Graft-versus-host disease (GVHD) is a main barrier for the success of allogenic hematopoietic cell transplantation (allo-HCT). Lysosomal acid lipase (LAL) mediated cell-intrinsic lipolysis to generate free fatty acids and cholesterol in the cells. It plays an essential role in the development, proliferation and function of T cells. LAL deficiency decreases Th1 and Th2 differentiation while inducing the generation of myeloid-derived suppressor cells (MDSC) and regulatory T cells (Tregs). Treg and MDSC are suppressive and Th1/Th2/memory CD8 cells are pathogenic in GVHD. LAL is also required for CD8 memory T cells development. Due to its importance in alloreactive T cell metabolism, we hypothesize that LAL is a valid potential target for the control of GVHD.
Using murine models of allo-HCT, we show here that transfer of reconstituted donor LAL-/- T-cells is associated with significantly less GVHD, compared with LAL+/+ donors in MHC-mismatched (B6->BALB/c or FVB->B6) (Figure 1A) and haploidentical (B6->BDF1) model (Figure 1B). To investigate the effect of pharmacologic LAL inhibition, Orlistat, a specific LAL inhibitor was chosen. Oral treatment of transplanted recipients with Orlistat significantly reduced GVHD severity and improves mortality of recipient mice in B6-BDF1 model. Mechanistically, LAL-/- donor T cells significantly reduced proliferation in allogeneic recipients compared to WT counterpart. Furthermore, LAL deficiency in donor T cells also reduced T cell activation and Th1 differentiation after transplantation. Strikingly, we observed that LAL-/- T-cells or Orlistat treatment largely preserved graft-versus-leukemia (GVL) activity against P815 mastocytoma in B6->BDF1 model (Figure 1, C&D).
Taken all together, our current study provides evidences that LAL can be a valid target for the treatment of GVHD while maintaining GVL effect. Lipid lipase inhibitors could be a potential pharmacological agents for treating GVHD. Our findings thus explore a novel therapeutic strategy for the control of GVHD by altering lipid metabolism in donor T cells.
*Hung Nguyen and Sandeepkumar Kuril contributed equally to this work
No relevant conflicts of interest to declare.
Asterisk with author names denotes non-ASH members.