Alloreactive T cells temporarily increased in peripheral blood of patients before liver allograft rejection.

T cells are key mediators of alloresponse during liver transplantation (LTx). However, the dynamics of donor-reactive T cell clones in peripheral blood during a clinical T-cell-mediated rejection (TCMR) episode remain unknown. Here, we collected serial peripheral blood mononuclear cells (PBMCs) samples spanning from pre-LTx to one-year post-LTx and available biopsies during the TCMR episodes from 26 rejecting patients, and serial PBMC samples were collected from 96 non-rejectors. Immunophenotypic and repertoire analyses were integrated on T cells from rejectors and longitudinally compared them to non-rejected patients. Donor-reactive T cell clone was identified and tracked by cross-matching with mappable donor-reactive TCR repertoire of each donor-recipient pair in 9 rejectors and 5 non-rejectors. Before transplantation, the naive T cell percentage and TCR repertoire diversity of rejectors was comparable to healthy control, it was reduced in non-rejectors. After transplantation, the naïve T cell percentages decreased and TCR repertoires were skewed in rejectors, the phenomenon was not observed in non-rejectors. Alloreactive clones increased in proportion in peripheral blood of rejectors before TCMR for weeks. The increase was accompanied by the naïve T cell decline and memory T cell increase and acquired an activated phenotype. Intragraft alloreactive clone tracking in pre- and post-LTx PBMC samples revealed that the pre-transplant naïve T cells were significant contributors to the donor-reactive clones, and they temporarily increased in proportion and subsequently reduced in blood at the beginning of TCMR. Together, our findings offer an insight into the dynamic and origin of alloreactive T cells in clinical LTx TCMR cases, and may facilitate disease prediction and management.

Immunosuppressive enzyme-responsive nanoparticles for enhanced accumulation in liver allograft to overcome acute rejection.

Acute rejection is a life-threatening complication after liver transplantation. Immunosuppressants such as tacrolimus are used to inhibit acute rejection of liver grafts in clinic. However, inefficient intragraft accumulation may reduce the therapeutic outcomes of tacrolimus. Here, an enzyme-responsive nanoparticle is developed to selectively enhance the accumulation of tacrolimus in liver allograft through enzyme-induced aggregation to refine immunotherapeutic efficacy of tacrolimus. The nanoparticles are composed of amphiphilic tacrolimus prodrugs synthesized by covalently conjugating tacrolimus and matrix metalloproteinase 9 (MMP9)-cleavable peptide-containing methoxy poly (ethylene glycol) to poly (l-glutamic acid). Upon exposure to MMP9, which is overexpressed in rejected liver allografts, the nanoparticles undergo a morphological transition from spherical micellar nanoparticles to microscale aggregate-like scaffolds. Intravenous administration of MMP9-responsive nanoparticles into a rat model of acute liver graft rejection results in enhanced nanoparticle accumulation in allograft as compared to nonresponsive nanoparticles. Consequently, the MMP9-responsive nanoparticles significantly inhibit intragraft inflammatory cell infiltration and proliferation, maintain intragraft immunosuppressive environment, alleviate graft damage, improve liver allograft function, abate weight loss and prolong recipient survival. This work proves that morphology-switchable enzyme-responsive nanoparticles represent an innovative strategy for selectively enhancing intragraft accumulation of immunosuppressive agents to improve treatment of liver allograft rejection.

Immature and activated phenotype of blood NK cells is associated with acute rejection in adult liver transplant.

Natural killer (NK) cells contribute to liver transplant (LTx) rejection. However, the blood-circulating NK-cell dynamics of patients who experience acute rejection (AR) are unclear. Herein, we longitudinally profiled the total NK cells and their subsets, along with the expression of activating and inhibitory receptors in sequential peripheral blood mononuclear cell samples, spanning from before LTx to the first year after LTx of 32 patients with AR and 30 patients under a steady immune status. Before transplantation, patients with AR (rejectors) contained a significantly higher proportion of the immature CD56 bright CD16 - subset and a lower cytolytic CD56 dim CD16 + in the total blood-circulating NK cells than patients with steady immunity. Both subsets contained a high NKp30-positive population, and CD56 dim CD16 + additionally exhibited a high NKp46-positive ratio. The NKp30-positive ratio in CD56 dim CD16 + subset showed the most prominent AR predictive ability before LTx and was an independent risk factor of LTx AR. After transplantation, the blood-circulating NK cells in rejectors maintained a higher CD56 bright CD16 - and lower CD56 dim CD16 + composition than the controls throughout the first year after LTx. Moreover, both subsets maintained a high NKp30-positive ratio, and CD56 dim CD16 + retained a high NKp46-positive ratio. The blood-circulating NK cell subset composition was consistent during AR, while the expressions of NKp30 and NKp46 were augmented. Collectively, a more immature CD56 bright CD16 - subset composition and an activated phenotype of high NKp30 expression were the general properties of blood-circulating NK cells in rejected LTx recipients, and the NKp30-positive ratio in CD56 dim CD16 + NK subset before LTx possessed AR predictive potential.

The role of natural killer T cells in liver transplantation.

Natural killer T cells (NKTs) are innate-like lymphocytes that are abundant in the liver and participate in liver immunity. NKT cells express both NK cell and T cell markers, modulate innate and adaptive immune responses. Type I and Type II NKT cells are classified according to the TCR usage, while they recognize lipid antigen in a non-classical major histocompatibility (MHC) molecule CD1d-restricted manner. Once activated, NKT cells can quickly produce cytokines and chemokines to negatively or positively regulate the immune responses, depending on the different NKT subsets. In liver transplantation (LTx), the immune reactions in a series of processes determine the recipients' long-term survival, including ischemia-reperfusion injury, alloresponse, and post-transplant infection. This review provides insight into the research on NKT cells subpopulations in LTx immunity during different processes, and discusses the shortcomings of the current research on NKT cells. Additionally, the CD56-expressing T cells are recognized as a NK-like T cell population, they were also discussed during these processes.

Expansion kinetics of graft-versus-host T cell clones in patients with post-liver transplant graft-versus-host disease.

Graft-versus-host disease (GVHD) following liver transplantation is induced by the graft-versus-host (GVH) T cell that is transferred with the liver graft, but the dynamics remain poorly investigated in clinical liver transplantation GVHD. Here, we report that in two liver transplantation recipients who developed GVHD, both of whom showed donor T cell macrochimerism in the blood before clinical GVHD onset. Longitudinal tracking of GVH T cell clones in one of these recipients revealed that GVH T cell clonal expansion occurred before disease onset, and the dominant GVH T cells might also derive from non-hepatic tissue-resident memory T cells in the liver-graft. Additionally, a comparison of the inflammatory cytokine levels and TCR repertoire diversities in recipient pre-liver transplantation blood between 4 patients with GVHD and 12 non-GVHD patients showed that the levels of TNF-α and IL-8, and the overall TCR repertoire skewness in pre-transplant recipient blood samples may serve as potential independent risk factors for the disease.

Sirolimus-Induced Delayed Severe Thrombocytopenia After Liver Transplantation: A Case Report.

OBJECTIVE: Thrombocytopenia is a common condition in patients undergoing liver transplantation (LT). Thrombocytopenia is prevalent in early postoperative phase, and it gradually improves after several weeks. Delayed severe thrombocytopenia occurring after the initial recovery of platelets is rare. We report a case of a patient with delayed severe thrombocytopenia 59 weeks after LT. CASE PRESENTATION: Our patient was a 61-year-old man who presented to our institution 59 weeks after undergoing LT. He presented for removal of a bile duct stent that was inserted 3 months prior. Tacrolimus replaced sirolimus for immunosuppression during the seventh week after transplantation due to sirolimus-induced nephrotoxicity. On admission, the patient's vital signs were normal and his physical examination was unremarkable. Laboratory parameters demonstrated that the platelet (PLT) level was significantly decreased to 18 × 109/L. PLTs reached a nadir of 3 × 109/L even after utilization of interleukin-11, thrombopoietin, and low-dose prednisone. Although rare, sirolimus toxicity was suspected. Therefore, sirolimus was gradually replaced by cyclosporin A in combination with low-dose prednisone. Subsequently, a normal PLT level was gradually recovered. This study was approved by the ethical committee of the First Hospital of Jilin University and was performed in accordance with the ethical standards of the Helsinki Congress and Istanbul Declaration. CONCLUSIONS: Recurrent delayed severe thrombocytopenia is rare after LT. Sirolimus toxicity might be a reason for its occurrence if other possible factors are excluded. After diagnosis, sirolimus therapy should be discontinued and patients should be treated with an alternative immunosuppressive regimen.

Ethnicity and anticoagulation management of hospitalized patients with atrial fibrillation in northwest China.

The therapeutic management and health challenges caused by atrial fibrillation (AF) differ between different groups. The purpose of this study was to investigate the clinical features of patients hospitalized with AF and to explore the use of anticoagulation treatments in Han and Uygur patients in Xinjiang, northwest China. Data were collected from a retrospective descriptive study involving patients hospitalized at 13 hospitals in Xinjiang, China from Jul 1, 2014 to Jun 31, 2015. Anticoagulation management was measured according to guideline-recommended risk scores. A total of 4,181 patients with AF were included (mean age 69.5 ± 11.7 years, 41.4% females; 71.5% Han, 28.5% Uygur). The prevalence of AF in Uygur individuals may occur earlier than in Han individuals (mean age 64.9 vs 71.3, P < 0.001). Most of the hospitalized patients with AF had a high risk of stroke (CHA2DS2-VASc score ≥2; 80.6% Han vs 73.7% Uygur, P < 0.05); this risk was especially high in elderly patients. In AF patients, the application of anticoagulants according to the guidelines is far from expected, and the underutilization of anticoagulants exists in both ethnic groups.