Pharmacodynamics of T‐cell function for monitoring immunosuppression

Barten, Markus J.; Tárnok, Attila; Garbade, Jens; Bittner, Hartmuth B.; Dhein, Stefan; Mohr, F. W.; Gummert, Jan

doi:10.1111/j.1365-2184.2007.00413.x

Cited by 53 publications

(47 citation statements)

References 24 publications

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“…The results of these studies differed regarding the relation between the drug pharmacokinetics and drug pharmacodynamics as well as regarding the specification of one to the other cytokine to measure the pharmacodynamic drug effect. This is in line with results of our study about the conversion of a initial immunosuppression of CsA by TRL or SRL [41]. We found that inhibition of cytokine expression correlated with the whole blood TRL concentrations, whereas in the SRL group the increased blood SRL concentration reflected an increase of cytokine inhibition only on day 4 after conversion.…”

Section: Clinical Studiessupporting

confidence: 81%

“…In a study in stable HTx recipients treated with a combination therapy of CsA plus MMF, we obtained a high correlation between CsA effects and both blood CsA concentrations and CsA dose. A significant increase in blood CsA concentration 2 h after dosing led to a significant decrease in PCNA as well as T cell surface antigen expression [41]. Furthermore, it could be shown that CsA blood concentrations were more strongly correlated to T cell proliferation and surface antigen expression than to T cell cytokine release.…”

Section: Clinical Studiesmentioning

confidence: 75%

“…We found that inhibition of cytokine expression correlated with the whole blood TRL concentrations, whereas in the SRL group the increased blood SRL concentration reflected an increase of cytokine inhibition only on day 4 after conversion. The least effect on expression in our study, regardless of the basis immunosuppressive drug used, was detected for IL-4 when compared to inhibitory effects on IL-2, TNF-α and IFN-γ expression [41].…”

Section: Clinical Studiesmentioning

confidence: 84%

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Biomarkers in Transplantation Medicine: Prediction of Pharmacodynamic Drug Effects

Barten¹,

Gummert²

2007

Transfus Med Hemother

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Conventional therapeutic drug monitoring based on measuring of blood concentrations (pharmacokinetic) is important in the clinical management of immunosuppressive therapy in transplantation medicine. Since rejection or infection occurs at irregular drug concentrations, immunosuppressive drug therapy is often empiric and prophylactic in nature. In addition, blood immunosuppressant levels are only indirect predictors of the pharmacologic effects on immune cells (pharmacodynamic) because, due to the genetic heterogeneity, the immune systems of the transplant recipients are not equally sensitive to drug effects. Therefore, therapeutic drug monitoring requires the application of reliable and effective methods to study the pharmacodynamic variability by direct measurements of drugs effects on immune cell functions. Against this background we developed assays which are based on whole blood, flow cytometry and biomarkers of diverse functions of T cells and of dendritic cell subsets. These biomarker assays allow us to differentiate between synergistic and antagonistic pharmacodynamic effects of an immunosuppressive drug combination therapy in vitro and to predict the pharmacodynamic drug effects in heart-transplanted recipients. Such a pharmacodynamic drug monitoring based on biomarkers may offer the opportunity to complete conventional therapeutic drug monitoring and, therefore, to tailor immunosuppressive therapy more individually.

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Section: Clinical Studiessupporting

confidence: 81%

Section: Clinical Studiesmentioning

confidence: 75%

Section: Clinical Studiesmentioning

confidence: 84%

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Biomarkers in Transplantation Medicine: Prediction of Pharmacodynamic Drug Effects

Barten¹,

Gummert²

2007

Transfus Med Hemother

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“…Two parametersexpression of CD25 and CD95 on T-cells show impairment of T lymphocyte activation in blood from patients after CPB. Further studies are to show the predictive value of antigen expression on T-cells in respect to clinical outcome (76)(77)(78)(79).…”

Section: Clinical Cytomics In Differentiation Andmentioning

confidence: 99%

Cytomics and nanobioengineering

Pierzchalski¹,

Robitzki²,

Mittag³

et al. 2008

Cytometry Part B Clinical

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The finding that an individual's genome differs as much as by many million variants from that of the human reference assembly diminished the great enthusiasm that every disease could be predicted based on nucleotide polymorphisms. Even individual cells of an organ may be specifically equipped to perform specific tasks and that the information of individual cells in a cell system is key information to understand function or dysfunction. Therefore, cytomics received great attention during the last years as it allows to quantitatively and qualitatively analyzing great number of individual cells, cell constituents, and of their intracellular and functional interactions in a cellular system and also giving the concept of analysis of these data.Exhaustive data extraction from multiparametric assays and multiple tests are the prerequisite for prediction of drug toxicity. Cytomics, as novel approach for unsupervised data analysis give a chance to find the most predictive parameters, which describe best the toxicity of a chemical. Cytomics is intrinsically connected to drug development and drug discovery.Focused on small structures, nanobioengineering is the ideal partner of cytomics, the systems biological discipline for cell population analysis. Realizing the idea ''from the molecule to the patient'' develops and offers chemical compounds, proteins, and other biomolecules, cells as well as tissues as instruments and products for a wide variety of biotechnological and biomedical applications.The integrative nanobioengineering combining different disciplines of nanotechnology will promote the development of innovative therapies and diagnostic methods. It can improve the precision of the measurements with focus on single cell analysis. By nanobioengineering and whole body imaging techniques, cytomics covers the field from molecules through bacterial cells, eukaryotic tissues, and organs to small animal live analysis. Toxicological testing and medical drug development are currently strongly broadening. It harbors the promise to substantially impact on various fields of biomedicine, drug discovery, and predictive medicine.As the number of scientific data is rising exponentially, new data analysis tools and strategies like cytomics and nanobioengineering take a lead and get closer to application. Bionanoengineering may strongly support the quantitative data supply, thus strengthening the rationale for cytomics approach. q

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“…Drug discovery demands that thousands of compounds are rapidly tested for their biological activity in order to detect those rare events that may bear the potential of becoming useful pharmaceutics somewhere in the future (1,2). This requires the combination of appropriate cell systems for testing, robust high-throughput technological platforms allowing for high-content screening (mostly imaging systems) as well as fast and stable automated image and data analysis systems enabling unbiased data scrutiny.…”

mentioning

confidence: 99%

Cytomics for discovering drugs

Tárnok

2009

Cytometry Pt A

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THERE are two major fields of applications for the cytomics approach: Predictive medicine for preventative medicine and drug discovery. Drug discovery demands that thousands of compounds are rapidly tested for their biological activity in order to detect those rare events that may bear the potential of becoming useful pharmaceutics somewhere in the future (1,2). This requires the combination of appropriate cell systems for testing, robust high-throughput technological platforms allowing for high-content screening (mostly imaging systems) as well as fast and stable automated image and data analysis systems enabling unbiased data scrutiny. Ideally, such cytomic oriented detection work flow should help to reduce the frequency of false positive hits (requiring substantial effort and costs for further testing) and false negative hits (leading to loss of potentially precious compounds).Evensen et al. (3) established a unique co-culture assay of endothelial cells and vascular smooth muscle cells for screening of anti-angiogenic drugs for cancer therapy. Their system enables investigation of drug efficacy on immature, VEGFdependent, and growing endothelium as well as on mature, nonproliferating endothelium. The authors tested in a pilot study several anti-angiogenic drugs using a microtiter-plate imaging system. They found that tube total length is the most informative parameter derived from the images and they discovered by their quantitative assay some unexpected compound activity.Automated high-throughput imaging combined with quantitative analysis of the actin cytoskeleton opens the opportunity for rapid standardized determination of the effects of treatment or infection on cell structure. An image analysis tool for automated measurement of cytoskeleton modifications in a high-throughput imaging system is demonstrated by Weichsel et al. (4). They introduce the parameter image coherency and show that it is suitable to detect accurately global alterations in the cytoskeleton organization.De Vos et al. (5) focus their interest on the fully automated multivariate phenotypic classification of individual cell nuclei and subnuclear spots by automated classification and supervised machine learning. These authors recently developed controlled light exposure microscopy, a novel technology that strongly reduces photodamage by limiting excitation in parts of the image where full exposure is not needed (6). In their present publication, they applied fluorescence mosaic microscopy for image acquisition and ImageJ for image analysis of DAPI and histone gamma-H2AX (7) labeled cells. The authors developed a comprehensive work flow for highcontent screening of the nuclear architecture of cell lines treated with a genotoxic agent without or in combination with ionizing or UV irradiation. This approach is suitable for highthroughput screening in drug discovery.Image quality is crucial in image-based screening and quantitation. Low quality images may render unreliable results and need to be further processed or discarded. Now Zeder et ...

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Pharmacodynamics of T‐cell function for monitoring immunosuppression

Abstract: Our results show that PD effects on T-cell function can be used to monitor immunosuppression bringing potential to increase the efficacy and safety of immunosuppressive therapy after HTx.

Cited by 53 publications

References 24 publications

Biomarkers in Transplantation Medicine: Prediction of Pharmacodynamic Drug Effects

Biomarkers in Transplantation Medicine: Prediction of Pharmacodynamic Drug Effects

Cytomics and nanobioengineering

Cytomics for discovering drugs

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