Donor specific reactivity & nonresponsiveness

Manipulation of the immunosystem is necessary for successful clinical organ transplantation. This may be achieved by prescribing immunosuppressive regimen, allowing engraftment, which is traded with debilitating comorbidity associated with aspecific immunosuppression. Success may also be accomplished by tapering the immunosuppresive load allowing the emergence of immunological countermechanisms leading to non responsiveness. In the setting of clinical organ transplantation we study donor specific alloreactivity in an attempt to understand the immunological pathways leading to success or failure. For this purpose it is essential to explore in detail the donor-specific effector, regulatory and memory immune responses in relation to graft acceptance and failure. The identification of immune and non-immune cells with suppressive activities has opened an important new area of cellular immuno therapy and individual immunosuppression. Our specific aim is to find optimal therapeutic strategies for the individual patient.

Pharmacotherapy and pharmacogenetics in organ transplantation

Most immunosuppressive drugs are critical dose drugs: they have a narrow therapeutic index. Therapeutic drug monitoring (TDM) is an important tool to optimize immunosuppressive therapy after organ transplantation. Our research focusses on the combination of the following three main topics: Pharmacokinetics (PK): kinetics of immunosuppressive drugs and drug interactions

Pharmacodynamics (PD): how to optimize drug therapy after organ transplantation, optimal efficacy with minimal toxicity. New drugs or new drug combinations, sequential regimens.

Pharmacogenetics: how do variants in genes encoding for drug-metabolizing enzymes, drug transporters, or drug targets influence PK and PD. Pharmacogenetic research aims to predict clinically important interindividual differences.

• Regulatory T cell function is impaired in end stage renal disease patients
• Identification of patients who generated donor-specific suppressor cells in the presence of immunosuppressive drugs
• Regulatory T cells control damage response at the graft site
• Development of novel tools to monitor the consequences of immunosuppressive medication on immune cells
• Recognition of donor and patient mesenchymal stem cells are suppressors of alloreactivity
• Cyclosporine interacts with mycophenolate mofetil by inhibiting the multidrug resistance-associated protein 2
• Limited sampling strategies drawn within 3 hours postdose poorly predict mycophenolic acid area-under-the-curve after enteric-coated mycophenolate sodium
• Inosine monophosphate dehydrogenase messenger RNA expression is correlated to clinical outcomes in mycophenolate mofetil-treated kidney transplant patients.

Donor specific reactivity & nonresponsiveness

Studies to further unravel the contributions of effector, memory and regulatory T cells in the anti-donor response in an attempt to identify patients who developed graft acceptance not necessitating full dose immmunosprressive medication and patients who are at risk to reject their allograft. Introduction of new, less toxic and more specific immunosuppressive agents in the transplantation clinic. Furthermore, we aim to exploit mesenchymal stem cell therapy by expanding recipient cells derived at transplantation. Ex vivo generated mesenchymal stem cells might suppress all-reactive effector T cells in organ transplantation.

Pharmacotherapy and pharmacogenetics in organ transplantation

Abbreviated AUC or concentrations at time points other than C_min better reflect overall drug exposure. We aim to perform studies comparing these parameters with traditional TDM to show their true value. The influence of genetic factors on PK/PD will be studied and can then be prospectively used to aid in individual dosing of immunosuppressive drugs in order to reach target concentrations and thus optimize efficacy and avoid side effects. A crucial factor is the need for well-characterized patients who have been uniformly treated and systematically evaluated. To this end we are setting up basic requirements for the collection of genomic DNA from all our future transplant recipients.

1. Baan CC, van der Mast BJ, Klepper M, Mol WM, Peeters AMA, Korevaar SS, Balk AHMM, Weimar W. Differential effect of calcineurin inhibitors, anti-CD25 antibodies and rapamycin on the induction of FOXP3 in human T-cells. Transplantation 2005;80(1):110-7.
2. Hoogduijn MJ, Crop MJ, Peeters AM, Korevaar SS, Eijken M, Drabbels JJ, Roelen DL, Maat AP, Balk AH, Weimar W, Baan CC. Donor-Derived Mesenchymal Stem Cells Remain Present and Functional in the Transplanted Human Heart. Am J Transplant. 2009;9:222-30.
3. Dijke IE, Caliskan K, Klepper M, de Kuiper R, Balk AH, Maat AP, Weimar W, Baan CC. Donor-specific Immune Regulation by CD8(+) Lymphocytes Expanded from Rejecting Human Cardiac Allografts. Am J Transplant. 2009;9(2):397-403
4. van Gurp EAFJ, Schoordijk-Verschoor W, Klepper M, Korevaar SS, Chan G, Weimar W, Baan CC. The effect of the JAK inhibitor CP-690,550 on peripheral immune parameters in stable kidney allograft patients. Transplantation 2009;87(1):79-86.
5. Gerrits JH, van de Wetering J, Weimar W, van Besouw NM. T-cell reactivity during tapering of immunosuppression to low-dose monotherapy prednisolone in HLA-identical living-related renal transplant recipients. Transplantation. 2009;87(6):907-14.
6. Hesselink DA, Van Schaik RHN, Van der Heiden IP, Van der Werf M, Smak Gregoor PJH, Lindemans J, Weimar W, Van Gelder T. Genetic polymorphisms of the CYP3A4, CYP3A5 and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharm Ther 2003;74:245-54.
7. Hesselink DA, Van Gelder T, Van Schaik RHN, Balk AHMM, Van der Heiden IP, Van Dam T, Van der Werf M, Weimar W, Mathot RAA. Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in the MDR-1, CYP3A4, and CYP3A5 genes. Clin Pharmacol Ther 2004;76:545-56.
8. Hesselink DA, Van Hest RM, Mathot RAA, Bonthuis F, Weimar W, De Bruin RWF, Van RAA, Van Gelder T. Cyclosporine interacts with mycophenolate mofetil by inhibiting the multidrug resistance-associated protein 2. Am J Transpl 2005;5:987-994.
9. Hesselink DA, Van Gelder T. Genetic and non-genetic determinants of between-patient variability in the pharmacokinetics of mycophenolic acid. Clin Pharm Ther 2005;78:317-21.
10. Van Hest RM, Mathôt RAA, Pescovitz MD, Gordon R, Mamelok RD, Van Gelder T. Explaining variability in mycophenolic acid (MPA) exposure to optimize mycophenolate mofetil dosing: a population pharmacokinetic meta-analysis of MPA in renal transplant recipients. J Am Soc Nephrol 2006;17:871-80.