561Several novel immunosuppressive agents and new formulations, including siro-
limus, mycophenolic acid (the active metabolite of mycophenolate mofetil), tacro-
limus, and microemulsion cyclosporine, have signifi cantly improved the clinical
outcome of transplant recipients. However, the majority of immunosuppressive
agents need a constant monitoring of drug levels to reduce the risk of graft rejection
as well as drug-induced toxicities. Many factors may affect the pharmacokinetic
characteristics of immunosuppressive agents, potentially reducing treatment effec-
tiveness. Absorption and metabolism of immunosuppressive drugs are infl uenced
by patient genotype and comedications, while comorbidities (i.e., diabetes and cys-
tic fi brosis) are responsible for altered pharmacokinetics. There are a number of
associations between genotype and pharmacology and donor genotype may play a
signifi cant role in immunosuppressive drug pharmacokinetics and pharmacody-
namics (Fu Liang et al. 2007 ). Dose individualization in transplant recipients is
performed according to their health status, graft function, and drug therapeutic
range. Therapeutic drug monitoring plays a crucial role in achieving optimal immu-
nosuppression, improving the effi cacy of drugs, and lowering toxic effects. Recent
studies have investigated treatment individualization by evaluating drug pharmaco-
genetics based on the expression level or mutations of their molecular targets,
including calcineurin for cyclosporine and tacrolimus, and inosine monophosphate
dehydrogenase for mycophenolic acid. Although no conclusions can be drawn from
the data of preliminary trials, further studies are underway to address the role of
pharmacogenetics in clinical decision making for immunosuppression.
Pharmacogenomics can be used to match patients to immunosuppressants. The
discoveries of genomic science can be used to build a new set of tools so that doc-
tors can measure and predict how a patient will respond to immunosuppressive
drugs. With such tools, transplant physicians could monitor patients regularly to
make sure their treatment is always optimal. In fact, these same tools could also
guide therapy of patients with diabetes, systemic lupus, rheumatoid arthritis and
other immune-related diseases. The basis of this approach is that there may be some
genetic “signature” within donors and recipients that predict the best course of treat-
ment following a transplant surgery. This signature could be within the tissues of the
transplanted organ or in the blood cells. An example of application of personaliza-
tion of immunosuppression is kidney transplantation.
Role of Immunological Biomarkers in Monitoring
Grafted Patients
Following transplantation of major organs such as heart, kidney, and liver, rejection
of grafted organs is an important problem. There is a need for non-invasive tests to
monitor these patients for adjusting their immunosuppressive drug treatment and
early detection of rejection. There is a need for discovery of predictive biomarkers
for these patients.
Gene expression signatures have been studied in peripheral blood mononu-
clear cells isolated from patients with autoimmune GvHD and immunosuppressed
Personalized Approaches to Improve Organ Transplantation