Our Faculty : Primary Faculty

Robert Levy, Ph.D.

Current Research Interests
We are actively pursuing strategies to regulate graft versus host disease (GVHD), a major and too frequent lethal complication of allogeneic hematopoietic stem cell transplantation (HSCT). One strategy focusses on in vivo expansion of CD4+FoxP3+ regulatory (Treg) cells by targeting two receptors – a TNF family receptor (TNFRS25) and the IL-2 receptor (CD25). Our studies with Dr. Dietlinde Wolf have demonstrated a remarkable increase in the Treg compartment which is transient and without apparent negative affect on the immune system. Interestingly with the help of Shirin Razdan a medical student, we identified a gender disparity finding greater expansion in female animals. A potentially exciting application of our strategy is manipulation of donors prior to use of their cells for HSCT. Transplants using such donors have shown not only amelioration of GVHD – but retention of anti-tumor activity (GVL) as evidenced by tumor imaging studies with lymphoma cells. Together with my long-time collaborators Drs. Krishna Komanduri (Chief of the Adult HSCT Program) and Tom Malek we want to apply this strategy to clinical transplants. A recent emphasis in the laboratory involves investigation of bromodomain inhibitors (BRDi) which are transcriptional regulators which read acetylated lysine residues on histone proteins. We have learned that several bromodomain inhibitors can interfere with inflammatory genes important in GVHD but notably, discovered they do not interfere with IL-2 gene expression or receptor signaling. We therefore posit that the combinational use of BRDi with Treg therapy may generate a new strategy to regulate GVHD and experiments with Dr. Sabrina Copsel and John Manov, a medical student will test this hypothesis.

We have also been studying the mechanism of how the use of post-transplant cyclophosphamide (PTC) successfully diminishes acute GVHD following mismatched allogeneic HSCT together with collaborators at Johns Hopkins. Experiments are being performed to directly assess comparative efficacy to regulate GVHD and permit GVL between our Treg strategy and PTC treatment – the latter representing the most significant advance in the HSCT field during the last two decades. Cameron Bader, a graduate student in the laboratory has identified a surprising role of the stimulator of interferon genes (sting) in. We are collaborating with the lab of Dr. Glen Barber and hypothesize the sting pathway is important in the transition from acute to chronic GVHD. Another major lab effort is focused on understanding the pathway leading to ocular GVHD (oGVHD), i.e. damage in the ocular compartment which occurs at high frequency following allogeneic HSCT which unfortunately is currently treatable only with restasis (cyclosporine). Combining our experience using pre-clinical mouse HSCT models with the ophthalmic expertise of Dr. Victor Perez – a surgeon in the Dept. of Ophthalmology (where I hold a secondary faculty appointment) has generated a highly productive interdisciplinary collaboration. We currently have an R01 (NEI) award supporting studies to understand the cross talk between T cells and macrophages in the anterior compartment (cornea) and ocular adnexa. Discoveries in our laboratories and active collaborations with ocular pharmaceutical companies are driving studies to examine interventional strategies directed to block local inflammation and pathology in ophthalmic tissue disorders. We are excited that a new ocular clinic at UM has been initiated and patients post-HSCT with chronic GVHD are being evaluated so we can access and examine clinical material enabling ‘a circle’ between mice and man to advance understanding of ocular GVHD.

Thus we hypothesize the combinational use of BRDi with Treg therapy may generate a new strategy o regulate GVHD and experiments with Dr. Sabrina Copsel and John Manov, a medical student will move us in this direction.

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