In his current laboratory, Dr. Levine has several projects under active investigation pertaining to the role of regulatory T cells (Treg) in transplantation tolerance induction. This work is being done in collaboration with Dr. Wayne Hancock at the Children’s Hospital of Philadelphia. The first of these investigations involves the study of chromatin conformational regulation by histone acetylation/deacetylation and how this impacts the number and function of Treg in murine transplantation models. It is becoming apparent that inhibitors of histone deacetylases (HDACs) can improve both the number and the function of Tregs and that this can induce tolerance to MHC-mismatched transplants in mice with reduced or no conventional immunosuppression. The overall aim of this work is to provide understanding of the role that Tregs play in transplant tolerance and to dissect pathways in Treg induction that may be clinically relevant for drug targeting in animal models and eventually in humans.
A second, more clinically-directed, area of active interest is in the impact that conventional immunosuppression has on the numbers and function of Treg in human transplant recipients. We are studying the Treg profile in liver transplant recipients as immunosuppression utilization is diminished during the first year after transplantation. This should give some information about what impact conventional immunosuppression such as calcinuerin inhibitors have on the function of Treg. This information could impact the strategy of immunosuppressive management in transplant recipients.
Additionally, we are investigating the role that HDACs and heat shock proteins (hsps) play in the tolerance of and recovery from ischemia-reperfusion injury in a murine model. This model utilizes unilateral murine renal ischemia and recovery to investigate the impact the HDAC inhibition, through small molecules and knockouts, has on end organ function and survival. Heat shock proteins are known to play a role in ischemia-reperfusion tolerance but the interaction between HDACs, chromatin conformational modification, gene expression, and heat shock proteins is not well-understood and this is an area that is under active investigation at this time. This work has the potential to impact such diverse areas of clinical medicine as organ preservation, vascular ischemic injury such as myocardial infarction and stroke, and tolerance of ischemia in acute vascular insufficiency or during vascular surgery.
Lastly, Dr. Levine has active ongoing clinical research that includes a detailed analysis of liver transplantation for hepatocellular carcinoma, outcomes in particular subgroups of living and deceased donor renal transplant recipients and donors, and factors associated with favorable and unfavorable outcomes in renal transplantation.