Logo Annals of Transplantation Logo Annals of Transplantation Logo Annals of Transplantation

Biomarkers - as an adjunct to immunosuppressive drug monitoring

M. Oellerich

Ann Transplant 2008; 13(1): 17-17 :: ID: 880171

Abstract

The inability to measure effects of immunosuppressive drugs on immune cells in vivo has severely limited preclinical drug development, design, and interpretation of clinical trials, as well as the optimal clinical use of these drugs in transplantation. As TDM of blood immunosuppressant levels does not always predict pharmacologic effects on immune cells appropriate biomarkers could be helpful to individually tailor immunosuppression. The development of "tolerance permissive" immunosuppressive regimens would be desirable. Proposed biomarkers include drug target enzymes (calcineurin, inosine monophosphate dehydrogenase (IMPDH)), cytokines, markers of lymphocyte proliferation or activation, markers of immune cell response and potential predictors of tolerance. Calcineurin activity may be useful to assess the efficacy of different calcineurin inhibitor-based regimens. IMPDH activity in peripheral blood mononuclear cells or CD4+ cells has been proposed to assess mycophenolic acid (MPA) pharmacodynamics. Patients with high IMPDH activity and who received a dose reduction had the highest incidence of acute rejection. Another approach to assess the pharmacodynamic effects of calcineurin inhibitors has been to study their inhibition of the products of T-cell activation (IL-2, IFN-g, TNF-a). An optimal pharmacodynamic target range however is not known. Furthermore, a delayed increase in cytokine (IL-2, IL-4, TNF-a) mRNA expression during T-cell costimulation may represent a sensitive effect of immunosuppression. Flow cytometry has been used to assess the intracellular production of cytokines by T-cells (IL-2, IFN-g, TNF-a) after ex-vivo stimulation of lymphocytes in whole blood. The observed lack of correlation between CsA trough levels and decreased IL-2 production seems to confirm that immunosuppressive drugs have a different effect in different patients even when the drug level and dosage is similar. An immune cell function assay (Cylex ImmuKnow) has become available in which the increase in intracellular adenosine-triphosphate (ATP) after T-lymphocyte activation by mitogenic stimulation is measured. From a meta-analysis a target immunological response zone was derived for assessing relative risks of infection or rejection. In a further approach mitogen stimulated lymphocyte proliferation can be measured through flow cytometric determination of the expression of proliferating cell nuclear antigen in the S/G2-M phase and T-lymphocyte activation by determination of the expression of CD11A, CD25, CD71, CD95, CD134 and CD154. Lymphocyte function assays have been successfully used in a rat model comparing sirolimus mono-therapy to a combination treatment with CsA. In comparison with the monodrug group the combination drug treatment, however, did not lead to a further proportional decrease of lymphocyte function, if CsA dosage was doubled. Dose-dependent effects of tacrolimus, cyclosporin, sirolimus, mycophenolic acid and methylprednisolone on such biomarkers were recently studied in human whole blood cultures. Few data on the use of such tests in transplant patients are available. In stable renal transplant recipients lymphocyte proliferation was strongly inhibited and expression of surface activation antigens on T-cells was significantly reduced. In a further study conversion of 10 heart transplant recipients from cyclosporin to sirolimus caused a signifi cant decrease in IFN-g expression and a significant increase in CD25 and CD95 expression. Finally biomarkers might be helpful to identify tolerant patients where immunosuppression can be safely weaned. Preliminary clinical studies indicate that the numbers of circulating CD4[sup]+ [/sup]CD25[sup]high[/sup]FOXP3[sup]+[/sup] regulatory T cells (Treg) may contribute to determining the long-term fate of renal transplants. So far, however, the clinical usefulness of this parameter for guiding immunosuppressive drug weaning has not been verified in prospective multicenter trials. Future prospective outcome studies would be necessary to assess the potential of the discussed biomarkers to complement immunosuppressive drug level monitoring.

Keywords: immunosuppressive drugs, In vivo, Transplantation

0 Comments

In Press

20 Jan 2022 : Original article  

Impact on Waitlist Outcomes from Changes in the Medical Eligibility of Candidates for Simultaneous Liver-Ki...

Ann Transplant In Press; DOI: 10.12659/AOT.934850  

19 Jan 2022 : Original article  

Carbohydrate Metabolism Disorders in Relation to Cardiac Allograft Vasculopathy (CAV) Intensification in He...

Ann Transplant In Press; DOI: 10.12659/AOT.933420  

18 Jan 2022 : Original article  

PLGA+Fe₃O₄+PFP Nanoparticles Drug-Delivery Demonstrates Potential Anti-Tumor Effects on Tumor Cells

Ann Transplant In Press; DOI: 10.12659/AOT.933246  

17 Jan 2022 : Original article  

Impact of Thyroid Incidentaloma on Liver Transplant: A Study of 1010 Recipients at a Single Center

Ann Transplant In Press; DOI: 10.12659/AOT.934988  

Most Viewed Current Articles

29 Dec 2021 : Original article  

Efficacy and Safety of Tacrolimus-Based Maintenance Regimens in De Novo Kidney Transplant Recipients: A Sys...

DOI :10.12659/AOT.933588

Ann Transplant 2021; 26:e933588

22 Dec 2021 : Original article  

Comparison of Coronary Artery Calcium Scoring with Dobutamine Stress Echo for Detection of Coronary Artery ...

DOI :10.12659/AOT.934163

Ann Transplant 2021; 26:e934163

12 Jan 2022 : Original article  

Risk Factors for Developing BK Virus-Associated Nephropathy: A Single-Center Retrospective Cohort Study of ...

DOI :10.12659/AOT.934738

Ann Transplant 2022; 27:e934738

01 Dec 2021 : Original article  

Solid-Phase C1q/C3d Fixing Readouts Correlate with High Median Fluorescence Intensity (MFI) De Novo Donor-S...

DOI :10.12659/AOT.934175

Ann Transplant 2021; 26:e934175

Your Privacy

We use cookies to ensure the functionality of our website, to personalize content and advertising, to provide social media features, and to analyze our traffic. If you allow us to do so, we also inform our social media, advertising and analysis partners about your use of our website, You can decise for yourself which categories you you want to deny or allow. Please note that based on your settings not all functionalities of the site are available. View our privacy policy.

Annals of Transplantation eISSN: 2329-0358
Annals of Transplantation eISSN: 2329-0358