Research Group

  • Dr. Rakesh Sindhi, Principal Investigator
  • Ms. Amy Magill, Research Technician
  • Ms. Xiaoting Tang, Research Technician
  • Dr. Janine Janosky, Statistical Consultant
  • Dr. Jeff Paslay, Scientific Consultant
  • Dr. Suren Sehgal, Scientific Consultant


  • Children's Hospital of Pittsburgh, Pittsburgh, USA


  • Designing Biomarker-Assisted Clinical Trials for Immunosuppressants

Current evaluation of immunosuppressant agents in transplantation involves the use of fixed doses or concentrations, and non-numeric measures of clinical success or failure. Because nearly half of all subjects enrolled in clinical trials experience some form of failure, e.g. acute rejection or side effects, other ways are needed to evaluate new immunosuppressive drugs. We have previously evaluated several proteins, such as cytokines and cell surface receptors, which mediate lymphocyte responses to transplanted antigens, as potential measures of drug effect. These proteins are sensitive to two commonly used classes of drugs: calcineurin inhibitors such as tacrolimus; and anti-proliferative drugs such as sirolimus and mycophenolate mofetil. Also, their degree of inhibition predicts drug concentrations that are associated with a stable post-transplant course. In the current proposal, our first step will be to identify additional proteins sensitive to immunosuppression with tacrolimus, sirolimus and mycophenolate mofetil in residual human blood samples from subjects enrolled in ongoing studies at our center. One of two high-throughput techniques will allow us to evaluate up to 2000 proteins in plasma and cells with surface-enhanced laser desorption ionization (SELDI)-time of flight (TOF)-mass spectrometry, for potential sensitivity to immunosuppressant agents. Subcellular translocation of proteins or their disruption during proliferation and stimulation will be measured in a 6-channel, fluorescent cell-imaging platform that can focus on the cell membrane, cytoplasm, nucleus, and cytoplasmic organelles. As a second step, protein targets that demonstrate sensitivity to the drugs mentioned will be subjected to effect:concentration modeling to identify thresholds for maximal or sub-maximal effect on protein biomarkers. Within the scope of this effort, a clinical trial design will be proposed at the end of the study period. In this trial, the concentration-dependent, measurable response of biomarkers will be used as an endpoint for drug evaluation instead of non-numeric endpoints. Our prior studies suggest that such a trial would enhance the safety of clinical trial participation and reduce numbers of human subjects needed for drug evaluation.