All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional.
Fatty acid metabolism has been implicated in graft-versus-host disease (GvHD) development after allogeneic hematopoietic cell transplantation. Oxidation of fatty acids in mitochondria is responsible for the generation of alloreactive T cells and blocking fatty acid oxidation leads to apoptosis of alloreactive T cells. Supply of fatty acids for oxidation is regulated by a number of enzymes. One of them is the lysosomal acid lipase (LAL) that induces hydrolysis of triglycerides in lysosomes. LAL has shown to be required for the function of a variety of cells, such as T cells, where its absence impairs T-cell receptor activation, T-cell proliferation, and cytokine secretion. Furthermore, studies have shown that LAL deficiency reduces T helper 1 and 2 cell differentiation while increasing the generation of regulatory T cells (Treg), supporting the hypothesis that LAL targeting may be beneficial for controlling GvHD.
Hung D. Nguyen and colleagues investigated the effects of LAL inhibition and deficiency on T-cell responses in mice models of leukemia. The results of the study were recently published in Cell Reports.1
Transplanted LAL-deficient donor T cells induced lower GvHD scores and improved survival in two bone marrow transplant models (major histocompatibility complex-mismatched B6 [H2b] → BALB/c [H2d], and FVB [H2q] → B6 [H2b]).
Additionally, LAL-deficient T cells retained sufficient activity to mediate GvT response as evidenced using a haploidentical B6 (H2b)/BDF1 (H2b/d) bone marrow transplantation model transplanted with luciferase-transduced P815 mastocytoma cells:
Similar to LAL deficiency, pharmacological inhibition of LAL using orlistat led to significant effects on T cells, such as
LAL inhibition with orlistat also prevented GvHD in bone marrow transplant recipients, indicated by improved survival and lower clinical scores. Doses between 8 and 20 mg/kg/day for 14 days were found to be nontoxic.
Additionally, orlistat treatment maintained GvT effects in two mice models. In one model (B6 → BDF1 model transplanted with P815 mastocytoma cells), LAL inhibition with orlistat rescued 40% of bone marrow transplant recipients from GvHD mortality and tumor relapse, which was confirmed with similar results in a second model.
LAL deficiency affects T cells differentially in the spleen and gut in the development of GvHD (see Figure 1):
Overall, the treatment with orlistat simulated LAL deficiency. However, orlistat treatment failed to increase Treg generation from donor T cells.
Figure 1. LAL deficiency and orlistat effects on donor T cells in recipient spleens and guts1
LAL, lysosomal acid lipase; ROS, reactive oxygen species.
↑ increase; ↓ decrease; – no change. All increases and decreases were significant.
Expert Opinion from our Chair, Mohamad Mohty, on COVID-19 and GvHD
This transcript is provided from a call held between the GvHD/Multiple Myeloma Hub and Professor (Prof.) Mohamad Mohty. We would like to thank Prof. Mohty for taking the time to speak...
How can we maintain a high-diversity microbiome after allo-transplant?
The GvHD Hub are proud to present expert interviews directly from the 61st American Society of Hematology (ASH) meeting in Orlando, US. This interview with Jonathan Peled was...
Subscribe to get the best content related to GvHD delivered to your inbox