Table 1.
Selected in vivo studies investigating the effect of immuno-metabolic interventions and conventional GvHD therapy on T-cell metabolism and on outcome in allo-HSCT.
| Metabolic pathway | Type of intervention | Mechanism of action | ROA | Effect on GvHD | Species | Ref. | |
|---|---|---|---|---|---|---|---|
| Metabolic inhibitors (or affected pathways) | |||||||
| Glycolysis | 2-DG | HK2 inhibition |
systemic (i.p.) | none | mouse | (6) | |
| 3-PO | PFKFB3 inhibition | systemic (i.p.) | reduction | mouse | (6) | ||
| IL-1Ra antagonist | IL-1 receptor inhibition | in vitro treatment of donor T-cells | reduction | mouse | (7) | ||
| GLUT1 KO in donor T-cells | GLUT1 inhibition | genetic | reduction | mouse | (8) | ||
| OXPHOS | BZ-423 | F1F0-ATPase inhibition | systemic (i.p.) | reduction | mouse | (9) | |
| LYC-31138 | F1F0-ATPase inhibition | systemic (oral) | reduction | mouse | (10) | ||
| AMPK KO in donor T-cells | AMPK inhibition | genetic | reduction | mouse | (11) | ||
| Metformin | AMPK activation | systemic (i.p.) | reduction | mouse | (12) | ||
| Lipid metabolism | FAS | ACC1 KO in donor T-cells | ACC1 inhibition | genetic | reduction | mouse | (13) |
| FAO | Etomoxir | CPT1 inhibition | systemic (i.p.) | reduction | mouse | (14) | |
| FAO | Orlistat | LAL inhibition | systemic (i.p.) | reduction | mouse | (15) | |
| FAO | 5-LO KO in donor leukocytes | 5-LO inhibition | genetic | reduction | mouse | (16) | |
| FAO | Zileuton | 5-LO | systemic (oral) | reduction | mouse | (16) | |
| SCFA signaling | GPR109a KO on donor T-cells | GPR109a inhibition | genetic | reduction | mouse | (17) | |
| Glutamine metabolism | Glutamine administration | Substrate substitution | systemic (i.p.) | reduction | mouse | (18) | |
| Glutamine administration | Substrate substitution | systemic (oral) |
reduction of GvHD related deaths | human | (19) | ||
| Conventional GvHD therapy | |||||||
| N/A | GCR KO in donor T-cells | GCR inhibition | genetic | increase | mouse | (20) | |
| Glycolysis | Rapamycin | mTORC1 inhibition | systemic (i.p.) | reduction | mouse | (6) | |
| N/A | BEZ235 | PI3K/mTOR inhibition | systemic (oral) | reduction | mouse | (21) | |
| N/A | CC214-2 | mTORC1/2 inhibition | systemic (oral) | reduction | mouse | (22) | |
| Glycolysis | Echinomycin | HIF-1α inhibition | systemic (i.p.) | reduction | mouse | (23) | |
| N/A | NFAT KO in donor T-cells | NFAT inhibition | genetic | reduction | mouse | (24, 25) | |
2-DG, 2-deoxy-D-glucose; 5-LO, 5-lipoxygenase; 3-PO, 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one; ACC1, acetyl-CoA-carboxylase-1; AMPK, AMP-activated protein kinase; CPT1, carnitine-palmitoyl-transferase; FAO, fatty acid oxidation; FAS, fatty acid synthesis; GCR, glucocorticoid receptor; GvHD, Graft-versus-Host-Disease; HIF1-α, hypoxia-inducible factor 1-alpha; HK2, Hexokinase 2; i.p., intraperitoneal; KO, knock out; LAL, lysosomal-acid-lipase; N/A, not available; NFAT, nuclear factor of activated T-cells; mTOR, mechanistic target of rapamycin; OS, overall survival; OXPHOS, oxidative phosphorylation; PFKFB3, 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase-3; PI3K, phosphoinositide-3-kinase; Ref., reference; ROA, route of administration; SCFA, short-chain fatty acids.