scholarly journals Liver Transplant Tolerance and Its Application to the Clinic: Can We Exploit the High Dose Effect?

2013 ◽  
Vol 2013 ◽  
pp. 1-9 ◽  
Author(s):  
Eithne C. Cunningham ◽  
Alexandra F. Sharland ◽  
G. Alex Bishop

The tolerogenic properties of the liver have long been recognised, especially in regard to transplantation. Spontaneous acceptance of liver grafts occurs in a number of experimental models and also in a proportion of clinical transplant recipients. Liver graft acceptance results from donor antigen-specific tolerance, demonstrated by the extension of tolerance to other grafts of donor origin. A number of factors have been proposed to be involved in liver transplant tolerance induction, including the release of soluble major histocompatibility (MHC) molecules from the liver, its complement of immunosuppressive donor leucocytes, and the ability of hepatocytes to directly interact with and destroy antigen-specific T cells. The large tissue mass of the liver has also been suggested to act as a cytokine sink, with the potential to exhaust the immune response. In this review, we outline the growing body of evidence, from experimental models and clinical transplantation, which supports a role for large tissue mass and high antigen dose in the induction of tolerance. We also discuss a novel gene therapy approach to exploit this dose effect and induce antigen-specific tolerance robust enough to overcome a primed T cell memory response.

Cells ◽  
2019 ◽  
Vol 8 (7) ◽  
pp. 665 ◽  
Author(s):  
Markus Düchler ◽  
Liliana Czernek ◽  
Lukasz Peczek ◽  
Wojciech Cypryk ◽  
Malgorzata Sztiller-Sikorska ◽  
...  

Background: Cancer-induced immunosuppression is antigen-specific rather than systemic and the mechanisms for the antigen specificity are incompletely understood. Here we explore the option that tumor-associated antigens (TAAs) may be transferred to antigen-presenting cells (APCs), together with immunosuppressive molecules, through cancer-derived small extracellular vesicles (sEVs), such as exosomes. Stimulation of a suppressive phenotype in the very same APCs that take up TAAs may yield antigen-specific tolerance. Methods: sEVs isolated from patient-derived or well-established melanoma cell lines were used to demonstrate the transfer of major histocompatibility complex (MHC) molecules to the surface of APCs. The immunosuppressive influence of sEVs was assessed by flow cytometry analysis of activation markers, cytokine expression, and mixed lymphocyte reactions. Results: MHC class I molecules were transferred from melanoma cells to the cell surface of APCs by sEVs. Concomitantly, CD86 and CD40 co-stimulatory molecules were down-regulated and IL-6 production was strongly induced. TGF-β transported by sEVs contributed to the promotion of a suppressive phenotype of APCs. Conclusion: The presented results indicate the existence of a hitherto undescribed mechanism that offers an explanation for antigen-specific tolerance induction mediated by cancer-derived sEVs.


2009 ◽  
Vol 29 (02) ◽  
pp. 155-157 ◽  
Author(s):  
H. Hauch ◽  
J. Rischewski ◽  
U. Kordes ◽  
J. Schneppenheim ◽  
R. Schneppenheim ◽  
...  

SummaryInhibitor development is a rare but serious event in hemophilia B patients. Management is hampered by the frequent occurrence of allergic reactions to factor IX, low success rates of current inhibitor elimination protocols and the risk of development of nephrotic syndrome. Single cases of immune tolerance induction (ITI) including immunosuppressive agents like mycophenolat mofetil (MMF) or rituximab have been reported. We present a case of successful inhibitor elimination with a combined immune-modulating therapy and high-dose factor IX (FIX). This boy had developed a FIX inhibitor at the age of 5 years and had a history of allergic reactions to FIX and to FEIBA→. Under on-demand treatment with recombinant activated FVII the inhibitor became undetectable but the boy suffered from multiple joint and muscle bleeds. At the age of 11.5 years ITI was attempted with a combination of rituximab, MMF, dexamethasone, intravenous immunoglobulins and high-dose FIX. The inhibitor did not reappear and FIX half-life normalized. No allergic reaction, no signs of nephrotic syndrome and no serious infections were observed.


2021 ◽  
Vol 8 ◽  
pp. 205435812110297
Author(s):  
Jean Maxime Côté ◽  
Isabelle Ethier ◽  
Héloïse Cardinal ◽  
Marie-Noëlle Pépin

Background: Chronic kidney disease following liver transplantation is a major long-term complication. Most liver transplant recipients with kidney failure will be treated with dialysis instead of kidney transplantation due to noneligibility and shortage in organ availability. In this population, the role of peritoneal dialysis (PD) as a modality of kidney replacement therapy (KRT) remains unclear. Objective: To determine the feasibility regarding safety, technique survival, and dialysis efficiency of PD in liver transplant recipients requiring KRT for maintenance dialysis. Design: Systematic review. Setting: Interventional and observational studies reporting the use of PD after liver transplantation. Patients: Adult liver transplant recipients with kidney failure treated with maintenance KRT. Measurements: Extracted data included eligibility criteria, study design, demographics, and PD modality. The following outcomes of interest were extracted: rate of peritonitis and microorganisms involved, noninfectious peritoneal complications, technique survival, and kidney transplantation-censored technique survival. Non-PD complications included overall survival, liver graft dysfunction, and hospitalization rate. Methods: The following databases were searched until July 2020: MedLine/PubMed, EMBASE, CINAHL, and Cochrane Library. Two reviewers independently screening all titles and abstracts of all identified articles. Due to the limited sample size, observational designs and study heterogeneity expected, no meta-analysis was pre-planned. Descriptive statistics were used to report all results. Results: From the 5263 identified studies, 4 were included in the analysis as they reported at least 1 outcome of interest on a total of 21 liver transplant recipients, with an overall follow-up duration on PD of 19.0 (Interquartile range [IQR]: 9.5-29.5) months. Fifteen episodes of peritonitis occurred in a total cumulative PD follow-up of 514 patient-months, representing an incidence rate of 0.35 per year. These episodes did not result in PD technique failure, mortality, or impairment of liver graft function. Limitations: Limitations include the paucity of studies in the field and the small number of patients included in each report, a risk of publication bias and the impossibility to directly compare hemodialysis to PD in this population. These results, therefore, must be interpreted with caution. Conclusions: Based on limited data reporting the feasibility of PD in liver transplant recipients with kidney failure, no signal was associated with an increased risk of infectious complications. Long-term studies evaluating this modality need to be performed. Registration (PROSPERO): CRD42020218374.


1991 ◽  
Vol 636 (1 Antigen and C) ◽  
pp. 79-94 ◽  
Author(s):  
STEPHEN D. MILLER ◽  
L. J. TAN ◽  
MARY K. KENNEDY ◽  
MAURO C. CANTO

2003 ◽  
Vol 197 (12) ◽  
pp. 1635-1644 ◽  
Author(s):  
Elmar Jaeckel ◽  
Ludger Klein ◽  
Natalia Martin-Orozco ◽  
Harald von Boehmer

Experiments in nonobese diabetic (NOD) mice that lacked expression of glutamic acid decarboxylase (GAD) in β cells have suggested that GAD represents an autoantigen essential for initiating and maintaining the diabetogenic immune response. Several attempts of inducing GAD-specific recessive tolerance to support this hypothesis have failed. Here we report on successful tolerance induction by expressing a modified form of GAD under control of the invariant chain promoter resulting in efficient epitope display. In spite of specific tolerance insulitis and diabetes occurred with normal kinetics indicating that GAD is not an essential autoantigen in the pathogenesis of diabetes.


2000 ◽  
Vol 118 (4) ◽  
pp. A1426
Author(s):  
Michael Bismuth ◽  
Georges-Philippe Pageaux ◽  
Christophe Duvoux ◽  
Val\'erie Costes ◽  
Elie-Serge Zafrani ◽  
...  

1998 ◽  
Vol 79 (02) ◽  
pp. 338-341 ◽  
Author(s):  
C. Navarro ◽  
J. P. Cambus ◽  
H. Caplain ◽  
P. d’Azemar ◽  
J. Necciari ◽  
...  

SummaryVenous thromboembolism may be efficiently treated by once-a-day (o.d.) administration of a high dose of low molecular weight heparin (LMWH) instead of administration of the same total dose in two injections a day (b.i. d.). To reduce the volume of the subcutaneous (s.c.) injection, a more concentrated form of the drug is advisable. This study was designed to compare the bioavailability of 2 formulations of nadroparin containing 10,250 and 20,500 anti-Xa IU·ml-1 respectively. This was an open, randomized, cross-over study where 12 healthy volunteers (age 18-35) were enrolled. They received either 90 anti-Xa IU·kg-1 b.i. d. of the 10,250 IU preparation (treatment A), or 180 anti-Xa IU·kg-1 o.d. of the 20,500 IU preparation (treatment B) for 10 days. On day 1, the subjects were sampled between 0 and 12 h (treatment A) or between 0 and 24 h (treatment B). On day 10, they were sampled between 0 and 12 h and between 12 and 24 h (treatment A) or between 0 and 24 h (treatment B). Anti-Xa and anti-IIa activities were determined by specific chromogenic assays. The main result of the study was that the bioavailability of the anti-Xa activity of the 2 nadroparin formulations was equivalent, as shown by the comparison of the AUC0-12 h plus AUC12-24 h (treatment A) and the AUC0-24 h (treatment B), calculated on day 10. This study also allowed a number of interesting observations to be made. 1) Between day 1 and day 10, there was an accumulation of the anti-Xa activity for treatment A but not for treatment B (accumulation factors: 1.6 and 1.1 respectively); 2) On day 10, the AUC0-12 h were slightly but significantly lower than the AUC12-24 h suggesting a circadian effect for anti-Xa and anti-IIa activities; 3) the clearance of the anti-Xa activity was comparable at the 2-dose regimens, while that of the anti-IIa activity was lower in treatment B than in treatment A, indicating a significant dose effect for the pharmacodynamics of the longer heparin chains; 4) On average, the clearance of the anti-IIa activity was twice as high as that of the anti-Xa activity; 5) For treatment B, significant APTT prolongations were noticed at Tmax (prolongation factor: 1.7 ± 0.25), in relation with the anti-IIa activity (0.3 ± 0.1 IU·ml–1).


2012 ◽  
Vol 34 (2) ◽  
pp. 269-271 ◽  
Author(s):  
Alessio Provenzani ◽  
Monica Notarbartolo ◽  
Manuela Labbozzetta ◽  
Paola Poma ◽  
Adele D’Antoni ◽  
...  

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