Immune monitoring of immunosuppression withdrawal of liver transplant recipients

Garza, Rocío García de la; Sarobe, Pablo; Merino, Juana; Lasarte, Juan José; D’Avola, Delia; Belsue, Virginia; Delgado, José A.; Silva, Leyre; Iñarrairaegui, Mercedes; Sangro, Bruno; Sola, Iosu; Pardo, Fernando; Quiroga, Jorge; Herrero, J.I.

doi:10.1016/j.trim.2015.07.006

Cited by 20 publications

(16 citation statements)

References 35 publications

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“…The non-regulation, especially group 4, demonstrated decreased Treg/Th17 ratios as tapering progressed from 75 to 50% of the initial drug dose. These findings are consistent with those of Pons et al who reported that Treg cells increased in tolerant patients ( 23 ), but contrast with those of García et al who reported that Treg cells were not altered in tolerant patients ( 24 ). Our finding that the Treg/Th17 ratio decreased in the non-regulation group (groups 3 and 4) also could be explained by the previous report suggesting that Th17 cells are a critical marker of acute rejection after LT ( 25 ).…”

Section: Discussionsupporting

confidence: 92%

Serial Monitoring of Immune Markers Being Represented Regulatory T Cell/T Helper 17 Cell Ratio: Indicating Tolerance for Tapering Immunosuppression after Liver Transplantation

Jhun¹,

Lee

et al. 2018

Front. Immunol.

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Recipients of liver transplantation (LT) require long-term immunosuppressive drug treatment, but lifelong immunosuppressive treatment has severe side effects. It is known that some LT recipients develop immune tolerance, and although the development of such operational tolerance should allow a decrease in the burden of immunosuppressive drug treatment, the factors that indicate operational tolerance are not clear. This study aimed to monitor immunological markers over time in LT recipients to identify those markers indicating the development of operational tolerance. We performed a prospective pilot study measuring immune markers, including the ratio of regulatory T (Treg) and T helper (Th) 17 cells in peripheral blood in the 14 most immunologically stable patients among 70 clinically stable LT recipients. The doses of immunosuppressive drugs given to these 14 LT recipients were tapered over time and they were monitored for immunological markers related to the development of immune tolerance. As the doses of immunosuppressive drugs were reduced, the Treg/Th17, Th1/Th17, and CD8/Th17 ratio in tolerant recipients was significantly increased compared with that of nontolerant recipients. These results suggest that monitoring of changes in the immune makers, including Treg/Th17 ratio during tapering of immunosuppression may allow prediction of the development of tolerance.

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Section: Discussionsupporting

confidence: 92%

Serial Monitoring of Immune Markers Being Represented Regulatory T Cell/T Helper 17 Cell Ratio: Indicating Tolerance for Tapering Immunosuppression after Liver Transplantation

Jhun¹,

Lee

et al. 2018

Front. Immunol.

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“…In contrast to recipient-derived cells, donor-derived NK cells do not lose the inhibitory KIR-MHC class I signal upon interaction with donor cells, instead being potentially activated by infiltrating recipient-derived leukocytes. In line with this hypothesis, expanded NK cell populations have been identified in liver transplant patients successfully weaned from immunosuppression ( 134 ). Donor-derived NK cells cause direct lysis of alloreactive recipient immune cells via NKG2D-MIC-A and TRAIL-TRAILR interactions leading to caspase-induced cell death ( 135 ).…”

Section: Tolerance Mechanisms In the Liver Allograftmentioning

confidence: 93%

The Immunological Basis of Liver Allograft Rejection

et al. 2020

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Liver allograft rejection remains a significant cause of morbidity and graft failure in liver transplant recipients. Rejection is caused by the recognition of non-self donor alloantigens by recipient T-cells. Antigen recognition results in proliferation and activation of T-cells in lymphoid tissue before migration to the allograft. Activated T-cells have a variety of effector mechanisms including direct T-cell mediated damage to bile ducts, endothelium and hepatocytes and indirect effects through cytokine production and recruitment of tissue-destructive inflammatory cells. These effects explain the histological appearances of typical acute T-cell mediated rejection. In addition, donor specific antibodies, most typically against HLA antigens, may give rise to antibody-mediated rejection causing damage to the allograft primarily through endothelial injury. However, as an immune-privileged site there are several mechanisms in the liver capable of overcoming rejection and promoting tolerance to the graft, particularly in the context of recruitment of regulatory T-cells and promotors of an immunosuppressive environment. Indeed, around 20% of transplant recipients can be successfully weaned from immunosuppression. Hence, the host immunological response to the liver allograft is best regarded as a balance between rejection-promoting and tolerance-promoting factors. Understanding this balance provides insight into potential mechanisms for novel anti-rejection therapies.

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“…Their research also revealed that NK cell tolerance is associated with perturbation of the IL-12/STAT4 signaling pathway, which might be a therapeutic target for clinical practice ( 63 ). There are clinical studies that showed that compared with the recipients who developed post-operation immune rejection, those with post-operation immune tolerance had significantly higher percentages and absolute counts of NK cells in their peripheral blood ( 64 ). Li et al ( 65 ) have found that there are 13 genes that are significantly overexpressed in the NK cells of immune tolerant recipients after liver transplantation.…”

Section: Natural Killer Cells (Nk Cells) In Tolerancementioning

confidence: 99%

Innate Immune Cells in Immune Tolerance After Liver Transplantation

Huang

Zhou

et al. 2018

Front. Immunol.

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Currently, liver transplantation is the most effective treatment for end-stage liver disease. Immunosuppressive agents are required to be taken after the operations, which have significantly reduced rejection rates and improved the short-term (<1 year) survival rates. However, post-transplant complications related to the immunosuppressive therapy have led to the development of new protocols aimed at protecting renal function and preventing de novo cancer and dysmetabolic syndrome. Donor specific immune tolerance, which means the mature immune systems of recipients will not attack the grafts under the conditions without any immunosuppression therapies, is considered the optimal state after liver transplantation. There have been studies that have shown that some patients can reach this immune tolerance state after liver transplantation. The intrahepatic immune system is quite different from that in other solid organs, especially the innate immune system. It contains a variety of liver specific cells, such as liver-derived dendritic cells, Kupffer cells, liver sinusoidal endothelial cells, liver-derived natural killer (NK) cells, natural killer T (NKT) cells, and so on. Depending on their specific structures and functions, these intrahepatic innate immune cells play important roles in the development of intrahepatic immune tolerance. In this article, in order to have a deeper understanding of the tolerogenic functions of liver, we summarized the molecular mechanisms of immune tolerance induced by intrahepatic innate immune cells after liver transplantation.

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Immune monitoring of immunosuppression withdrawal of liver transplant recipients

Cited by 20 publications

References 35 publications

Serial Monitoring of Immune Markers Being Represented Regulatory T Cell/T Helper 17 Cell Ratio: Indicating Tolerance for Tapering Immunosuppression after Liver Transplantation

Serial Monitoring of Immune Markers Being Represented Regulatory T Cell/T Helper 17 Cell Ratio: Indicating Tolerance for Tapering Immunosuppression after Liver Transplantation

The Immunological Basis of Liver Allograft Rejection

Innate Immune Cells in Immune Tolerance After Liver Transplantation

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