The role of AMP-activated protein kinase in alloreactive T cells
AMPK is a well-known energy sensor and is activated early in T cells during a GVHD response. Dr. Byersdorfer has shown that lack of AMPK leads to decreased rates of GVHD but preserves anti-leukemia responses. Further work has demonstrated that a lack of AMPK has consequences for both effector T cells and the generation of regulatory T cells, favoring a tolerogenic response. Future studies will utilize animal models and AMPK KO cells to determine the exact mechanism of improved GVHD in the absence of AMPK signaling.
Transcriptional control of fatty acid metabolism in alloreactive T cells
The Byersdorfer lab has previously demonstrated that GVHD-causing T cells increase their dependence on the oxidation of fat. In recent research, they have found that transcriptional control of fat oxidation depends upon signaling through peroxisome proliferator-activated receptors (PPARs), notably PPAR-δ. His lab is currently generating PPAR-δ deficient mice to determine its role in GHVD propagation and more importantly, to define whether PPAR-δ represents a potential therapeutic target for treatment of GVHD in humans.
Using metabolic manipulation to improve anti-leukemia responses
One of the challenges to treatment with chimeric antigen receptor (CAR) T cells for acute lymphoblastic leukemia is a frequent inability to persist in vivo. The Byersdorfer lab will attempt to improve the in vivo persistence of CAR T cells by reprogramming their metabolism through constitutive expression of activated AMPK or PPAR-δ. These changes are expected to increase in vivo T cell and thus increase anti-leukemia efficacy.