Association Between the Intracellular Tacrolimus Concentration in CD3+ T Lymphocytes and CD14+ Monocytes and Acute Kidney Transplant Rejection

Supplemental Digital Content is Available in the Text. Background: Intracellular tacrolimus concentration in peripheral blood mononuclear cells (PBMCs) (TAC[PBMC]) has been proposed to better represent its active concentration than its whole blood concentration. As tacrolimus acts on T lymphocytes and other white blood cells, including monocytes, we investigated the association of tacrolimus concentration in CD3+ T lymphocytes (TAC[CD3]) and CD14+ monocytes (TAC[CD14]) with acute rejection after kidney transplantation. Methods: From a total of 61 samples in this case–control study, 28 samples were obtained during biopsy-proven acute rejection (rejection group), and 33 samples were obtained in the absence of rejection (control group). PBMCs were collected from both cryopreserved (retrospectively) and freshly obtained (prospectively) samples. CD3+ T lymphocytes and CD14+ monocytes were isolated from PBMCs, and their intracellular tacrolimus concentrations were measured. Results: The correlation between tacrolimus whole-blood and intracellular concentrations was poor. TAC[CD3] was significantly lower than TAC[CD14] (median 12.8 versus 81.6 pg/million cells; P < 0.001). No difference in TAC[PBMC] (48.5 versus 44.4 pg/million cells; P = 0.82), TAC[CD3] (13.4 versus 12.5 pg/million cells; P = 0.28), and TAC[CD14] (90.0 versus 72.8 pg/million cells; P = 0.27) was found between the rejection and control groups. However, freshly isolated PBMCs showed significantly higher TAC[PBMC] than PBMCs from cryopreserved samples. Subgroup analysis of intracellular tacrolimus concentrations from freshly isolated cells did not show a difference between rejectors and nonrejectors. Conclusions: Differences in TAC[CD3] and TAC[CD14] between patients with and without rejection could not be demonstrated. However, further optimization of the cell isolation process is required because a difference in TAC[PBMC] between fresh and cryopreserved cells was observed. These results need to be confirmed in a study with a larger number of patients.

[1]  D. Hesselink,et al.  Monitoring Intracellular Tacrolimus Concentrations And Its Relationship With Rejection In The Early Phase After Renal Transplantation. , 2021, Clinical biochemistry.

[2]  B. Sallustio.  Monitoring Intra-cellular Tacrolimus Concentrations in Solid Organ Transplantation: Use of Peripheral Blood Mononuclear Cells and Graft Biopsy Tissue , 2021, Frontiers in Pharmacology.

[3]  D. Hesselink,et al.  Therapeutic drug monitoring of immunosuppressive drugs in hepatology and gastroenterology. , 2021, Best practice & research. Clinical gastroenterology.

[4]  D. Hesselink,et al.  Monitoring the tacrolimus concentration in peripheral blood mononuclear cells of kidney transplant recipients , 2020, British journal of clinical pharmacology.

[5]  D. Hesselink,et al.  Measuring Intracellular Concentrations of Calcineurin Inhibitors: Expert Consensus from the International Association of Therapeutic Drug Monitoring and Clinical Toxicology (IATDMCT) Expert Panel. , 2020, Therapeutic drug monitoring.

[6]  M. Stegall,et al.  The Banff 2019 Kidney Meeting Report (I): Updates on and clarification of criteria for T cell– and antibody‐mediated rejection , 2020, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[7]  M. van der Zwan,et al.  Molecular Analysis of Renal Allograft Biopsies: Where Do We Stand and Where Are We Going? , 2020, Transplantation.

[8]  J. Farber,et al.  The Implications of B-lineage Cells in Kidney Allografts , 2020, Transplantation.

[9]  Elena Kokuina,et al.  Normal Values of T, B and NK Lymphocyte Subpopulations in Peripheral Blood of Healthy Cuban Adults. , 2019, MEDICC review.

[10]  M. D. de Kam,et al.  Immunomonitoring of Tacrolimus in Healthy Volunteers: The First Step from PK- to PD-Based Therapeutic Drug Monitoring? , 2019, International journal of molecular sciences.

[11]  U. Christians,et al.  Therapeutic Drug Monitoring of Tacrolimus-Personalized Therapy: Second Consensus Report , 2019, Therapeutic drug monitoring.

[12]  B. Shi,et al.  Circulating NK cell subsets and NKT-like cells in renal transplant recipients with acute T-cell-mediated renal allograft rejection , 2019, Molecular medicine reports.

[13]  Min Chang Kim,et al.  The level of intracellular tacrolimus in T cell is affected by CD44+ ABCB1+ activities triggered by inflammation , 2019, European Journal of Inflammation.

[14]  D. Hesselink,et al.  Highly sensitive and rapid determination of tacrolimus in peripheral blood mononuclear cells by liquid chromatography–tandem mass spectrometry , 2018, Biomedical chromatography : BMC.

[15]  G. Pettigrew,et al.  T cell Allorecognition Pathways in Solid Organ Transplantation , 2018, Front. Immunol..

[16]  S. Bremer,et al.  Longitudinal Study of Tacrolimus in Lymphocytes During the First Year After Kidney Transplantation , 2018, Therapeutic drug monitoring.

[17]  A. Somogyi,et al.  Mycophenolic acid concentrations in peripheral blood mononuclear cells are associated with the incidence of rejection in renal transplant recipients , 2018, British journal of clinical pharmacology.

[18]  R. Hendriks,et al.  T Follicular Helper Cells As a New Target for Immunosuppressive Therapies , 2017, Front. Immunol..

[19]  R. Hendriks,et al.  IL-21 Receptor Antagonist Inhibits Differentiation of B Cells toward Plasmablasts upon Alloantigen Stimulation , 2017, Front. Immunol..

[20]  A. Valujskikh,et al.  Role of Memory T Cells in Allograft Rejection and Tolerance , 2017, Front. Immunol..

[21]  D. Hesselink,et al.  Targeting the Monocyte–Macrophage Lineage in Solid Organ Transplantation , 2017, Front. Immunol..

[22]  D. Hesselink,et al.  The Effect of Tacrolimus and Mycophenolic Acid on CD14+ Monocyte Activation and Function , 2017, PloS one.

[23]  G. Benichou,et al.  Allorecognition by T Lymphocytes and Allograft Rejection , 2016, Front. Immunol..

[24]  H. Louagie,et al.  Performance evaluation of the Sysmex® XP‐300 in an oncology setting: evaluation and comparison of hematological parameters with the Sysmex® XN‐3000 , 2016, International journal of laboratory hematology.

[25]  Min Chang Kim,et al.  Monitoring the Intracellular Tacrolimus Concentration in Kidney Transplant Recipients with Stable Graft Function , 2016, PloS one.

[26]  Qianying Chen,et al.  Chronic inflammation up-regulates P-gp in peripheral mononuclear blood cells via the STAT3/Nf-κb pathway in 2,4,6-trinitrobenzene sulfonic acid-induced colitis mice , 2015, Scientific Reports.

[27]  D. Roelen,et al.  Follicular T helper cells and humoral reactivity in kidney transplant patients , 2015, Clinical and experimental immunology.

[28]  K. Boudjema,et al.  Pharmacokinetics and pharmacodynamics of tacrolimus in liver transplant recipients: inside the white blood cells. , 2015, Clinical biochemistry.

[29]  Flora Musuamba Tshinanu,et al.  Plasma and intracellular pharmacokinetic-pharmacodynamic analysis of mycophenolic acid in de novo kidney transplant patients. , 2015, Clinical biochemistry.

[30]  A. Prémaud,et al.  Exposure to Mycophenolic Acid Better Predicts Immunosuppressive Efficacy Than Exposure to Calcineurin Inhibitors in Renal Transplant Patients , 2014, Clinical pharmacology and therapeutics.

[31]  N. Sachdeva,et al.  Reference ranges of lymphocyte subsets in healthy adults and adolescents with special mention of T cell maturation subsets in adults of South Florida. , 2014, Immunobiology.

[32]  Eric W. Cross,et al.  T cell responses: naive to memory and everything in between. , 2013, Advances in physiology education.

[33]  F. Lemaitre,et al.  Monitoring of tacrolimus concentrations in peripheral blood mononuclear cells: application to cardiac transplant recipients. , 2013, Clinical biochemistry.

[34]  W. Weimar,et al.  Genetic Polymorphisms in ABCB1 Influence the Pharmacodynamics of Tacrolimus , 2013, Therapeutic drug monitoring.

[35]  W. Weimar,et al.  Tacrolimus Predose Concentrations Do Not Predict the Risk of Acute Rejection After Renal Transplantation: A Pooled Analysis From Three Randomized‐Controlled Clinical Trials † , 2013, American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons.

[36]  V. Haufroid,et al.  Correlation of tacrolimus levels in peripheral blood mononuclear cells with histological staging of rejection after liver transplantation: preliminary results of a prospective study , 2012, Transplant international : official journal of the European Society for Organ Transplantation.

[37]  K. Wood,et al.  Role of T cells in graft rejection and transplantation tolerance , 2010, Expert review of clinical immunology.

[38]  H. Russcher,et al.  Ficoll-separated mononuclear cells from sepsis patients are contaminated with granulocytes , 2008, Intensive Care Medicine.

[39]  P. Halloran,et al.  Reduced exposure to calcineurin inhibitors in renal transplantation. , 2007, The New England journal of medicine.

[40]  W. Weimar,et al.  Interleukin-21: An Interleukin-2 Dependent Player in Rejection Processes , 2007, Transplantation.

[41]  M. Rieder,et al.  Inhibition of Cytokine Production and Cytokine-Stimulated T-Cell Activation by FK506 (Tacrolimus)1 , 2001, Cell transplantation.

[42]  T. Grogan,et al.  P-glycoprotein expression and function in circulating blood cells from normal volunteers. , 1994, Blood.

[43]  I. Roninson,et al.  Expression and activity of the multidrug resistance P-glycoprotein in human peripheral blood lymphocytes. , 1992, Blood.

[44]  S. Zhao,et al.  Subpopulations of normal peripheral blood and bone marrow cells express a functional multidrug resistant phenotype. , 1992, Blood.

[45]  J. Coon,et al.  Multidrug resistance activity in human lymphocytes. , 1991, Human Immunology.

[46]  A. B. Kay,et al.  Lymphocytes , 1991 .

[47]  A. Chervonsky,et al.  Multidrug-resistance phenotype of a subpopulation of T-lymphocytes without drug selection. , 1989, Experimental cell research.