Clinical operational tolerance in liver transplantation: state-of-the-art perspective and future prospects

doi:10.1016/S1499-3872(13)60002-8

Hepatobiliary & Pancreatic Diseases International

Volume 12, Issue 1, 15 February 2013, Pages 12-33

https://doi.org/10.1016/S1499-3872(13)60002-8 Get rights and content

Background

Liver transplantation is the definite treatment for end-stage liver diseases with satisfactory results. However, untoward effects of life-long immunosuppression prevent the development of alternative strategies to achieve better long-term outcome. Achieving clinical operational tolerance is the ultimate goal.

Data Sources

A PubMed and Google Scholar search using terms: “immune tolerance”, “liver transplantation”, “clinical trial”, “operational tolerance” and “immunosuppression withdrawal” was performed, and relevant articles published in English in the past decade were reviewed. Full-text publications relevant to the field were selected and relevant articles from reference lists were also included. Priority was given to those articles which are relevant to the review.

Results

Because of the inherent tolerogenic property, around 20%–30% of liver transplantation recipients develop spontaneous operational tolerance after immunosuppression withdrawal, and the percentage may be even higher in pediatric living donor liver transplantation recipients. Several natural killer and γδT cell related markers have been identified to be associated with the tolerant state in liver transplantation patients. Despite the progress, clinical operational tolerance is still rare in liver transplantation. Reprogramming the recipient immune system by creating chimerism and regulatory cell therapies is among newer promising means to achieve clinical liver transplantation tolerance in the future.

Conclusion

Although clinical operational tolerance is still rare in liver transplantation recipients, ongoing basic research and collaborative clinical trials may help to decipher the mystery of transplantation tolerance and extend the potential benefits of drug withdrawal to an increasing number of patients in a more predictable fashion.

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Liver transplantation is one of the most challenging areas in the medical field. Despite that, it has already been established as a standard treatment option, especially in decompensated cirrhosis and selected cases of hepatocellular carcinoma and acute liver failure. Complications due to graft rejection, including mortality and morbidity, have greatly improved over time due to better immunosuppressive agents and management protocols. Currently, immunosuppression in liver transplant patients makes use of the best possible combinations of effective agents to achieve optimal immunosuppression for long-term graft survival. Induction agents are no longer used routinely, and the aim is to provide minimal immunosuppression in the maintenance phase. Currently available immunosuppressive agents are mainly classified as biological and pharmacological agents. Though the protocols may vary among the centers and over time, the basics of effective use usually remain similar. Most protocols use the combination of multiple agents with different mechanisms of action to reduce the dose and minimize the side effects. Along with the improvement in operative and perioperative techniques, this art of immunosuppression has contributed to the recent progress made in the outcomes of liver transplants. In this review, we will discuss the various types of immunosuppressive agents currently in use, the different protocols of immunosuppression used, and the art of optimal use for achieving maximum immunosuppression without increasing toxicity. We will also discuss the practical aspects of various immunosuppression regimens, including drug monitoring, and briefly discuss the concepts of immunosuppression minimization and withdrawal.
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Children receive transplants at a younger age, and the period of immunosuppression therapy may extend over decades. However, immunosuppression seems to be responsible for long-term mortality and morbidity. Pediatric liver transplant recipients can benefit from achieving immune tolerance and the opportunity of freedom from lifelong immunosuppression. This study aimed to investigate the frequency of prope tolerance among pediatric liver transplant recipients and the characteristics of these patients.
In this retrospective cohort study of pediatric liver transplant recipients, the medical records of transplant recipients treated at Shiraz Organ Transplant Center between 1994 and 2017 were reviewed. Prope tolerance was defined as normal laboratory values and stable clinical status on low-dose monotherapy. Children treated with low-dose monotherapy were categorized as the prope tolerant group. We compared the characteristics of prope tolerant recipients on low-dose monotherapy with patients on standard immunosuppression, i.e. full-dose tacrolimus plus steroids and mycophenolate mofetil. The data were analyzed with the t-test, chi-squared test, and a Cox proportional hazard model at a 5% significance level in SPSS software version 16.
A total of 585 children with a mean age of 8.32 ± 5.23 years were enrolled. 341 patients were categorized as prope tolerant and 244 comprised the full immunosuppression regimen group. Mean age at transplantation and rejection frequency were lower in the prope tolerant group (p < 0.001, p < 0.001). Based on the underlying diseases, metabolic/genetic, biliary tract, and cryptogenic liver diseases were significantly more prevalent in the prope tolerant group (p < 0.001). However, autoimmune liver disease was found to be more prevalent in the full immunosuppression regimen group. Also, those who received living organs (p = 0.001) and recipients of organs from female donors had a greater likelihood of achieving prope tolerant. According to the multiple Cox regression results, age at transplantation (p = 0.022), rejection frequency (p < 0.001), and autoimmune liver diseases (p = 0.028) had a prognostic effect on prope tolerance.
Factors as underlying disease, age at transplantation, and rejection frequency were factors that were predictive of prope tolerance in this sample of children. However, the risk of rejection should be considered during the tapering period.
Influence of everolimus-based treatment on circulating regulatory T cells after liver transplantation: Comparative study with tacrolimus-based therapy
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The establishment of this ‘operational tolerance’ is one of the main focuses of research in transplantation. The operational tolerance may be defined as having a stable function of the graft one year after complete discontinuation of immunosuppression drug regimen, while maintaining a functional immune system [5]. Contrary to the process of ‘true’ tolerance which consists in the clonal deletion of autoreactive immune cells, it is believed that the operational tolerance is an active inhibitory process mediated by immunosuppressive cells, such as regulatory T cells.
Liver transplantation remains the only treatment for terminal liver diseases. However, immunosuppressive drugs required for allograft acceptance are toxic and may be responsible for severe side effects. Modulating the immune system to induce tolerance is a promising approach to reduce immunosuppressive regimen. More particularly, promoting natural CD4⁺ CD25⁺ FoxP3⁺ Tregs could be crucial in achieving tolerance. Contrary to calcineurin inhibitors, reports indicate that mTOR inhibitors may have a positive impact on Tregs.
Here we present the first randomized prospective clinical study where Tregs levels from liver transplanted patients receiving either tacrolimus or everolimus were monitored for 6 months, starting from the day of transplantation. A total of 30 patients from four centers were monitored. Blood samples were obtained at day 0, day 14, one month, three months and six months post-transplantation. Flow-cytometry immunophenotyping of Tregs (CD4⁺ CD25⁺ CD127⁻ FoxP3⁺) and functional assays with Tregs were performed to assess their immunosuppressive capacity. Levels of Tregs were significantly reduced after one month of standard tacrolimus-based immunosuppressive regimen (p < 0.05). Four months after conversion, levels of Tregs from patients treated with everolimus was significantly higher than patients under tacrolimus (p < 0.02). Functional assays demonstrated that Tregs conserved their capacity to suppress the proliferation of activated PBMC.
XBP1s repression regulates Kupffer cell polarization leading to immune suppressive effects protecting liver allograft in rats
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Currently, immunosuppressants are the main treatment for AR, but their therapeutic effects are still poor [6,7]. Consider able evidence indicates that induced immune tolerance post-transplant is the most achievable way to avoid AcR [8], which itself is a complicated synergistic process, including antigen presenting cells (APCs), the signal transduction pathway, and immune-associated factors expression among others [9,10]. The tolerogenic property of the liver is well recognized and evidence suggests that liver non-parenchymal cells, such as dendritic cells (DCs), Kupffer cells (KCs), and sinusoidal endothelial cells are involved [11,12].
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Review ArticleClinical operational tolerance in liver transplantation: state-of-the-art perspective and future prospects

Background

Data Sources

Results

Conclusion

Transpl Immunol

Transplant Proc

Am J Transplant

Transpl Immunol

J Hepatol

Transpl Immunol

Lancet

Transpl Immunol

Am J Transplant

Blood

Lancet

Transpl Immunol

Am J Transplant

Am J Transplant

Am J Transplant

Transplant Proc

Hum Immunol

Transplant Proc

Am J Transplant

Clin Immunol

Semin Immunol

Lancet

Transplant Proc

Semin Immunol

Blood

Am J Transplant

Am J Transplant

Blood

Clin Immunol

Hepatobiliary Pancreat Dis Int

Am J Transplant

Am J Transplant

Am J Transplant

Am J Transplant

Some observations on prope tolerance

Curr Opin Organ Transplant

Bringing transplantation tolerance into the clinic: lessons from the ITN and RISET for the establishment of tolerance consortia

Curr Opin Organ Transplant

The Immune Tolerance Network at 10 years: tolerance research at the bedside

Nat Rev Immunol

Cellular and molecular mechanisms of liver tolerance

Immunol Rev

Monitoring of human liver and kidney allograft tolerance: a tissue/histopathology perspective

Transpl Int

Cell migration and chimerism after whole-organ transplantation: the basis of graft acceptance

Hepatology

Frequent achievement of a drug-free state after orthotopic liver transplantation

Transplant Proc

Human allograft acceptance is associated with immune regulation

J Clin Invest

Chimerism and tolerance in a recipient of a deceased-donor liver transplant

N Engl J Med

Early immunological monitoring after pediatric liver transplantation: cytokine immune deviation and graft acceptance in 40 recipients

Liver Transpl

Living donor liver transplantation and tolerance: a potential strategy in cholangiocarcinoma

Transplantation

Liver transplantation 27 years after bone marrow transplantation from the same living donor

N Engl J Med

Liver transplantation after stem cell transplantation with the same living donor in a monozygotic twin with acute myeloid leukemia

Ann Hematol

Organ tolerance following cadaveric liver transplantation for chronic graft-versus-host disease after allogeneic bone marrow transplantation

Bone Marrow Transplant

Living related liver transplant following bone marrow transplantation from same donor: long-term survival without immunosuppression

Pediatr Transplant

Weaning of immunosuppression in liver transplant recipients

Transplantation

Review Article
Clinical operational tolerance in liver transplantation: state-of-the-art perspective and future prospects