Biopsies Are Essential During Monitoring of Response to Mesenchymal Stromal Cell Therapy in Children with Gastrointestinal Acute Graft Versus Host Disease

Abstract

SLC27a2) 40-fold and increased FA transport 4-fold compared to resting (naïve) T cells (see Table). Donor T cells also increased levels of enzymes necessary for FA oxidation (e.g. CPT2) 100-fold and oxidized more FAs. Mitochondrial mass (required for FA oxidation) increased in donor T cells, as did the ratio of mitochondrial to nuclear DNA, and the expression of PGC-1a, a key regulator of mitochondrial biogenesis. Importantly, T cells proliferating during routine immune reconstitution (following syngeneic BMT) minimally increased FA transport (10% vs. 40% in GVHD T cells). Finally, inhibition of FA oxidation in vivo, through irreversible blockade of CPT1 with etomoxir, decreased the total number of well-divided donor T cells after a single dose. Furthermore, two weeks of etomoxir treatment, beginning on day +7, improved both GVHD clinical score (1.1 vs. 3.8 in untreated animals, P ¼ .02) and weight loss at day 40. In total, these data demonstrate that GVHD T cells up-regulate FA metabolism in vivo and that proliferating, donor cells can be selectively eliminated through inhibition of FA oxidation. Our data provide novel insights into the metabolism of lymphocytes activated in vivo and show that inhibition of FA oxidation may be a therapeutic target for the prevention and/ or treatment of GVHD.