munological damage during acute and chronic liver allograft on the T cell can also augment the activation process; these rejection and autoimmune diseases, such as primary biliary receptors include the adhesion molecules LFA-1 and CD2. 16,17 cirrhosis (PBC) and primary sclerosing cholangitis. 1 Biliary Indeed, certain nonhematogenous cells have been shown to epithelial cells are primarily damaged during each of these induce specific activation of CD4 / T cells in the absence of processes by T-cell-mediated immune effector mechanisms. 2-6 significant expression of B7 molecules. For example, class II However, in addition to their function as immunological tar-MHC molecule-expressing human vascular endothelial cells stimulate the proliferation of alloreactive and peptide antigen-specific CD4 / lymphocytes. 18,19 It has been shown that stimulation of CD2 on the lymphocyte by interaction with Abbreviations: PBC, primary biliary cirrhosis; HIBEC, human intrahepatic biliary epi-LFA-3 on the endothelial cell can provide costimulation in thelial cells; MHC, major histocompatibility complex; IFN-g, interferon gamma; ICAM-1, this system. 20 intercellular adhesion molecule-1; LFA, lymphocyte-associated antigen; MoAb, monoclonal antibody; IgG, immunoglobulin G; EBV, Epstein-Barr virus; RT, reverse transcriptase;
A previous study has shown that partially purified human PCR, polymerase chain reaction; IL-2, interleukin-2; mRNA, messenger RNA.
liver epithelial cells can induce the proliferation of primed From the Departments of 1 Medicine and 2 Surgery, The Medical School, University of allospecific T cells 3 ; similar observations have been made us-Newcastle upon Tyne, England.
ing parenchymal cells from sources such as the kidney. 21