Abstract:
:Mycophenolate mofetil (MMF) a potent immunosuppressive agent, has recently been approved for clinical use (CellCept) in renal transplant patients in combination with cyclosporine (CsA). With the expanded use of tacrolimus (Prograf) as well in renal transplant patients, there is a lack of pharmacokinetic studies clarifying drug interactions between the three agents. A pharmacokinetic study was performed on 18 stable renal transplant patients receiving MMF and tacrolimus together, and four control groups, one receiving tacrolimus alone, two receiving CsA, in combination with MMF (1.0 or 1.5 g bid), and one receiving CsA microemulsion (Neoral). Area-under-the-curve values were calculated for each drug to assess if there was a reciprocal effect on the respective bioavailability of each. In vitro, the immunosuppressive effect of trough level plasma from each patient group was studied using mixed lymphocyte culture (MLC), as well as MLC reactions spiked with various combinations of each drug. There was a minimal effect of MMF on tacrolimus pharmacokinetics. However, patients receiving tacrolimus and MMF displayed significantly higher levels (Cmin and area under the curve) of mycophenolic acid (MPA) than those receiving CsA (Sandimmune or Neoral) and the same dose of MMF (50.2 +/- 16.5 vs 32.1 +/- 16.7 micrograms h/ml AUC, p < 0.02). Equivalent MPA levels could be attained in patients receiving CsA if the MMF dose was increased by 50% (1.5 g bid). There were also significantly lower levels of the glucuronide metabolite of MPA (MPAG) (755 +/- 280 vs 1230 +/- 250 micrograms h/ml AUC, p = 0.02), suggesting a specific inhibition (either direct or indirect) of the conversion of MPA to MPAG in tacrolimus patients, as opposed to those receiving CsA. For each drug combination, there was a positive correlation between the plasma immunosuppressive effect seen in MLC assays and the MMF dose. In addition, trough plasma from patients receiving tacrolimus and MMF was significantly more MLC inhibitory than from those receiving CsA or CsA microemulsion and equivalent-dose MMF. Culture media containing MPA and tacrolimus equal to clinical therapeutic trough concentrations (10 ng/ml) were significantly more MLC inhibitory than CsA at equivalent clinical therapeutic trough concentrations (200 ng/ml) with equivalent MPA levels. These studies in renal transplant patients suggest that tacrolimus in combination with MMF may result in a greater degree of immunosuppression than may be anticipated.
journal_name
Transpl Immunoljournal_title
Transplant immunologyauthors
Zucker K,Rosen A,Tsaroucha A,de Faria L,Roth D,Ciancio G,Esquenazi V,Burke G,Tzakis A,Miller Jdoi
10.1016/s0966-3274(97)80042-1subject
Has Abstractpub_date
1997-09-01 00:00:00pages
225-32issue
3eissn
0966-3274issn
1878-5492pii
S0966-3274(97)80042-1journal_volume
5pub_type
临床试验,杂志文章abstract::The interaction of antibodies with cell surface antigens may induce redistribution of immune complexes, followed by antigen depletion, with increased resistance to injurious effect of antibody and complement (antigenic modulation). Human natural antibodies to Gal alpha 1,3Gal beta 1,4GlcNAc-R (alpha Gal) epitopes expr...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/s0966-3274(99)80026-4
更新日期:1999-06-01 00:00:00
abstract::Introduction of MHC class I Kb cDNA via recombinant retrovirus into B10.AKM (Kk) bone marrow cells (BMC) has been shown to confer specific hyporesponsiveness to B10.MBR (Kb) allogeneic skin grafts in lethally irradiated B10.AKM recipients of the transduced syngeneic BMC. We have recently developed a nonmyeloablative c...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/s0966-3274(96)80044-x
更新日期:1996-03-01 00:00:00
abstract::This study provides data on HLA-A, -B, and -DRB1 frequencies among 861 end-stage renal disease (ESRD) patients from Croatia and estimates the benefit of the kidney exchange program by comparing HLA distribution and assessing HLA mismatches (MMs) within a group of ESRD patients who received kidney grafts from 707 cadav...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2020.101318
更新日期:2020-10-01 00:00:00
abstract::There have been several reports that xeno-MHC-restricted T-cells have a cytotoxic function through a direct xenoantigen recognition, but yet no report that they have a helper function. Previously we showed that both xeno-MHC-restricted CD4(+) and CD8(+) T-cells recognized xenoantigens directly in a mouse anti-rat comb...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/S0966-3274(02)00158-2
更新日期:2003-04-01 00:00:00
abstract::Induction of donor-specific hyporesponsiveness would minimize the need for intensive immunosuppression in the clinical setting of graft rejection and dendritic cells (DCs) might be useful tools for this purpose. Besides their ability to induce immunogenic T-cell responses, these antigen presenting cells can lead to T-...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2006.03.001
更新日期:2006-06-01 00:00:00
abstract::Previously, we established a murine model, that involves the engraftment of fully allogeneic T cell depleted donor bone marrow cells in sublethally irradiated and single dose anti-CD3 treated recipient mice. These mice developed permanent stable multilineage mixed chimerism and donor-specific tolerance without graft-v...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/S0966-3274(02)00157-0
更新日期:2003-07-01 00:00:00
abstract::Administration of anti-intercellular adhesion molecule (ICAM)-1 monoclonal antibody (mAb) plus anti-lymphocyte function associated antigen (LFA)-1 mAb induces tolerance in murine cardiac transplantation, while anti-vascular cell adhesion molecule (VCAM)-1 mAb plus anti-very late antigen (VLA)-4 mAb administration prol...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/s0966-3274(99)80021-5
更新日期:1999-03-01 00:00:00
abstract::Calcineurin a calmodulin-dependent phosphatase plays a critical role in calcium-dependent activation of T-lymphocytes and is the major target for the inhibitory actions of the immunosuppressive drugs Tacrolimus (FK506) and Cyclosporin A (CsA). Calcineurin is a dimeric protein consisting of distinct A (catalytic) and B...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/s0966-3274(00)00020-4
更新日期:2000-06-01 00:00:00
abstract:BACKGROUND:So far, the ImmuKnow Immune Cell Function Assay (Cylex, Inc., Columbia, MD, USA) has been used to assess risks of infection and rejection in transplant patients. We hypothesized that the ImmuKnow assay might be used for mortality screening in transplant patients overall. METHODS:In the period of February 20...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2010.12.005
更新日期:2011-05-01 00:00:00
abstract::Mixed lymphocyte reaction (MLR) assays were performed serially over 24 months in 19 first cadaver renal transplant recipients. Immunosuppression consisted of cyclosporine, methylprednisolone and azathioprine. Cyclosporine was withdrawn at 6 months postoperatively. The MLR reactivity gradually decreased over the first ...
journal_title:Transplant immunology
pub_type: 临床试验,杂志文章
doi:10.1016/s0966-3274(98)80016-6
更新日期:1998-12-01 00:00:00
abstract::New immunosuppressive strategies have improved short- and long-term graft survival. The current aim is to decrease the intensity of the immunosuppressive regimen, in an attempt to limit side effects and the direct toxicity of calcineurin inhibitor (CNI) for kidney function. We describe here current experience in liver...
journal_title:Transplant immunology
pub_type: 杂志文章,评审
doi:10.1016/j.trim.2006.11.007
更新日期:2007-02-01 00:00:00
abstract:BACKGROUND:Pigs are frequently used as animal models for experiments in the surgical field, including allo- and xeno-transplantation. Regeneration studies, including studies dealing with human- and monkey-induced pluripotent stem cells (iPSC), have gradually progressed, with pigs sometimes being used as the scaffold. H...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2016.12.002
更新日期:2017-02-01 00:00:00
abstract::The immune system is an adaptive defense system capable of specifically recognizing and eliminating an apparently limitless variety of foreign invaders. This highly specific response is provided by T and B lymphocytes. The enormous diversity of the antigen-specific receptors on these cells is generated by random rearr...
journal_title:Transplant immunology
pub_type: 杂志文章,评审
doi:10.1016/s0966-3274(02)00056-4
更新日期:2002-08-01 00:00:00
abstract::Circulating host lymphocytes recognize, bind to, become activated by, and infiltrate engrafted allogeneic tissues. The mechanisms responsible for these early events which lead to acute immunological rejection have not been precisely defined. We have examined sequentially in vitro lymphocyte binding patterns in a kidne...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/0966-3274(95)80035-2
更新日期:1995-06-01 00:00:00
abstract::The neomacrolide antibiotic azithromycin is known to have an anti-inflammatory effect and is increasingly being used in the treatment of chronic inflammatory pulmonary diseases. We investigated whether azithromycin influenced matrix remodeling. Matrix metalloproteinase (MMP)-9 protein levels were measured by ELISA in ...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2011.06.006
更新日期:2011-09-01 00:00:00
abstract::Immunological monitoring of transplant recipients is an attractive concept. Cytokines provide an obvious focus for research, as they are central to the human immune response. This study aimed to identify cytokines whose sequential gene expression differentiated rejectors from non-rejectors immediately following renal ...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2005.02.003
更新日期:2005-06-01 00:00:00
abstract::Pancreas grafts do not survive for lengthy periods, especially in a high-responder rat combination. Recent data indicated that a combined spleen/pancreas graft protects against acute graft rejection and induces donor-specific tolerance. In this study, we performed a combination spleen/pancreas transplantation using hi...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/s0966-3274(01)00049-1
更新日期:2001-10-01 00:00:00
abstract:BACKGROUND:Although high-mobility group box-1 (HMGB1), which is a nuclear protein, was reported to enhance the allogeneic responses in transplantation, the effect of HMGB1 on bronchiolitis obliterans syndrome (BOS) is unknown. METHODS:A murine heterotopic tracheal transplantation model was used. Protein concentrations...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2018.11.007
更新日期:2019-04-01 00:00:00
abstract::Humoral rejection and its relationship with anti HLA antibodies have been extensively studied in organ transplantation with the exception of liver transplantation (LT). Recently, association between donor specific anti HLA antibodies (DSA) and increased risk of rejection and graft loss has been suggested in LT. When s...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2016.01.007
更新日期:2016-03-01 00:00:00
abstract::Adenovirus-mediated CTLA4Ig gene transfer has been reported to enhance graft survival in several rodent transplantation models. In this study, we investigated the efficacy of ex vivo and systemic transfer of the CTLA4Ig gene by adenoviral vectors in pancreatic islet allo-transplantation. Islet grafts from BN rats were...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/S0966-3274(02)00153-3
更新日期:2003-01-01 00:00:00
abstract:BACKGROUND:The potential of mesenchymal stem cells (MSCs) for immunosuppression has been tested in transplantation, but its mechanisms are not fully understood. This study investigated the role of MSC-expressing B7-H1 in the induction of immune tolerance to cardiac allografts by the combination therapy of MSCs and rapa...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2014.06.005
更新日期:2014-08-01 00:00:00
abstract::Models of severe combined immuno-deficient (SCID) mice reconstituted with a competent human immune system represent a valuable tool for the study of human immune responses in vivo. Reconstitution with human cells can be achieved using large numbers of peripheral blood lymphocytes, but levels of engraftment are poor an...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2005.07.002
更新日期:2005-12-01 00:00:00
abstract::The effect of blocking the expression of the mucosal addressin cell adhesion molecule-1 (MAdCAM-1) in a graft by an antibody, and immunohistochemical changes in the graft were monitored, using a rat small intestinal transplantation model. Dark Agouti (DA) rat small intestines were heterotopically transplanted into Lew...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2007.01.011
更新日期:2007-06-01 00:00:00
abstract::Persistent rejection in the face of treatment and multiple episodes of rejection are associated with the development of chronic rejection and graft loss in solid organ transplantation. The factors that create an environment for rejection that persists in the face of treatment are as yet not understood. The objective o...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2004.11.001
更新日期:2005-03-01 00:00:00
abstract:INTRODUCTION:Regulatory T cells (Tregs) have been related to acute rejection as have the cytotoxic T cells, their immunological counterpart. High expression of cytotoxic markers has been related to acute rejection incidents following both kidney and intestine transplantation, while the correlation between FoxP3 express...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2010.06.011
更新日期:2010-10-01 00:00:00
abstract::The outcome of hyperacute grade 3-4 steroid-refractory graft-versus-host-disease (SR-GVHD) remains dismal despite a plethora of agents being tried alone or in combination. Following T replete haploidentical transplantation with post-transplantation cyclophosphamide on 75 patients, 10 patients (13%) aged 2-20years, dev...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2016.08.009
更新日期:2016-11-01 00:00:00
abstract::The aetiologies of accelerated or transplant-associated coronary artery disease (TxCAD) following cardiac transplantation and chronic rejection following renal transplantation remain ill-defined. Previous studies have used Western blotting to demonstrate an association between the formation of anti-endothelial (anti-E...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/s0966-3274(97)80021-4
更新日期:1997-03-01 00:00:00
abstract::FTY720 alters lymphocyte recirculation and homing by interfering with S1P receptors on lymphocytes, possibly in combination with chemokine receptors, and induces a decrease in PBL counts. In fresh, whole blood samples of 14 kidney transplant patients, we analyzed by flow cytometry the effect of FTY on the number of NK...
journal_title:Transplant immunology
pub_type: 杂志文章,多中心研究,随机对照试验
doi:10.1016/j.trim.2006.02.002
更新日期:2006-04-01 00:00:00
abstract::Recently, the signal transducer and activator of transcription 4 (STAT4) gene have been associated with multiple autoimmune diseases. Taking into consideration that the different autoimmune diseases may share some common pathogenetic pathways, the aim of the present study was to evaluate the role of STAT4 rs7574865 po...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/j.trim.2011.01.001
更新日期:2011-05-01 00:00:00
abstract::TCR-beta (T cell receptor-beta chain) transgenic mice have altered lymphocyte development. TCR-beta transgenic mice are hyporesponsive to alloantigens in vivo and are deficient in gamma delta T cells. In order to begin a study of the relationship between a deficiency of alloreactive gamma delta cells and the defective...
journal_title:Transplant immunology
pub_type: 杂志文章
doi:10.1016/0966-3274(94)90063-9
更新日期:1994-09-01 00:00:00