Operational tolerance after liver transplantation

doi:10.1016/j.jhep.2009.03.006

Journal of Hepatology

Volume 50, Issue 6, June 2009, Pages 1247-1257

https://doi.org/10.1016/j.jhep.2009.03.006 Get rights and content

The achievement of an immunosuppression (IS)-free state after transplantation represents the ultimate goal of any immunosuppressive regimen. While clinical operational tolerance (COT) remains the exception after other types of solid organ transplantation, several cases of COT have been described after liver transplantation (LT). Overall, the experience gained so far worldwide demonstrates that COT can be achieved safely in one quarter of selected individuals, irrespective of the immunological background of donor and recipient, patient age, indication for LT, study endpoint, length of the weaning period and of pre/post-weaning follow-up, presence or not of chimerism. However, most transplant physicians still believe that the achievement of COT is still out of reach for the majority of LT recipients because of the potential risk for transplant survival, the non-randomized nature of most of the studies reported so far, and the selective nature of the patients enrolled in such studies, making them non-representative of the whole population of LT recipients. Despite these concerns, the present article demonstrates that this attitude is potentially no longer justified, given the growing evidence that a permanent and stable IS-free state can be achieved in a proportion of individuals who have received a LT for non-immune mediated liver diseases.

Introduction

The clinical era of transplantation began on December 23rd 1954, when Dr. Joseph Murray and co-workers performed the first successful renal transplant on the Herrick twins [1]. As a result of the genetic identity between the brothers, Richard Herrick did not receive any immunosuppression (IS) after the operation, thus representing the very first case of clinical operational tolerance (COT) in solid organ transplantation (SOT). In the same year, Billingham, Brent and Medawar first introduced the term transplantation tolerance, with the report of skin graft acceptance in mice that had received neonatal injections of donor mononuclear cells [2]. More than 50 years later, COT remains an extremely difficult goal to achieve in the majority of transplant recipients. However, in liver transplantation (LT) there is a growing body of evidence that COT can be achieved safely in a proportion of recipients. In this article, we will summarize and comment on all of the cases of COT described after LT reported to date, and will demonstrate that the achievement of an IS-free state – namely, COT – is definitely possible and safe after LT. The manuscript will emphasise the clinical perspectives, and will touch only briefly on the immunological mechanisms relevant to the understanding of the IS-free state achieved in the different studies described herein where, despite improved knowledge, understanding of the immune mechanisms underlying the phenomenon remains inadequate.

The cases of COT discussed will be divided into four different groups and sorted timewise according to the weaning strategy adopted. The first group identifies cases in which no tolerogenic molecule- or cell-based protocols were used, whereas the second and third groups will include cases in which tolerogenic molecule- and cell-based regimens were implemented, respectively. The cases of COT that developed after bone marrow transplantation will be included in the last group.

The authors define COT as the condition whereby a liver transplant retains function and lacks histological signs of rejection in the absence of any IS. The LT recipient in question is an immunocompetent host capable of responding to other immune challenges, including infections [3].

Section snippets

Pittsburgh – the original work

The very first cases of COT after LT were documented by Starzl and colleagues in the early 1990s [4], [5], [6], [7], [8], [9], [10]. Based on the finding that 11 LT recipients had been IS-free as a consequence of non-compliance or post-transplant lymphoproliferative disorders, the authors designed a prospective trial in which IS was intentionally withdrawn in patients experiencing IS-derived chronic toxicity. Out of 95 patients enrolled, 28 (29%, Table 1) were successfully weaned off IS after a

Pittsburgh – the tolerogenic protocol

In 2003, Starzl and colleagues published the results of a trial in which they administered ab initio an immunosuppressive protocol expected to be tolerogenic, to 82 adult kidney, liver, pancreas and intestinal transplant recipients [33]. The hypothesis on which this protocol was designed was that the need for continuous high dose IS can be avoided in most cases with the use of a strong lymphocyte-depleting regimen prior to engraftment, followed by the administration of low dose tacrolimus

Innsbruck–Vienna

Gadner and colleagues reported on the case of a 4-month-old girl with familial hemophagocytic lymphohistiocytosis, an inherited disorder whose only curative treatment is allogeneic stem cell transplantation [46]. The little girl underwent stem cell transplantation from her haploidentical mother, 2 months after receiving a living-related LT from the same donor for acute hepatic failure of unknown origin. The diagnosis of familial hemophagocytic lymphohistiocytosis could only be made after the

Innsbruck

Margreiter and colleagues reported the case of a 7.5-year-old patient who received a deceased-donor LT for skin- and liver-based chronic GVHD, occurring 7 years after an allogeneic bone marrow transplantation performed for sideroblastic anemia [57]. The donor was an HLA-identical female cousin. After the operation, the pre-existing chronic GVHD of the skin disappeared, and the immunosuppressive therapy – consisting of azathioprine, prednisone and cyclosporine – was gradually tapered and finally

How does the mechanism for COT occur?

Thus far, our efforts to understand the mechanisms underlying the phenomenon of COT have been mostly in vain. We know that the liver has immunomodulatory properties and that LT recipients are more prone to develop COT than recipients of other types of solid organ allografts. However, we do not know how the cells and mechanisms involved cooperate in order to induce and maintain COT, why COT occurs and when the chances for COT to develop are at their highest. Production of donor-strain soluble

What is the ‘gold standard’ to induce COT after LT?

This article of the current literature demonstrates that strategies that have been investigated to date with the objective of achieving a permanent IS-free state are numerous and very heterogeneous in terms of concept, immunological background and rationale, patient age, underlying indication for LT, endpoint, type of LT (deceased versus living donor), length of the weaning period, length of follow-up, presence or not of donor chimerism, full or partial chimerism, tolerogenic tools adopted,

Conclusions

Effective COT has been reported more frequently in LT recipients than after transplantation of any other organ. In some cases COT has been documented as an accidental finding, but in the last decade it has been obtained intentionally in selected patients, in a number of clinical trials. The present paper reviews 163 cases of COT and demonstrates that the belief that COT cannot be achieved without exposing the recipient to an increased and unacceptable risk of graft loss is no longer justified

Future perspectives

The failure of tolerogenic molecule-based protocols means that the molecular strategies investigated to date may be sub-optimal. The pathways of the immune response triggered by the engraftment of an allogeneic organ, may be too numerous to be controlled by just one or few compounds. In the stem cell era, the field of SOT has just started to address its interest towards progenitor cells which show impressive immunomodulatory properties. As stem cells have been used to treat conditions

Acknowledgements

The authors would like to address a special thank to Robert J. Stratta and Peiman Hematti for critical review. Gratitude is expressed by GO to Giuseppe Tisone and Jan Lerut for education, and to Alberto Sanchez-Fueyo for inspiration.

Giuseppe Orlando is recipient of the Marie Curie International Outgoing Fellowship POIF-GA-2008-221850, financed by the European Commission under the 7th Framework Program for Research and Development.

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Establishing tolerance remains a central, if elusive, goal of transplantation. In solid-organ transplantation, one strategy for inducing tolerance has been cotransplantation of various forms of thymic tissue along with another organ. As one of the biological foundations of central tolerance, thymic tissue carries with it the ability to induce tolerance to any other organ or tissue from the same donor (or another donor tissue-matched to the thymic tissue) if successfully transplanted. In this review, we outline the history of this approach as well as work to date on its application in organ transplantation, concluding with future directions. We also review our experience with allogeneic processed thymus tissue for the treatment of congenital athymia, encompassing complete DiGeorge syndrome and other rare genetic disorders, and consider whether allogeneic processed thymic tissue implantation may offer a novel method for future experimentation with tolerance induction in organ transplantation.
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Citation Excerpt :
Two studies reported that weaning off IS in LT recipients with non-immunological disease was not harmful in terms of the increased risk of graft loss, and liver allograft rejection rarely affects the clinical outcomes. The clinical rejection during the weaning time is responsive to treatment with increased immunosuppression [22–24]. On the other hand, using clinical biomarkers that detect subclinical rejection could help the transplant team to monitor the patients and improve the therapeutic strategy [25].
The liver transplant recipients are often subjected to excessive therapy by immunosuppressive drugs which produce several complications. Consequently, the minimization or even withdrawal of immunosuppression in selected patients is an attractive alternative. We investigated the frequency and characteristics of these near (or prope from Latin) tolerance in liver transplant recipients in Shiraz Organ Transplant Center.
We reviewed the medical records of over 3800 adult liver transplant recipients to select a group treated with a low-dose tacrolimus monotherapy (n = 90) between 1994 and 2017 in our transplant center. The patients with the best liver function parameters were selected; then, the clinician arbitrarily decided to withdraw steroids first and then mycophenolate mofetil and maintain each patient on a low dose tacrolimus.
We compared the characteristics of prope tolerant recipients on a low-dose tacrolimus with those on standard immunosuppression, namely full-dose tacrolimus plus steroids and mycophenolate mofetil (n = 233). Data were analyzed by t-test, chi-square test using SPSS software version 16.
Out of over 3800 liver transplant patients, 90 (2.34%) recipients were treated with a minimum dose of tacrolimus monotherapy. These recipients were compared to a selected group of 233 (6.1%) recipients treated with full-dose tacrolimus plus steroids and mycophenolate mofetil. In a prope tolerant group, there were 55 males (61.1%) and 35 females (38.9%) recipients. Mean age at the time of transplant was 39.92 ± (SD = 13.40) years with an average time from the transplantation time to completed weaning from triple immunosuppression to low-dose monotherapy of 41.35 months (SD = 17.27). The most common etiology of liver disease among both groups was viral hepatitis.
The achievement of prope (almost) immune tolerance was possible only in some liver transplant recipients with a relatively low risk of rejection. Our analysis suggests that there is a difference in the underlying diseases and recipients' age and the number of rejections between the two groups.
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Liver allografts are unique in solid organ transplantation as they are less susceptible to both acute and chronic rejection. Operational tolerance, defined as prolonged graft survival in the absence of immunosuppression, is also achieved more frequently with liver allografts. It is unknown if the presence of multiple allografts in the same individual, levels of immunosuppression, or the presence of cystic fibrosis (CF) impacts the livers ability to ward off rejection or achieve operational tolerance. We describe an unsensitized, ABO-compatible patient with CF who underwent double lung transplantation and several years later a combined liver-kidney transplant. He developed isolated late acute T-cell mediated rejection of his liver allograft despite a high level of immunosuppression (IS) required for his lung and kidney allografts. To our knowledge, this is the first case of isolated liver rejection in a patient with 3 separate organ allografts, or in a patient with CF, to be reported in the literature. This isolated liver rejection is out of keeping with typically accepted ideas about orthotopic liver tolerance.
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Organ transplantation faces two major challenges. First, we need to urgently identify a potentially inexhaustible source of organs. Second, we need to make immunosuppression-free transplantation possible. Many strategies have been implemented to increase the donor pool, yet the gap between the demand and the offer remains too wide and, as a consequence, the number of patients dying on the waiting list keeps rising. Tolerance has been pursued for decades, yet it remains an elusive goal outside liver transplantation, where the weaning off immunosuppression appears a safe option in selected cases. As the field of regenerative medicine has shown immense potential to address these challenges, transplant medicine should embrace the opportunity to join forces and partner with it. Regenerative medicine will enable organ-on-demand whereby patients will receive organs that will not be rejected and in a timely fashion. This will make registration in the waiting list and antirejection medications unnecessary and, as the new organs will be implanted immediately after fabrication, ischemia-reperfusion injury secondary to organ preservation will not be a problem anymore. The journey has just begun.
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^☆: The authors who have taken part in this study declared that they do not have anything to disclose regarding funding from industry or conflict of interest with respect to this manuscript.

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Special articleOperational tolerance after liver transplantation☆

Introduction

Section snippets

Pittsburgh – the original work

Pittsburgh – the tolerogenic protocol

Innsbruck–Vienna

Innsbruck

How does the mechanism for COT occur?

What is the ‘gold standard’ to induce COT after LT?

Conclusions

Future perspectives

Acknowledgements

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Successful homotransplantation of the human kidney between identical twins

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Special article
Operational tolerance after liver transplantation☆