Next level of immunosuppression: Drug/immune monitoring

Levitsky, Josh

doi:10.1002/lt.22385

Cited by 19 publications

(14 citation statements)

References 38 publications

(39 reference statements)

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“…It should be noted that one of the potential limitations of our study is that any in vitro assay may not mimic the in vivo environment in transplant patients, given that drug levels may vary substantially in vivo compared to our controlled cultures. However, we believe our in vitro studies [ 7 , 9 , 33 ], with clinically relevant drug combinations, set the stage to determine if EVL is as immunoregulatory in vivo and, as such, can facilitate more favorable management strategies in such patient populations.…”

Section: Discussionmentioning

confidence: 99%

Immunoregulatory Effects of Everolimus on In Vitro Alloimmune Responses

et al. 2016

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Everolimus (EVL) is a novel mTOR-inhibitor similar to sirolimus (SRL) that is used in organ transplant recipients, often in combination with tacrolimus (TAC) or mycophenolate (MPA). The current study aims to determine its effects on regulatory T cells. Increasing concentrations of EVL, MPA and TAC alone or in combination were added to MLRs of healthy volunteers. Lymphoproliferation by 3H-TdR incorporation and the percentage of newly generated CD4+CD127-CD25+FOXP3+ (total Treg) and CD4+CD127-CD25HighFOXP3+ (natural Treg) in CFSE labeled responder cells were assessed by flow cytometry. In comparison to medium controls, EVL and other agents dose-dependently inhibited 3H-TdR incorporation in HLA-2DR-matched and HLA-mismatched MLRs (n = 3–10). However, EVL significantly amplified newly generated total and natural Tregs in CFSE labeled responder cells (p<0.05) at all concentrations, while MPA and SRL did this only at sub-therapeutic concentrations and inhibited at therapeutic levels. In contrast, TAC inhibited newly generated Tregs at all concentrations. When tested in combination with TAC, EVL failed to reverse TAC inhibition of Treg generation. Combinations of EVL and low concentrations of MPA inhibited proliferation and amplified Treg generation in an additive manner when compared to medium controls or each drug tested alone (p<0.05). The relative tolerogenic effect from high to low was EVL > SRL> MPA > TAC. If the results from these in vitro studies are extrapolated to clinical transplantation, it would suggest EVL plus low concentrations of MPA may be the most tolerogenic combination.

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Section: Discussionmentioning

confidence: 99%

Immunoregulatory Effects of Everolimus on In Vitro Alloimmune Responses

et al. 2016

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“…As immunosuppressive therapy is an important risk factor of post-LT infection (27, 28), research should focus on controlling MDR-GNB infection through novel immunosuppressive agents (29). Data on drug/immune monitoring specific to LT are fairly limited (30); thus, immunosuppression remains a critical posttransplant risk-factor for infection in transplant recipients. Additional or higher doses of immunosuppressants increase the risk of invasive and potentially fatal infections.…”

Section: Concerning Immunosuppressive Therapymentioning

confidence: 99%

Prevalence and risk factor for MDR-GNB infection in liver transplantation

Zhong

Men²,

Li³

et al. 2013

Front Biosci

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Liver transplantation (LT) has emerged as a viable therapy for various end-stage liver diseases. Multi-drug resistant Gram-negative bacilli (MDR-GNB) have emerged as predominant pathogens. The prevalence of MDR-GNB infection has been increasing in LT recipients, especially in early post-LT stages. MDR-GNB infection has become a main cause of death following LT. Since key elements of MDR-GNB infection after LT mainly include the pre-LT severity of underlying disease, technical problems, acute rejection, and so on, appropriate measures, such as improvement of LT technology and management, restriction of antibiotic use and immunosuppressive therapy advancement, should be commenced to prevent and control the occurrence of MDR-GNB infection. A better understanding of the prevalence of and risk factors for MDR-GNB infection complications is needed to improve quality of life and survival rate after LT.

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“…However, the benefit of induction regimens in SLKT has been challenged recently by a retrospective 15-year analysis of SLKT data in UNOS database, which looked at the long-term outcomes of all adult combined transplant recipients who were maintained with TAC and MMF. 40 In this analysis, the study population was stratified in three groups according to a separate induction strategy (r-ATG, IL2RA, and no induction) and found that use of r-ATG was associated with increased all-cause mortality, and that no induction overall appeared beneficial. Unfortunately, there are no guidelines on specific immunosuppressive medication levels in the SLKT scenario, and most clinicians rely on expert opinion or derive their management from experience with OLT patients who suffer from chronic kidney dysfunction.…”

Section: Management Of Immunosuppression In Liver-kidney Allograft Rementioning

confidence: 99%

Immunosuppressive Drug Levels in Liver Transplant Recipients: Impact in Decision Making

Kourkoumpetis

Levitsky

2019

Semin Liver Dis

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To prevent rejection, liver transplant providers largely base their management decisions on their clinical impression and pharmacokinetics. Clinical impression relies on assessing graft function, liver enzymes, and biopsy. High immunosuppressive drug levels, although minimizing rejection, are related to significant side effects such as nephrotoxicity and metabolic syndrome, contributing to long-term morbidity and mortality. Similarly, levels that are lower than necessary can decrease the rate of side effects with a potential toll on rejection and graft survival. Herein, the authors present an update on immunosuppressive drug level monitoring and manipulation strategies according to different scenarios and time from transplant. They also provide a brief overview of next level immunosuppression monitoring strategies that aim to properly balance rejection rates with drug side effect profiles.

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Next level of immunosuppression: Drug/immune monitoring

Cited by 19 publications

References 38 publications

Immunoregulatory Effects of Everolimus on In Vitro Alloimmune Responses

Immunoregulatory Effects of Everolimus on In Vitro Alloimmune Responses

Prevalence and risk factor for MDR-GNB infection in liver transplantation

Immunosuppressive Drug Levels in Liver Transplant Recipients: Impact in Decision Making

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