Strategies for Liver Transplantation Tolerance

Cvetkovski, Filip; Hexham, J M; Berglund, Erik

doi:10.3390/ijms22052253

Cited by 17 publications

(9 citation statements)

References 144 publications

(166 reference statements)

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“…We could not evaluate the B-cell response in our model mainly because of the low engraftment of human B cells from PBMCs in NSG mice ( 38 ). Moreover, considering the crucial role of T cells, including Treg cells, in the immune tolerance and rejection of LT patients ( 28 , 39 ), our model is suitable for evaluating T-cell responses and predicting liver immunity without liver biopsy. Third, the immune response in this model may have been caused by various antigens including xenogeneic GVHD.…”

Section: Discussionmentioning

confidence: 99%

Patient-Derived Avatar Mouse Model to Predict the Liver Immune Homeostasis of Long-Term Stable Liver Transplant Patients

et al. 2022

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Although rejection or tolerance can occur in liver transplantation (LT) patients, there are no reliable non-invasive methods for predicting immune homeostasis. In this study, we developed a humanized mouse model to predict liver immune homeostasis in patients who underwent LT. The patient-derived avatar model was developed by injecting peripheral blood mononuclear cells from healthy controls (HCs) or LT patients with stable, rejection, or tolerance into NOD.Cg-PrkdcscidIL2rgtm1Wjl/SzJ (NSG) mice, followed by injection of human hepatic stellate cells and Carbone tetrachloride (CCl4). After 7 weeks, the patient’s T-cell engraftment and liver inflammation in the avatar model were evaluated and compared with the liver histology of LT patients. Changes in liver inflammation following treatment with tacrolimus and/or biguanide derivatives were also examined. The C-X-C Motif Chemokine Receptor 3 (CXCR3)-dependently engrafted patient T cells led to differences in liver inflammation in our model according to the status of LT patients. The livers of avatar models from rejection patients had severe inflammation with more T helper 17 cells and fewer regulatory T cells compared to those of models from tolerance and HCs showing only mild inflammation. Moreover, our model classified stable post-LT patients into severe and mild inflammation groups, which correlated well with liver immunity in these patients. Our models revealed alleviation of inflammation after combination treatment with tacrolimus and biguanide derivatives or monotherapy. Consequently, using our new patient-derived avatar model, we predicted liver immune homeostasis in patients with stable LT without biopsy. Moreover, our avatar model may be useful for preclinical analysis to evaluate treatment responses while reducing risks to patients.

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Section: Discussionmentioning

confidence: 99%

Patient-Derived Avatar Mouse Model to Predict the Liver Immune Homeostasis of Long-Term Stable Liver Transplant Patients

et al. 2022

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“…In Table 2 , potential therapies in clinical trials were summarized. Treatments including infusion of Tregs[ 83 - 85 ] and mesenchymal stromal cells (MSCs)[ 86 ], vaccines[ 87 - 89 ], and kinase inhibitors[ 90 ].…”

Section: Clinical Trialsmentioning

confidence: 99%

Regulatory T cells and their associated factors in hepatocellular carcinoma development and therapy

Zhang¹,

Liu²,

Yang³

2022

WJG

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Liver cancer is the third leading cause of cancer-related death worldwide with primary type hepatocellular carcinoma (HCC). Factors, including carcinogens, infection of hepatitis viruses, alcohol abuse, and non-alcoholic fatty liver disease (NAFLD), can induce HCC initiation and promote HCC progression. The prevalence of NAFLD accompanying the increased incidence of obesity and type 2 diabetes becomes the most increasing factor causing HCC worldwide. However, the benefit of current therapeutic options is still limited. Intrahepatic immunity plays critically important roles in HCC initiation, development, and progression. Regulatory T cells (Tregs) and their associated factors such as metabolites and secreting cytokines mediate the immune tolerance of the tumor microenvironment in HCC. Therefore, targeting Tregs and blocking their mediated factors may prevent HCC progression. This review summarizes the functions of Tregs in HCC-inducing factors including alcoholic and NAFLD, liver fibrosis, cirrhosis, and viral infections. Overall, a better understanding of the role of Tregs in the development and progression of HCC provides treatment strategies for liver cancer treatment.

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“…Immune regulation to terminate the anti‐antigen reaction is very complex and is orchestrated with various cells, including T‐reg, regulatory B‐cells (B‐reg), DC‐reg, and regulatory macrophages (M‐reg) 41 . Among them, T‐reg is well recognized as the main player, and most commonly used therapeutic cell; it has been shown to be reliably induced with antihuman CD80 and CD86 antibodies and to be successful in both DDLT and LDLT 42‐44 . The brief scheme of the immunosuppressive regulation by T‐reg 45‐47 is shown in Figure 1.…”

Section: Reported Series Of the Clinical Liver Transplant Tolerancementioning

confidence: 99%

“…41 Among them, T-reg is well recognized as the main player, and most commonly used therapeutic cell; it has been shown to be reliably induced with antihuman CD80 and CD86 antibodies and to be successful in both DDLT and LDLT. [42][43][44] The brief scheme of the immunosuppressive regulation by T-reg [45][46][47] is shown in Figure 1. Several clinical trials have been ongoing as phase I or II studies in both western and eastern countries (Table 2).…”

Section: Cell Therapy Followed By Elective Weaning Of Ismentioning

confidence: 99%

Clinical liver transplant tolerance: Recent topics

Takatsuki

Eguchi

2021

J Hepato Biliary Pancreat

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Background Immunosuppression is essential after organ transplantation to prevent severe graft injury due to rejection, but in long‐term, transplanted organs are generally accepted with minimal dose of immunosuppression, and adverse effects of it such as renal dysfunction, diabetes and development of malignancies might become to exceed over the benefits in majority of the cases. Accordingly, to achieve the immunologic tolerance has been the ultimate goal in organ transplantation, and the liver has been well recognized as the tolerogenic organ compared to other organs. Methods We referred the reported studies showing the actual protocol to achieve the immunologic tolerance after clinical liver transplantation. Results Actually, two main procedures as “elective weaning of immunosuppression” and/or “cell therapy” using various immune‐related cells have been introduced to induce the immunologic tolerance in clinical liver transplantation. The cell therapy, especially using regulatory T‐cell has been reported to achieve definitive immunologic tolerance in living donor liver transplantation. Conclusion Although it is still developing, the induction of immunologic tolerance in clinical liver transplantation is realistic. Herein, the current topics of immunologic tolerance in liver transplantation is described.

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Strategies for Liver Transplantation Tolerance

Cited by 17 publications

References 144 publications

Patient-Derived Avatar Mouse Model to Predict the Liver Immune Homeostasis of Long-Term Stable Liver Transplant Patients

Patient-Derived Avatar Mouse Model to Predict the Liver Immune Homeostasis of Long-Term Stable Liver Transplant Patients

Regulatory T cells and their associated factors in hepatocellular carcinoma development and therapy

Clinical liver transplant tolerance: Recent topics

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