Emerging Entities of Immune-Mediated Allograft Dysfunction After Liver Transplantation?
Article first published online: 5 SEP 2013
© Copyright 2013 The American Society of Transplantation and the American Society of Transplant Surgeons
American Journal of Transplantation
Volume 13, Issue 11, pages 2792–2793, November 2013
How to Cite
Manns, M. P. and Mix, H. (2013), Emerging Entities of Immune-Mediated Allograft Dysfunction After Liver Transplantation?. American Journal of Transplantation, 13: 2792–2793. doi: 10.1111/ajt.12416
- Issue published online: 28 OCT 2013
- Article first published online: 5 SEP 2013
- Manuscript Accepted: 3 JUL 2013
- Manuscript Revised: 2 JUL 2013
- Manuscript Received: 20 JUN 2013
When Thomas E. Starzl performed the first liver transplantation 50 years ago, knowledge about the fundamental requirements for successful allograft transplantation was in its infancy. Just 5 years before, the first HLA antigen had been identified and subsequent continuation in the identification and characterization of these molecules paved the way for the increasing success in solid organ transplantation. The advent of new immunosuppressive drugs, especially the identification and utilization of cyclosporine A, can be considered a milestone in transplantation medicine, transforming allograft transplantation from an experimental state into a worldwide accepted life-saving routine procedure. Advances in elucidating the mechanisms in cellular and molecular immunology allowed the identification and development of new immunosuppressive drugs and biologicals to further enhance long-term graft survival.
However, drug toxicities have limited the overall benefits of immunosuppressive agents in organ transplantation. New innovative immunosuppressive agents with fewer side effects have been rather limited over recent years and long-term organ tolerance after weaning of all immunosuppressive agents remains a dream—despite all recent experimental progress including the application of regulatory T cells (Tregs). Short-term posttransplant survival has dramatically improved over the last decades mainly due to progress in surgical techniques and the advent of cyclosporine A and other immunosuppressive agents. However, long-term outcomes need to be improved further. Major factors contributing to posttransplant morbidity and mortality diminishing long-term survival include toxicities of immunosuppressive agents, chronic rejection and recurrence of diseases leading to transplantation like hepatitis C. Recently, survival rates after liver transplantation have even decreased in some countries like Germany . Reasons are the introduction of the MELD score system for organ allocation, increasing donor age and a more frequent use of marginal organs to overcome organ shortage. This means that more and more marginal organs become transplanted into marginal recipients. In addition, multiple poorly defined syndromes contribute to posttransplant morbidity and mortality. A hitherto unidentified entity of immune-mediated allograft dysfunction has been described in liver allograft recipients [2, 3]. The serological and histological features were reminiscent of autoimmune hepatitis (AIH) in native patients including a beneficial response to corticosteroids. However, these organ recipients had not been diagnosed with AIH prior to transplantation. The terms “de novo AIH” or “plasma cell hepatitis (PCH)” have been coined for this condition.
Recurrent AIH in liver transplant recipients is well documented, affecting up to 68% of patients, and is broadly acknowledged as a cause of late graft dysfunction with the potential to result in organ failure, if this condition is left untreated . The observation of AIH-like features in a group of liver graft recipients without underlying autoimmune liver disease caused difficulties with regard to the definition and terminology of this entity of immune-mediated graft dysfunction until today. Currently, this condition termed “de novo AIH” or “PCH” suggests an autoimmune pathogenesis rather than an alloimmune response as seen in cellular and humoral mediated rejection. “De novo AIH” presents with all the hallmarks of native AIH, that is portal lymphocytic and plasma cell inflammation, interface hepatitis, bridging and perivenular necrosis in association with elevated immunoglobulin G (IgG) and significant titers of autoantibodies, including anti-nuclear (ANA), anti-smooth muscle (SMA) and others (anti-gastric parietal cells, anti-liver/kidney microsome [LKM]). Typical features of acute or chronic rejection as well as signs of recurrent disease are missing, and patients generally respond immediately to standard immunosuppressive therapy for AIH. However, “de novo AIH” as well as “recurrent AIH” represent corticosteroid-responsive immune-mediated syndromes where the recipient's immune system attacks the donor liver, which is genetically distinct. Thus, the term “de novo AIH” is somewhat misleading. “Non-self is becoming self” over time . It is well documented that within 4 weeks after transplantation Kupffer cells of the donor liver are replaced by Kupffer cells derived from the recipient's own bone marrow. Furthermore, recipient-derived bile duct cells, to some extent, replace donor bile duct cells. However, this phenomenon is much less important than originally anticipated, in particular, for hepatocytes. Pathogenetic mechanisms in immune-mediated diseases like “de novo AIH” targeting the donor liver are immunologically more complex than in “native AIH.”
In this issue of the American Journal of Transplantation, Castillo-Rama et al  describe a subgroup of liver allograft recipients presenting as PCH with an increased ratio of immunoglobulin G4 (IgG4)-producing cells. They found evidence that this cohort may represent a distinct immune-mediated graft dysfunction by demonstrating that this entity showed higher plasma cell number/percentage, with more aggressive-appearing portal/periportal and perivenular necro-inflammatory activity, and more severe portal/periportal fibrosis compared to patients without an increased number of IgG4-producing plasma cells . The authors found no evidence that this condition belongs to the broad family of IgG4-related diseases (IgG4RD), which usually present with characteristic morphological features like dense lymphoplasmacytic infiltrates, organized in a storiform pattern with mild-to-moderate eosinophil infiltrates and obliterating phlebitis . Recently, IgG4-associated sclerosing cholangitis (IAC) was identified as a new disease entity that is corticosteroid sensitive and may be difficult to distinguish from primary sclerosing cholangitis (PSC) or cholangiocarcinoma (CCC) in cholangiography. In the majority but not in all cases, IAC is associated with increased serum levels for IgG4. IgG4-positive plasma cells dominate the cellular inflammatory infiltrate of affected tissues and are a diagnostic hallmark for IgG4RD in general and IAC in particular. IAC is often associated with autoimmune pancreatitis (AIP) as part of the spectrum of IgG4RD . Recently, Maillette de Buy Wenniger et al  have used novel next-generation sequencing technology to show that single IgG4-positive clones dominate the B cell receptor repertoire in IAC. The authors conclude that this observation supports the hypothesis that IAC is an antigen-driven disease and may be caused by an infectious agent in a genetically susceptible individual. This may also be relevant for other IgG4-associated diseases . Maybe this technology can also be used to further define posttransplant “de novo AIH/PCH” and further understand its etiopathogenesis, that is, whether it is a “variant of rejection” or a true “de novo autoimmune disease.” In this context, it would be of interest if the association of “de novo AIH/PCH” with HLA DR 15 could be confirmed. IgG4 is the least abundant of all IgG subclasses and represents less than 5% of all IgG immunoglobulins in serum. However, IgG4 has attracted much attention recently. “De novo AIH/PCH” may become another example of such a poorly understood IgG4-associated syndrome.
Accumulating evidence also suggests that, under certain conditions, immunosuppressive therapy itself may contribute to the emergence of formerly unrecognized immune-mediated allograft dysfunction.
Deciphering the immunological mechanisms of late allograft dysfunction is of fundamental importance in times of organ shortage. Identification and characterization of the underlying causes of conditions like “de novo AIH/PCH” will not only shed light on the still unresolved immunologic mechanisms of autoimmunity, but also help to increase graft survival by means of an individual fine-tuning of the immunosuppressive regimen. When the dream comes true that long-term organ tolerance can be achieved after weaning off all immunosuppressive drugs, such syndromes will hopefully no longer exist.
The authors of this manuscript have no conflicts of interest to disclose as described by the American Journal of Transplantation.