Current Research and Scholarly Interests
Solid organ transplantation is a life-saving procedure however graft rejection, and other adverse effects associated with immunosuppressive drugs do still pose significant challenges. Nevertheless, there is widespread agreement that some graft recipients are “operationally tolerant” and could maintain their graft without the need for immunosuppression. The major gap in the field is finding a method to identify those patients that would retain healthy graft function without immunosuppression. Our goal is the development of a rapid blood-based test, or biomarker, that indicates “operational tolerance” (stable graft function without the need for immunosuppression). We are utilizing cutting edge mass cytometry technology, termed Cytometry Time of Flight (CYToF), to acquire a previously unattainable picture of the immune system in patients who have been removed from immunosuppression for a variety of reasons but who maintain good graft function. We have identified a novel cell population, the T cell of Operational Tolerance "TOT", distinguished by surface marker expression of CD3+CD4+CD5+CD25+CD38-/lowCD45RA- that is a hallmark of tolerance in transplant recipients.
NK cell diversity/responses to alloantigen and viruses.
Natural killer (NK) cells have an important role in host defense to pathogens and transformed cells. The prevailing dogma has been that NK cells are not active participants in the mechanisms that culminate in graft rejection however studies from our lab implicate NK cells in both acute and chronic allograft rejection thus challenging this paradigm. Quite paradoxically, NK cells have also been shown to facilitate tolerance to an allograft. To reconcile these disparate observations we examined the expression and function of NK cell activating receptors using RNA interference to show that activation of NK cells by dendritic cells (DC) is dependent on signaling through the NKp46 receptor. DC-mediated activation of NK cells occurs both when the DC are MHC-matched and mismatched and this is important in transplantation as host NK cells, host DC, donor NK and donor DC are all present and can result in alloimmune responses after solid organ transplantation. Delivery of NK cell effector functions requires the establishment of an intercellular complex, known as the immune synapse. We have demonstrated using a novel live imaging cytotoxicity assay the distinct nature by which the NK cell activation receptor, NKp46, participates in NK immunological synapse formation and function. Our understanding of the role of NK cells in allograft immunity has evolved from “no role” to suggestions of a “detrimental role” to the current idea that NK cells have complex interactions, that are not yet completely understood, that impact effector functions.
MicroRNAs as Immune Regulators in Transplantation
MicroRNAs are increasingly recognized as master regulators of gene transcription in cells. We were the first to demonstrate the functional significance of microRNAs in alloimmune responses and transplantation. We demonstrated that one microRNA, miR-182 was significantly increased, in the CD4T cells in rejecting allografts and further showed that miR-182 targets FOXO1, a member of the Forkhead box (FOX) protein family of important transcription factors. Modulation of miR-182 increases FOXO1 expression and prolongs graft survival by altering T cell activation and decreasing graft infiltration. Importantly, not only is the microRNA miR-182 increased in the allograft, it is also significantly elevated in the blood during graft rejection. MicroRNAs have remarkable stability in blood thus miR-182 may prove to be a specific biomarker of graft status and could be developed as a non-invasive harbinger of graft function. More recently we has identified a microRNA that is expressed by tolerogenic plasmacytoid dendritic cells (pDC) and is necessary for the prolongation of allograft survival.