Abstract
Liver transplant (LT) recipients require life-long immunosuppression (IS) therapy to preserve allograft function. The risks of chronic IS include an increased frequency of malignancy, infection, renal impairment, and other systemic toxicities. Despite advances in IS, long-term LT outcomes have not been improved over the past three decades. Standard-of-care (SoC) therapy can, in rare cases, lead to development of operational tolerance that permits safe withdrawal of maintenance IS. However, successful IS withdrawal cannot be reliably predicted and, in current prospective studies, is attempted several years after the transplant procedure, after considerable exposure to the cumulative burden of maintenance therapy. A recent pilot clinical trial in liver tolerance induction demonstrated that peri-transplant immunomodulation, using a regulatory T-cell (Treg) approach, can reduce donor-specific alloreactivity and allow early IS withdrawal. Herein we review protocols for active tolerance induction in liver transplantation, with a focus on identifying tolerogenic cell populations, as well as barriers to tolerance. In addition, we propose the use of novel IS agents to promote immunomodulatory mechanisms favoring tolerance. With numerous IS withdrawal trials underway, improved monitoring and use of novel immunomodulatory strategies will help provide the necessary knowledge to establish an active liver tolerance induction protocol for widespread use.
Highlights
Academic Editor: René Hany TolbaReceived: 29 January 2021Accepted: 21 February 2021Published: 24 February 2021Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations.Licensee MDPI, Basel, Switzerland.Transplantation is the life-saving procedure for end-stage liver disease of various etiologies
Alternatives to chronic IS therapy have been developed for other solid organ transplants using tolerance induction, a peri-transplant regimen that actively promotes tolerance of the donor allograft in the recipient, with the goal of safe and complete IS withdrawal [4]
Preparative regimens for active tolerance induction are essential to overcome the barrier against non-self, as the human immune repertoire contains a high frequency of alloreactive T-cells [50]. Both naïve and memory T-cell subsets found in the peripheral blood of healthy human subjects can proliferate in response to alloantigens in the mixed lymphocyte reaction (MLR)
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. We hypothesize that targeted peri-transplant immunomodulation may diminish the level and duration of alloreactivity to induce tolerance and allow complete IS withdrawal early post-LT, to reduce the long-term toxicities of chronic IS and improve patient outcomes (Figure 2). 2. Spontaneous Operational Liver Tolerance Is a Rare Outcome Post-Transplant on Standard-of-Care Immunosuppression. 66% to 92% [10] This improvement in short-term outcomes contrasts with stagnant patient survival rates beyond the first year post-LT, with high mortality driven by malignancies, non-rejection graft failure and infection. Human LT recipients receiving SoC can develop a spontaneous state of operational tolerance that allows safe complete IS withdrawal [22], characterized by a lack of harmful immune responses towards the graft, such outcomes are relatively rare in human trials (Table 1).
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