Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management

Kowalski, Richard; Post, David; Schneider, Mary C; Britz, Judith A.; Thomas, Jennifer; Deierhoi, Mark H.; Lobashevsky, Andrew L.; Redfield, Robert; Schweitzer, Eugene J.; Heredia, Alonso; Reardon, Elise; Davis, Charles B.; Bentlejewski, Carol; Fung, John J.; Shapiro, Ron; Zeevi, Adriana

doi:10.1034/j.1399-0012.2003.00013.x

Cited by 241 publications

(232 citation statements)

References 19 publications

Supporting

Mentioning

211

Contrasting

Unclassified

Order By: Relevance

“…This assay is marketed commercially as ImmunKnow-the Cylex Immune Cell Function Assay. On the basis of a multicenter study, this assay was approved by the Food and Drug Administration for monitoring cell-mediated immunity in immunosuppressed patients (65). This assay is performed by stimulating whole blood (i.e., lymphocytes in the presence of circulating levels of immunosuppressive drugs) with phytohemagglutinin for 12 to 15 h. CD4 ϩ T cells are isolated by magnetic bead selection.…”

Section: T Cell Responses To Polyclonal Non-antigen-specific Stimulamentioning

confidence: 99%

How Can We Measure Immunologic Tolerance in Humans?

Najafian

Albin²,

Newell³

2006

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

Prevention and treatment of allograft rejection in organ transplant recipients relies primarily on non-antigen-specific immunosuppression, with all its associated potential hazards and costs. Currently, the status of the recipient immune response is measured by monitoring pharmacologic drug levels and clinical/pathologic evaluation of graft function. Development of reliable assays that can measure accurately the status of the immune response not only would help clinicians customize the prescription of immunosuppressive drugs in individual patients but also may allow their complete withdrawal in some patients with immunologic tolerance. Furthermore, these assays would facilitate the safe evaluation of novel tolerogenic regimens. Achieving this goal has proved to be very difficult because it requires both a more in-depth understanding of complex mechanisms of tolerance and also identification of transplant patients with acquired tolerance to an allograft that can be studied. This review discusses the current understanding of tolerance mechanisms and outlines the unique and specific challenges in development of tolerance/monitoring assays in the field of transplantation. In addition, several of the most promising candidate assays are discussed in detail.

show abstract

Section: T Cell Responses To Polyclonal Non-antigen-specific Stimulamentioning

confidence: 99%

How Can We Measure Immunologic Tolerance in Humans?

Najafian

Albin²,

Newell³

2006

Journal of the American Society of Nephrology

View full text Add to dashboard Cite

show abstract

“…ImmuKnow® (Cylex, Columbia, MD) is a novel and promising in vitro assay for measuring the cell function of stimulated T cells. 1 Bhorade et al. 2 reported that ImmuKnow® levels were lower in lung transplant recipients with infection than in non-infected recipients.…”

Section: Introductionmentioning

confidence: 99%

Two Case Reports of Successful Withdrawal of Mycofenolate Mofetil After Living Donor Lobar Lung Transplantation

Miyazaki

Tagawa

Yamasaki

et al. 2013

Transplantation Proceedings

View full text Add to dashboard Cite

We have no personal conflicts of interest or outside support for this research to declare 2 INTRODUCTIONIn most cases of lung transplantation, immunosuppression is maintained using calcineurin inhibitors (CNIs), anti-metabolites and steroids. Lung transplant recipients on such a regimen of triple immunosuppressants are susceptible to infectious diseases.Moreover, many prophylactic antibiotics and laboratory studies are needed, including monitoring of immunosuppressant levels and respiratory function tests, to prevent or predict allograft rejection. However, serum immunosuppressant levels alone may not accurately reflect immune status. ImmuKnow® (Cylex, Columbia, MD) is a novel and promising in vitro assay for measuring the cell function of stimulated T cells. 1 Bhorade et al. 2 reported that ImmuKnow® levels were lower in lung transplant recipients with infection than in non-infected recipients. We report two clinical cases in which mycofenolate mofetil (MMF) was successfully withdrawn after living donor lobar lung transplantation while monitoring patient immune function with the ImmuKnow® assay. CASE REPORT Case 1A 43-year-old woman underwent living donor lobar lung transplantation (LDLLT) for pulmonary alveolar proteinosis. The left lower lobe was donated by her older brother, while the right lower lobe was donated by her husband. Both donors appeared healthy.Postoperative course was uneventful, and she was discharged without any oxygen support. She had been receiving a standard triple immunosuppressant regimen, comprising tacrolimus (target trough level, 15-20 ng/ml for the first 3 months, followed by 10-15 ng/ml), MMF (1500 mg/day), and prednisolone (0.4 mg/kg/day for the first 6 months, followed by 0.2 mg/kg/day). Our prophylactic strategies for fungal, viral, and protozoan infections were oral itraconazole at 100 mg/day, valganciclovir at 900 mg/day, and trimethoprim-sulfamethoxazole at 1 g every other day, respectively. Six months 3 after transplantation, the patient developed invasive pulmonary aspergillosis (IPA). MMF was withdrawn immediately, and the trough level of tacrolimus was reduced to around 5-8 ng/ml to allow the immune status of the patient to recover and battle this fatal infection. The patient was treated with oral voricocazole at 300 mg twice daily, inhalation of amphotericin B at 10 mg 5 times daily, and intravenous micafungin at 300 mg/day.Fortunately, her condition improved over 3 months of hospitalization, and she was discharged without any symptoms. Oral voriconazole and inhaled amphotericin B were continued as prophylaxis for 9 months. Details of the clinical course have been reported previously. 3 Immune function in this patient was monitored using the ImmuKnow® assay from 14 to 37 months after transplantation ( Case 2A 24-year-old man underwent LDLLT for cystic fibrosis. He had paranasal sinusitis, but curative surgery had already been performed before transplantation. The left lower lobe was donated by his father, while the right lower lobe was donated by his uncle. After LDLLT, ...

show abstract

“…The test requires an incubation of whole blood overnight in the presence of the mitogen phytohemagglutinin (PHA) and an isolation of CD4 T-cells with magnetic particles. The ATP is then measured by luminometry [4] . Whole blood anticoagulated with heparin can be stored up to 30 h at room temperature [5] .…”

Section: Biomarkers Of Immune Activation Atp Concentration In Cd4 T-cmentioning

confidence: 99%

Biomarkers in blood for individualization of the pharmacotherapy with immunosuppressive drugs after transplantation of solid organs

Wieland

Shipkova

2015

LaboratoriumsMedizin

View full text Add to dashboard Cite

Abstract:The success of transplantation medicine is closely associated with the introduction of potent immunosuppressive drugs. Therapy guidance of the calcineurin inhibitors cyclosporine and tacrolimus as well as the mammalian target of rapamycin (mTOR) inhibitors sirolimus and everolimus is achieved by therapeutic drug monitoring (TDM). For other immunosuppressive drugs such as mycophenolic acid, TDM is not established. It has been suggested that a better individualization of pharmacotherapy could be helpful in avoiding over-and underimmunosuppression, which have been associated with poor long-term outcome of grafts and patients. Therefore, a search for biomarkers that could complement TDM, thereby allowing a better individualization of therapy, is ongoing worldwide. Pharmacodynamic biomarkers in transplantation medicine can be either non-drug-specific, aiming at assessing the global effect on the immune system, or drug-specific, aiming at recording the pharmacologic effect on a drug target. Non-specific pharmacodynamic biomarkers can reflect the degree of immune activation by measuring T-or B-cell activation, the development of operational tolerance by monitoring, e.g., regulatory T-cells, or the graft damage by measuring cell-free DNA released by the graft in response to injury. Drug-specific pharmacodynamic biomarkers have been published for mycophenolic acid, calcineurin, and mTOR inhibitors. The field of biomarker research to complement TDM for a better individualization of immunosuppression is still in its infancy, and controlled prospective clinical trials are needed to unravel or dismiss the potential of particular biomarkers or biomarker combinations in various patient cohorts with different grafts.

show abstract

Immune cell function testing: an adjunct to therapeutic drug monitoring in transplant patient management

Cited by 241 publications

References 19 publications

How Can We Measure Immunologic Tolerance in Humans?

How Can We Measure Immunologic Tolerance in Humans?

Two Case Reports of Successful Withdrawal of Mycofenolate Mofetil After Living Donor Lobar Lung Transplantation

Biomarkers in blood for individualization of the pharmacotherapy with immunosuppressive drugs after transplantation of solid organs

Contact Info

Product

Resources

About