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The Effect of Immunosuppressive Drugs on MDSCs in Transplantation.

ABSTRACT: Myeloid-derived suppressor cells (MDSCs) are a group of innate immune cells that regulates both innate and adaptive immune responses. In recent years, MDSCs were shown to play an important negative regulatory role in transplant immunology even upstream of regulatory T cells. In certain cases, MDSCs are closely involved in transplantation immune tolerance induction and maintenance. It is known that some immunosuppressant drugs negatively regulate MDSCs but others have positive effects on MDSCs in different transplant cases. We herein summarized our recent insights into the regulatory roles of MDSCs in transplantation specially focusing on the effects of immunosuppressive drugs on MDSCs and their mechanisms of action. Studies on the effects of immunosuppressive drugs on MDSCs will significantly expand our understanding of immunosuppressive drugs on immune regulatory cells in transplantation and offer new insights into transplant tolerance. We hope to emphasize our concern for the negative effects of immunosuppressive agents on MDSCs, which may potentially attenuate the immune tolerance induction in transplanted recipients.

SUBMITTER: Yang F

PROVIDER: S-EPMC6051033 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The Effect of Immunosuppressive Drugs on MDSCs in Transplantation.

Yang Fan F Li Yang Y Zhang Qian Q Tan Liang L Peng Longkai L Zhao Yong Y

Journal of immunology research 20180703

Myeloid-derived suppressor cells (MDSCs) are a group of innate immune cells that regulates both innate and adaptive immune responses. In recent years, MDSCs were shown to play an important negative regulatory role in transplant immunology even upstream of regulatory T cells. In certain cases, MDSCs are closely involved in transplantation immune tolerance induction and maintenance. It is known that some immunosuppressant drugs negatively regulate MDSCs but others have positive effects on MDSCs in ...[more]

PMID: 30057917

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Project description:BACKGROUND:Concerns exist over the extrapolation of bioavailability studies of generic immunosuppressive drugs in healthy volunteers, regarding their efficacy and safety in kidney transplant recipients. We conducted a meta-analysis of trials examining the bioavailability of generic (test) immunosuppressive drugs relative to their brand (reference) counterparts in healthy volunteers, based on the US Food and Drug Administration requirements for approval of generics, and their efficacy and safety in kidney transplant recipients. METHODS:Eligible studies were identified in PubMed, Cochrane Central Register of Controlled Trials, Scopus, ClinicalTrials.gov, and conference abstracts. RESULTS:Twenty crossover trials of healthy volunteers (n = 641) and 6 parallel-arm randomized controlled trials of kidney transplant recipients (n = 594) were identified. The 90% CI of the pooled test-to-reference drug ratio for maximum or peak plasma concentration (Cmax) and area under the plasma concentration time-curve from time 0 to time of last determinable concentration (AUC(0-t)) fell within the required range (0.80-1.25) for cyclosporine (Cmax 0.91; 90% CI 0.86-0.95; and AUC(0-t) 0.97; 90% CI 0.94-1.00), tacrolimus (Cmax 1.17; 90% CI 1.09-1.24; and AUC(0-t) 1.00; 90% CI 0.97-1.03) and mycophenolate mofetil (Cmax 0.98; 90% CI 0.96-1.01; and AUC(0-t) 1.00; 90% CI 0.99-1.01). In subgroup analyses, some generic cyclosporine formulations did not meet criteria for bioequivalence. No significant differences were observed in the time to maximum plasma concentration and terminal plasma half-life between generic and brand drugs. In parallel-arm trials, generic cyclosporine was non-inferior to brand counterpart in terms of acute allograft rejection, infections, and death. CONCLUSIONS:Not all generic immunosuppressive drugs have similar relative bioavailability to their brand name counterparts. Evidence on their efficacy and safety is inconclusive. Tighter regulatory requirement for approval of generic drugs with narrow therapeutic index is needed.

Project description:BackgroundImmunosuppressive drugs have to be taken through the whole duration of kidney transplant survival to avoid rejection. Low adherence can increase the risk of allograft rejection. The objective was to evaluate the effectiveness of adherence-enhancing interventions (AEI) in kidney transplantation recipients taking immunosuppressive drugs.MethodsA search was performed in Medline, Embase, CINAHL, and PsycINFO. The search was performed in May 2016. We included comparative studies on AEI for kidney transplant recipients taking immunosuppressive drugs. The primary outcome was medication adherence. All identified articles were screened according to the predefined inclusion criteria. The risk of bias was assessed with the Cochrane risk of bias tool. Study selection and risk of bias assessment were performed by two reviewers independently. Data were extracted in standardized tables. Data extraction was verified by a second reviewer. All discrepancies were resolved through discussion. Data were synthesized in a structured narrative way. There is no registered or published protocol for this systematic review.ResultsWe identified 12 studies. The number of participants ranged from 24 to 1830. Nine studies included adults, two children, and one adults and children. Risk of bias was high. The main reasons for high risk of bias were inadequate allocation sequence (confounding) and that studies were not blinded. Eleven studies evaluated AEI consisting of educational and/or behavioral components. All these studies showed an effect direction in favor of the intervention. Intervention effect was only moderate. Most adherence measures in studies on educational and behavioral interventions showed statistically significant differences. Studies that combined educational and behavioral intervention components showed larger effects. All studies that were statistically significant were multimodal. Studies that included an individualized component and more intensive interventions showed larger effects. One study evaluated a reminder system. Effect size was not reported. This study showed no statistical significant difference (p > 0.05).ConclusionEducational and behavioral AEI can increase adherence. In particular, multimodal and individualized interventions seem promising. However, because of the small effect, the high risk of bias, and the invalidity of adherence measures, the actual benefit of adherence interventions for an unselected patient population (i.e., including also adherent patients) seems limited. No conclusion is possible for interventions combining adherence-enhancing components that address intentional (behavioral) as well as unintentional adherence (reminder).

Project description:BackgroundCoronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). It is currently unknown whether immunosuppressive drugs are advantageous or detrimental in patients with COVID-19. Immunosuppressive drugs could be harmful in the initial phase of COVID-19. In this phase, the host immune response is necessary to inhibit viral replication. However, immunosuppressive drugs might have a beneficial effect in the later, more severe phase of COVID-19. In this phase, an overshoot of the host immune response (the "cytokine storm") can cause ARDS, multiorgan failure and mortality.AimTo summarize the available evidence on the effect of immunosuppressive drugs on infection with SARS-CoV-2. The effects of immunosuppressive drugs on similar pandemic coronaviruses may resemble the effects on SARS-CoV-2. Thus, we also included studies on the severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV).MethodsThe study protocol was registered in PROSPERO (registration number CRD42020181137). We included randomized controlled trials (RCTs), cohort studies with a control group and case-control studies concerning humans ≥ 18 years old. We also included in-vitro studies and animal studies with a control group.Results and conclusionSixty-nine studies were included. Interestingly, MPA inhibits SARS-CoV-2 replication in-vitro. Clinical studies are needed to confirm the inhibitory effect of MPA on SARS-CoV-2 replication in-vivo. There are indications that corticosteroids and IL-6 inhibitors, like tocilizumab, can reduce mortality and prevent mechanical ventilation in patients with COVID-19. However, observational studies have contradictory results and the risk of bias is high. Thus, these results have to be confirmed in high-quality clinical trials before these drugs can be implemented as standard care. Based on the positive results of CNIs, mTOR inhibitors and thiopurine analogues in in-vitro studies with SARS-CoV and MERS-CoV, it would be interesting to investigate their effects on SARS-CoV-2 replication.

Dataset Information

The Effect of Immunosuppressive Drugs on MDSCs in Transplantation.

Publications

The Effect of Immunosuppressive Drugs on MDSCs in Transplantation.

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