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Activation of naïve helper T cells is thought to occur through a three signal pathway. Signal 1, antigen recognition by the T cell receptor complex. Antigens are presented by major histocompatibility complex II cells [antigen presenting cells (APC) such dendritic cells]. Signal 2, co-stimulation, the interaction between the APC (CD80 and CD86) and the T cell (CD28). Signal 3, cellular proliferation and T cell differentiation into effector phenotypes (Th1, Th2), through cytokine stimulation. MHC: Major histocompatibility complex; APC: Antigen presenting cells.
Source publication
The transplanted liver can modulate the recipient immune system to induce tolerance after transplantation. This phenomenon was observed nearly five decades ago. Subsequently, the liver's role in multivisceral transplantation was recognized, as it has a protective role in preventing rejection of simultaneously transplanted solid organs such as kidne...
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In the last years, several scoring systems based on pre- and post-transplant parameters have been developed to predict early post-LT graft function. However, some of them showed poor diagnostic abilities. This study aims to evaluate the role of the comprehensive complication index (CCI) as a useful scoring system for accurately predicting 90-day an...
Profiling of circulating immune cells provides valuable insight to the pathophysiology of acute rejection in organ transplantation. Herein we characterized the peripheral blood mononuclear cells in simultaneous kidney-pancreas transplant recipients. We conducted a retrospective analysis in a biopsy-matched cohort (n = 67) and compared patients with...
Systemically administered glucocorticoids constitute an essential part of the immunosuppressive regimen for transplant recipients, yet their known risks of causing hyperglycemia or posttransplant diabetes require close monitoring and minimisation of use, when possible, to prevent detrimental effects on patient morbidity and graft survival. Topical...
Background:
Results of both experimental and clinical studies suggest that metabolic acidosis (MA) contributes to the progression of chronic kidney disease (CKD) and mortality in CKD patients. It is unknown whether the same relationship exists in kidney transplantation (KTx) patients. The aim of this observational study was to examine this relatio...
We aimed to characterize patterns of differences in liver graft failure rates by recipient sex, accounting for the modifying effects of donor sex and recipient age.
Methods:
We evaluated 144 212 first deceased donor liver transplant recipients [1988-2019; Scientific Registry of Transplant Recipients (SRTR)]. We used multivariable time-varying Cox...
Citations
... These techniques also are preferred for re-transplantation, as the liver inclusion decreases the risk of rejection [16]. The mechanisms are not completely understood, but include the liver's unique immunologic microenvironment (modulating the reaction to food, microbiome, and graft antigens), the dual blood supply limiting ischemia (the cellular or antibody-mediated rejection targeting the vascular endothelium), the ability to absorb antibodies (limiting the risk of antibody-mediated rejection), the cross-talk between the liver and the recipient immune cells modulating the immune system towards tolerance [17]. For a multivisceral ITx, the recipient's diseased foregut (stomach and duodenum) is removed, and replaced. ...
... The cumulative exposure to immunosuppression and direct carcinogenicity of individual agents may contribute to the development of PTM [6]. Tacrolimus and mycophenolic acid (MPA) are the most commonly used backbone immunosuppressants post-LT, and are also utilised as maintenance monotherapy in 42% of LT recipients in the United States due to the relatively immune tolerant microenvironment of the liver [7,8]. Experimental data have demonstrated multiple prooncogenic effects of tacrolimus, whereas MPA may be protective against tumour growth and progression [9]. ...
BACKGROUND
De novo malignancy is a leading cause of late morbidity and mortality in liver transplant recipients. Cumulative immunosuppression has been shown to contribute to post-transplant malignancy (PTM) risk. There is emerging evidence on the differential carcinogenic risk profile of individual immunosuppressive drugs, independent of the net effect of immunosuppression. Calcineurin inhibitors such as tacrolimus may promote tumourigenesis, whereas mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil, may limit tumour progression. Liver transplantation (LT) is relatively unique among solid organ transplantation in that immunosuppression monotherapy with either tacrolimus or MPA is often achievable, which makes careful consideration of the risk-benefit profile of these immunosuppression agents particularly relevant for this cohort. However, there is limited clinical data on this subject in both LT and other solid organ transplant recipients.
AIM
To investigate the relative carcinogenicity of tacrolimus and MPA in solid organ transplantation.
METHODS
A literature search was conducted using MEDLINE and Embase databases using the key terms “solid organ transplantation”, “tacrolimus”, “mycophenolic acid”, and “carcinogenicity”, in order to identify relevant articles published in English between 1st January 2002 to 11th August 2022. Related terms, synonyms and explosion of MeSH terms, Boolean operators and truncations were also utilised in the search. Reference lists of retrieved articles were also reviewed to identify any additional articles. Excluding duplicates, abstracts from 1230 records were screened by a single reviewer, whereby 31 records were reviewed in detail. Full-text articles were assessed for eligibility based on pre-specified inclusion and exclusion criteria.
RESULTS
A total of 6 studies were included in this review. All studies were large population registries or cohort studies, which varied in transplant era, type of organ transplanted and immunosuppression protocol used. Overall, there was no clear difference demonstrated between tacrolimus and MPA in de novo PTM risk following solid organ transplantation. Furthermore, no study provided a direct comparison of carcinogenic risk between tacrolimus and MPA monotherapy in solid organ transplantation recipients.
CONCLUSION
The contrasting carcinogenic risk profiles of tacrolimus and MPA demonstrated in previous experimental studies, and its application in solid organ transplantation, is yet to be confirmed in clinical studies. Thus, the optimal choice of immunosuppression drug to use as maintenance monotherapy in LT recipients is not supported by a strong evidence base and remains unclear.
... Patients with melanoma were numerically more likely to have acute graft rejection than those with cSCC, while patients with cSCC were more likely to have their acute graft rejection progress to graft failure but the differences were not significant (p = 0.48 and p = 1). Liver transplant recipients tend to have lower rates of graft rejection and clinically, and it is possible that the selection of the type of and number of immunosuppressive agents may differ by type of transplant (71). In this series, patients with liver transplants received single agent immunosuppression (64.3%) at Frontiers in Transplantation a numerically higher rate than patients with kidney transplants (31.3%), who were more commonly on 2 immunosuppressive agents at ICI initiation (50.7%). ...
Background
Immune checkpoint inhibitors (ICI) are standard of care therapy for patients with cutaneous malignancies, the most frequently diagnosed cancers in solid organ transplant (SOT) recipients. The activity and rate of allograft rejection in SOT recipients with advanced skin cancers treated with ICI is understudied.
Methods
We conducted a retrospective analysis of SOT recipients with advanced melanoma, cutaneous squamous cell carcinoma (cSCC), and merkel cell carcinoma (MCC) who were treated with ICI. Unpublished cases from our institution and published cases from the literature were aggregated. Demographics, type of immunosuppressive therapy, type of ICI(s) administered, prior systemic therapies, tumor response to ICI, and evidence of organ rejection and/or failure were recorded. Objective response rates (ORR) and rates of graft rejection and failure are reported.
Results
Ninety patients were identified; four patients from our institution and 86 unique patients from a literature review. ORR to first-line ICI for the entire cohort was 41.1% (37/90). ORR by tumor type was 31% (18/58), 64.3% (18/28), and 25.0% (1/4) for melanoma, cSCC, and MCC, respectively. The rate of graft rejection was 37.8% (34/90) with 61.8% (21/34) of these cases progressing to graft failure. Number of immunosuppressive agents (0, 1, 2, or 3) was inversely associated with rate of graft failure.
Conclusions
In this retrospective analysis, ICIs demonstrate clinical activity in SOT recipients with cutaneous malignancies; however, the rate of graft rejection is high. Treatment plans should be individualized through thorough interdisciplinary discussion. Immunosuppressive modifications may be considered prior to starting treatment, but when feasible, enrollment on clinical trials is preferred.
... The liver is known for its ability to induce immune tolerance to antigens that it expresses (23,24). Mechanisms of tolerance induction by the liver elucidated in mouse studies include trapping and deletion of activated effector T cells, induction of T cell anergy and exhaustion, and inducing T regs (25)(26)(27)(28). ...
Promoting immune tolerance to transplanted organs can minimize the amount of immunosuppressive drugs that patients need to take, reducing lifetime risks of mortality and morbidity. Regulatory T cells (Tregs) are essential for immune tolerance, and preclinical studies have shown their therapeutic efficacy in inducing transplantation tolerance. Here, we report the results of a phase 1/2 trial (ARTEMIS, NCT02474199) of autologous donor alloantigen-reactive Treg (darTreg) therapy in individuals 2 to 6 years after receiving a living donor liver transplant. The primary efficacy endpoint was calcineurin inhibitor dose reduction by 75% with stable liver function tests for at least 12 weeks. Among 10 individuals who initiated immunosuppression withdrawal, 1 experienced rejection before planned darTreg infusion, 5 received darTregs, and 4 were not infused because of failure to manufacture the minimal infusible dose of 100 × 106 cells. darTreg infusion was not associated with adverse events. Two darTreg-infused participants reached the primary endpoint, but an insufficient number of recipients were treated for assessing the efficacy of darTregs. Mechanistic studies revealed generalized Treg activation, senescence, and selective reduction of donor reactivity after liver transplantation. Overall, the ARTEMIS trial features a design concept for evaluating the efficacy of Treg therapy in transplantation. The mechanistic insight gained from the study may help guide the design of future trials.
... AMR following liver transplant is relatively rare compared to TCMR and is also less common than in other solid organ transplants [44]. AMR is primarily mediated by donor-specific antibodies against non-self class I and II MHC molecules on the surface of the transplanted liver's endothelial cells [40]. ...
The management of hepatocellular carcinoma (HCC) has been transformed by the incorporation of immune checkpoint inhibitor therapy. Compared to traditional chemotherapy, these regimens have markedly improved outcomes in patients with HCC. Additionally, they are generally well-tolerated in patients with impaired hepatic function. This chapter will review the landmark trials which have paved the way for the use of ICIs in the treatment of HCC and summarize current consensus on best practices regarding their use in this setting. It will also discuss other prospective uses of immunotherapy for the treatment of HCC currently being investigated, including further incorporation of both checkpoint inhibitor and non-checkpoint inhibitor agents into treatment strategies. Furthermore, it will summarize the existing safety and efficacy data regarding the use of checkpoint inhibitors in patients who have previously undergone liver transplant.
... Due to its unique location at the crossroads of endotoxin-rich portal circulation and the systemic circulation, the liver microenvironment favors a more tolerogenic response to most stimuli at steady state (1). Interestingly, the liver-induced immune hyporesponsiveness remains in effect after liver transplantation, evidenced by the overall reduced alloresponses compared to transplants of other organs (2)(3)(4). Furthermore, liver appears to have an immunoprotective effect on simultaneously transplanted other organs from the same donor. This phenomenon stays active for a long time and is manifested through both the passive and active processes that decrease overall inflammation in the simultaneously transplanted organs (5)(6)(7)(8). ...
Liver-resident mesenchymal stem cells (L-MSCs) are superior inhibitors of alloreactive T cell responses compared to their counterparts from bone marrow (BM-MSCs) or adipose tissue (A-MSCs), suggesting a role in liver’s overall tolerogenic microenvironment. Whether L-MSCs also impact NK cell functions differently than other MSCs is not known. We generated and characterized L-MSCs, A-MSCs and BM-MSCs from human tissues. The mass spectrometry analysis demonstrated that L-MSC secretome is uniquely different than that of A-MSC/BM-MSC, with enriched protein sets involved in IFNγ responses and signaling. When co-cultured with primary human NK cells, L-MSCs but not other MSCs, decreased surface expression of activating receptors NKp44 and NKG2D. L-MSCs also decreased IFNγ secretion by IL-2-stimulated NK cells more effectively than other MSCs. Cytolytic function of NK cells were reduced significantly when co-cultured with L-MSCs, whereas A-MSCs or BM-MSCs did not have a major impact. Mechanistic studies showed that the L-MSC-mediated reduction in NK cell cytotoxicity is not through changes in secretion of the cytotoxic proteins Perforin, Granzyme A or B, but through increased production of HLA-C1 found in L-MSC secretome that inhibits NK cells by stimulating their inhibitory receptor KIRDL2/3. L-MSCs are more potent inhibitors of NK cell functions than A-MSC or BM-MSC. Combined with their T cell inhibitory features, these results suggest L-MSCs contribute to the tolerogenic liver microenvironment and liver-induced systemic tolerance often observed after liver transplantation.
... Moreover, antibody-mediated rejection (AMR) occurs less frequently in liver transplantation, [4] chronic rejection is observed in a fewer number of patients and the recipients generally need lower doses of IS drugs compared to the other types of solid organ transplantation [5]. Suggested mechanisms to explain the liver-induced tolerance include microchimerism effect [6], consistent presence of foreign antigens delivered from the gut [7], deletion of recipient T cells [8], active secretion of HLA-neutralizing alloantibodies [4], presence of tolerogenic mesenchymal stem cells [9], and deficient antigen presentation due to the lack of costimulatory molecules and expression of immunomodulatory ligands in hepatic stellate cells [10]. Accordingly, some liver transplant recipients display "operational"(well graft function without immunosuppression) [11], or "prope" tolerance (partial tolerance maintained by very low doses of IS) [12], while many do not require the standard immunosuppression [13]. ...
Background
Immune monitoring of transplanted patients may provide a reliable basis for the individualization of immunosuppressive therapy. In addition, it might be applied for realizing the early and non-invasive diagnosis of acute allograft rejection.
Methods
Percentages of TCD4 + IL-17+ (Th17) and TCD4 + CD25 + CD127dim/− (Treg) cells, as well as serum levels of interleukin (IL)-17 and transforming growth factor (TGF)-β1, were evaluated in 30 stable patients using flow cytometry and ELISA techniques before and six months after liver transplantation. Besides, the same cells and cytokines were quantified in 10 recipients with acute allograft rejection.
Results
Six months post-transplant, the percentage of Th17 and Treg cells in the peripheral blood of stable liver transplant recipients reduced significantly, but the Th17/Treg ratios were comparable to the pre-transplant period (1.24 vs. 1.56); however, Th17/Treg ratios in the rejection group was significantly higher than in the stable recipients (4.06 vs. 1.56, P-value = 0.001). Stable patients showed decreased amounts of serum IL-17 which was remarkably lower than in the rejection group (P-value = 0.01). Moreover, there was a significant correlation between the serum level of IL-17 and the percentage of Th17 cells (P-value <0.001). Th17 frequency was negatively associated with the liver allograft function. Notably, TGF-β1 levels differed neither between pre-and post-transplant samplings nor between stable and rejection groups.
Conclusion
Six months after liver transplantation, the mean Th17/Treg ratio in stable recipients remained comparable to the pre-transplant values; however, it was significantly elevated in patients with acute allograft rejection, suggesting the Th17/Treg ratio as a probable predictor of acute rejection.
... Operational tolerance that results in a stable long-term function without the need for immunosuppression remains difficult to achieve. Recent clinical studies demonstrate that induction of a stable mixed chimerism or inclusion of donor's liver in the combined transplantation with other parenchymal organs improve transplantation outcomes [3][4][5][6][7][8][9]. However, underlying immunological processes associated with tolerance remain unclear. ...
... Liver's TAPCs, supported by their autochthon environment, are likely to continue their function even in a MHC-mismatched host. Spontaneous operational tolerance of liver transplants is indeed more common than with other parenchymal organ transplants [9]. ...
The search for common mechanisms underlying the pathogenesis of chronic inflammatory conditions has crystalized the concept of continuous dual resetting of the immune repertoire (CDR) as a basic principle of the immune system function. Consequently, outlined was the first dynamic comprehensive picture of the immune system function. The goal of this study is to elaborate on regulation of immune responses and mechanisms of tolerance, particularly focusing on adaptive immunity. It is well established that the T/B cell repertoire is selected and maintained based on interactions with self. However, their activation also requires interaction with a self-specific major histocompatibility complex (MHC) “code,” i.e., the context of MHC molecules. Therefore, not only repertoire selection and maintenance but also the T/B cell activation and function are self-centered. Thus, adaptive effectors may be primarily focused on the state of self and maintenance of integrity of the self, and only to a certain degree on elimination of the foreign. Examples of such function are used immunologically that poorly understood MHC-disparate settings typical for transplantation and pregnancy. Transplantation represents an extreme setting of strong systemic compartment-level adaptive/MHC-restricted immune responses. Described are clinically identified conditions for operational tolerance of MHC-disparate tissues/living systems in allotransplantation, which are in line with the CDR-proposed self-centered regulatory role of T/B cells. In contrast, normal pregnancy is coexistence of semiallogeneic or entirely allogeneic mother and fetus, but without alloreactivity akin to transplantation settings. Presented data support the notion that maintenance of pregnancy is a process that relies predominantly on innate/MHC-independent immune mechanisms. By the inception of hemotrophic stage of pregnancy (second and third trimester), both mother and child are individual living systems, with established adaptive immune repertoires. Although mother-fetus interactions at that point become indirect systemic compartment-level communications, their interactions throughout gestation remain within the innate realm of molecular-level adaptations.
1. Introduction
The concept of continuous dual resetting of the immune repertoire (CDR) as a basic principle of the immune system function outlines a comprehensive, dynamic picture of the immune system function that is governed by the randomness of interactions and uncertainty of outcomes [1]. The original paper focuses on applying CDR to describe common mechanisms underlying the pathogenesis of chronic inflammatory conditions and autoimmune diseases, including processes associated with both pathologic and aging-related immunosenescence. It also defines the elusive immunological self and describes the dynamics of regulation of immune responses and tolerance [2]. This paper’s intention is to further develop the notion that adaptive effectors represent a high-level regulatory mechanism to maintain integrity of a living system. Discussed will be the role of major histocompatibility complex (MHC) in the proposed primary focus of adaptive immunity on the state of self. Prominent examples of regulation of immune responses and maintenance of states of tolerance/integrity of a living system(s) will be used allogeneic settings inherent to both, transplantation and pregnancy. First segment of this paper will tackle the coexistence of MHC-disparate tissues in transplantation and then proceed to analyze the physiologic setting that supports semiallogeneic or entirely allogeneic pregnancy.
This paper briefly outlines the segments of the CDR pertinent to discussed issues. However, broader familiarity with the CDR is advisable.
1.1. Getting Priorities Straight: Maintenance of Integrity Supersedes Elimination of the Foreign or Dangerous
The CDR puts immunity into a more general context of maintenance of organism’s integrity instead of perceiving immune processes as a battle against the foreign or dangerous. It outlines a rather pacifistic picture of the immune system function: continuous molecular-level resetting/adjustments in response to molecular-level changes/disturbances instead of antagonizing them. Disturbances that may trigger the immune repertoire resetting include (a) interactions with the environment and (b) intrinsic changes of self. There is no inherent animosity against intruders or unknowns. Although perceived as such, the drive to destroy or kill often used to describe immune reactions is not congruent with nature’s intrinsic mechanisms of adaptation. Instead, the main purpose of immune responses is about overcoming a disturbance (regardless of its nature) with minimum energy expenditure, and guiding innate responses (sometimes through actions of adaptive immunity) toward equilibrium/steady-states.
Such a seemingly subtle shift in understanding immunity has complex implications. This CDR-driven concept of integrity maintenance versus elimination/neutralization of everything sensed as a foreign is with an understanding that disturbances are not just the foreign. Disturbance can be also physiologic growth, hormonal effects, pregnancy, mechanical injury, etc. The system continues resetting toward more energy-efficient states, which are never the same as before. The change is continuous and a constant in living system’s existence, and there is no going back to previous states. In response to disturbances, the system takes thermodynamically optimal path to acquire appropriate steady-states. Those steady-states may not be always perceived as states of health but are the optimum for given parameters and under given circumstances.
2. Transplantation
Despite significant advances in transplantation approaches, conditioning procedures that deplete immune system of recipients, continuous immunosuppression required in many patients, and paucity of reliable markers to guide clinicians in decisions about caring for their patients make transplantation a difficult process with uncertain outcomes. Operational tolerance that results in a stable long-term function without the need for immunosuppression remains difficult to achieve. Recent clinical studies demonstrate that induction of a stable mixed chimerism or inclusion of donor’s liver in the combined transplantation with other parenchymal organs improve transplantation outcomes [3–9]. However, underlying immunological processes associated with tolerance remain unclear. The most limiting issue is the lack of a general understanding of immunity, which would provide more grounded rationale for various transplantation approaches.
2.1. Conventional Adaptive Immunity in Maintenance of Integrity: the Importance of Knowing Thy Self
The CDR describes regulation of adaptive responses through fluctuations in the phenotype profile of a T cell receptor- (TCR) diverse T cell population activated in a particular adaptive response, so that immune response eventually enters the phase of repair and resolution [1]. How does understanding of the T cell function as focused on the maintenance of system’s integrity makes a difference as compared to the perception of T cells as focused on a particular antigen and its elimination?
It is well established that T cell repertoire is selected based on interactions with self and therefore mirrors the self. This “self-obsession” continues as a requirement for homeostatic signaling from interactions with self (self-awareness), which is necessary in maintenance of T cell repertoire/specificities in the periphery [10]. Surprisingly, implementation of the CDR leads to a conclusion that not only T cell repertoire selection and its maintenance are self-centered, but the T cell function is self-centered as well: T cell repertoire, knowing/mirroring the self and responding only to MHC-restricted innate alerts, may primarily focus on the state of self (hence the MHC restriction of a self-based adaptive repertoire that is useless in a MHC-mismatched host). Here, it is important to keep in mind that the T cell repertoire selection in thymus proceeds through interactions between the MHC-bound self-antigens presented by thymic epithelial cells and the randomly assembled TCRs on newly formed T cells. The MHC is always a component of the molecular pattern that interacts with TCRs, i.e., TCRs recognize epitopes only in the MHC context. Therefore, MHC serves as a “code” that allows cognate interactions with T cells, but only with the code-matching antigen-presenting cells (APCs). The MHC code is unique to a particular living system, which implies that information exchanged through MHC-restricted communications is pertinent only to that particular living system and directed toward regulation of its integrity. Thus, such communication regulates innate immune responses in the context of self and toward maintenance of self’s integrity. More precisely, as APC-delivered antigen presentation does not discriminate self/altered self from the foreign, activation of T cell specificities in response to foreign epitopes is due to cross-reactivity of the T cells’ self-mirroring repertoire with the foreign, as well as with the APC-presented damaged self. Thus, T cell activity is determined by the self and proceeds in the context of self regardless whether elicited by a foreign or by the self-antigens. Innate mechanisms/effectors, guided and regulated by T/B cells, are actually doing the basic work—eliminating infectious agents, removing destructed tissue, etc. The self-regulating loop closes when innate signals, modulated by T/B cells’ regulatory capacity (determined by their repertoire’s granularity), eventually change the quality/intensity of integrated signaling toward T/B cells and terminate their engagement. So, it is the innate→adaptive→innate mutuality of signaling/interactions that eventually establish homeostasis (Figure 1).
... Data from the 35th International Society of Heart and Lung Transplantation report showed that patients who underwent multiorgan transplants had a lower 1-year incidence of acute rejection than patients who underwent a lung-only transplant or combined heart and lung transplants [1]. The tolerogenic mechanisms are not exactly known but may involve the presence of chimerism, the downregulation of effector T cells, the upregulation of regulatory T cells and the neutralization of DSA [20]. ...
Objectives:
A combined lung and liver transplant in patients with cystic fibrosis (CF) is an uncommon procedure. The goal of this study was to compare long-term outcomes between patients with CF who underwent either a combined lung-liver or a lung-only transplant.
Methods:
This is a retrospective single-centre study of patients with CF who underwent a lung transplant between January 2005 and May 2020. Since 2006, our preference for a combined lung-liver transplant was to transplant the liver first and then the lung. Outcomes were compared using the Kaplan-Meier analysis and the log-rank test. Median follow-up was 53 (23-97) months.
Results:
During the study period, among 357 patients with CF who underwent a lung transplant, 14 (4%) required a lung-liver transplant whereas 343 (96%) had a lung-only transplant. Lung cold ischaemic time was longer in the lung-liver transplant group, but no patient in this group showed primary graft dysfunction at 72 h after the transplant. Prevalence of anti-human leucocyte antigen donor-specific antibodies was 7.1% vs 13.7% in the lung-liver versus the lung-only transplant group (P = 0.42). At 5 years, lung graft survival (78% vs 69%) and freedom from chronic lung allograft dysfunction (79% vs 62%) did not differ between the lung-liver versus the lung-only groups (P = 0.45 and P = 0.55, respectively). Freedom from lung biopsy-confirmed rejection was significantly higher in patients undergoing a lung-liver transplant (91% vs 50%; P = 0.027).
Conclusions:
A lung-liver transplant did not impair lung graft function. The lower prevalence of donor-specific antibodies and the better freedom from lung biopsy-confirmed rejection suggest tolerogenic effects of the liver graft.
... Post-transplant, the liver's resistance to antibody-mediated rejection could be due to its dual blood supply from the high-pressure systemic and low-pressure portal circulation which meet at the fenestrated sinusoids and facilitate interaction between antigens, T cells, and other resident immune cells. Taner et al. hypothesized that this protects the liver allograft from rejection as the standard capillary microvasculature and single afferent blood supply in other organs get occluded easily by complement-activated immune complex resulting in ischemia [24,25]. Secondly, innate immune cells in the liver express undetectable levels of major histocompatibility complex (MHC) antigens and costimulatory molecules which make it difficult for them to induce an immune response [26]. ...
... Secondly, innate immune cells in the liver express undetectable levels of major histocompatibility complex (MHC) antigens and costimulatory molecules which make it difficult for them to induce an immune response [26]. Unlike other organs, if T cell-mediated rejection episodes occur in compliant liver recipients, they occur more frequently within six weeks post-transplant and do not appear to have a long-term effect on the survival of the allograft [24,25] Thirdly, there is a large population of migratory immune cells in liver allografts compared to other solid organs that can further explain its privileged status. In fact, the liver can be described as a lymphoid organ [27]. ...
Cell therapies using immune cells or non-parenchymal cells of the liver have emerged as potential treatments to facilitate immunosuppression withdrawal and to induce operational tolerance in liver transplant (LT) recipients. Recent pre-clinical and clinical trials of cellular therapies including regulatory T cells, regulatory dendritic cells, and mesenchymal cells have shown promising results. Here we briefly summarize current concepts of cellular therapy for induction of operational tolerance in LT recipients.
