Inhibition of Fatty Acid Metabolism in Alloreactive T Cells Minimizes Acute Graft-versus-host Disease 2303327
Acute Graft-Versus-Host Disease (GVHD) is a complication of allogeneic blood and marrow transplantation in which alloreactive T cells destroy tissues in the liver, skin, and gastrointestinal tract. The dual energetic demands of activation and proliferation push alloreactive T cells into adopting fatty acid oxidation (FAO), a pathway that then becomes a therapeutic target for mitigating GVHD. Here we demonstrate the results of genetic deletion of FAO machinery in donor T cells, and administration of a novel FAO-targeting pharmaceutical as a GVHD treatment. We utilized a C57BL/6 donor into B6D2F1/J recipient model of GVHD. Post-transplant, recipient clinical scores were calculated weekly and weight assessed twice weekly. Genetic FAO inhibition was achieved through a T cell-specific knockout (KO) of carnitine palmitoyltransferase 1a in C57BL/6 mice; recipient mice received either KO (n = 16) or wild-type (n = 16) splenic T cells in transplant. For compound testing, recipient mice with wild-type T cell transplants received either the drug (n = 12) or vehicle control (n = 13) intraperitoneally at days 3, 7, and 10 post-transplant. KO T cell recipients exhibited increased survival (Mantel-Cox p = 0.008). While the ongoing drug treatment experiment has not found a significant survival improvement, the drug-treated group exhibits a trend towards greater weights at day 21 post-transplant (Student’s t-test p = 0.06). Our results find that genetic inhibition of FAO reduces GVHD; as such, pharmacological inhibition of mitochondrial FAO could theoretically produce the same effect. Although preliminary results do not reveal a survival benefit to drug treatment, optimization of dosing strategy and formulation is underway to clarify the drug’s potential therapeutic benefit. Further investigations will characterize its role in post-transplant weight recovery and impact on specific T cell subpopulations early after transplantation, and determine whether similar effects manifest in human T cells. Department of Pediatrics, University of Minnesota Transplantation Immunology (TRAN)