Biliary epithelial cell antibodies induce expression of toll-like receptors 2 and 3: A mechanism for post–liver transplantation cholangitis?

✍ Scribed by Xupeng Ge; Mehmet Uzunel; Bo-Göran Ericzon; Suchitra Sumitran-Holgersson

• Publisher: John Wiley and Sons
• Year: 2005
• Tongue: English
• Weight: 447 KB
• Volume: 11
• Category: Article
• ISSN: 1527-6465
• DOI: 10.1002/lt.20420

✦ Synopsis

Studies to determine the role of preformed antibodies to biliary epithelial cells (BECs) in liver transplant rejections have been initiated. However, the clinical importance of these antibodies in the posttransplantation period still remains to be elucidated. Reactivity to BECs isolated from a normal healthy liver was investigated in sera of 56 patients before and after liver transplantation (LTX) using flow cytometry. Functional capacity of BEC antibodies was determined by the ability to induce expression of Toll-like receptors (TLRs) on BECs. Cytokine and chemokine production induced by BEC antibodies was determined by enzyme-linked immunosorbent assay. In all, 7 patients (13%) had BEC antibodies only pre-LTX, 14 (25%) only after LTX, 18 (32%) both before and after LTX, and 17 (30%) had no detectable antibodies. Presence of preformed BEC antibodies correlated with acute rejections (P < 0.03). Deposition of immunoglobulins in bile ducts was detected in biopsies of patients during rejections. Significantly higher numbers of patients with post-LTX antibodies (9 of 32) developed cholangitis, compared with 0 of 17 without antibodies (P < 0.02). Specificity studies indicated that these antibodies were both non -HLA-and HLA-specific. Normal BECs expressed mRNA but not the proteins for the TLRs. However, treatment with F(ab) 2 fragments of BEC antibodies induced protein expression of TLRs 2 and 3 and significantly high production of interleukin (IL)-6, monocyte chemoattractant protein (MCP)-1, macrophage inflammatory protein (MIP)-1␣, epithelial neutrophil activating peptide (ENA)-78, and IL-8. In conclusion, BEC antibodies via induction of TLR2 and TLR3 expression, as well as inflammatory cytokine and chemokine production may induce epithelial cell inflammatory responses to bacterial components and contribute to posttransplantation cholangitis. (Liver Transpl 2005;11:911-921.)

C urrently, hyperacute rejection is known to be mediated by preformed alloantibodies, and acute rejection is mainly considered to be caused by alloreactive T cells while both humoral and cellular immunity are responsible for chronic rejection. 1 The detection and treatment of allograft rejections has been mainly focused on T-cell -mediated processes. 2 The presence of antibodies reactive to donor human leukocyte antigen (HLA) and non-HLA antigens frequently found in the sera of recipients undergoing rejection has insti-gated an interest in the importance of humorally mediated rejections. 3 Furthermore, renewed interest in antibody-mediated rejection came partly from Feucht's discovery of using C4d as a marker for the detection of humoral rejection in kidney transplantations, 4 and it is believed that the incidence of biopsy-confirmed acute humoral rejections in renal transplant is about 8% to 9%. 5 Antibody-mediated rejection is typically unresponsive to conventional antirejection therapy. 1 The outcome for acute humoral rejection is worse than for acute cellular rejection and therefore has recently been recognized as a major cause of allograft loss. [6][7][8] Humoral rejection in other organ transplantations such as heart, lung, and liver is also well recognized. [9][10][11] Liver transplantation (LTX) is considered to be the choice of treatment for a wide variety of acute and chronic hepatic disorders. Over the years the 1-year survival rate for recipients of LTX has increased to about 90%. 12 These results reflect advances in organ preservation, immunosuppression, surgical techniques, and better management of complications. 12,13 However, infections including cholangitis, septicemia, and pneumonia occur in more than 70% of all transplant recipients within the first year after LTX. 14 Liver allo-