FIGURE 4.

Demonstrating how regulatory T-cells can be metabolically optimized through dietary changes, ex vivo cellular therapy or organ reperfusion machines. Dietary modification/supplementation: Different metabolites differentially modulate Treg cell metabolism and function. Treg cells metabolize mainly via non-mitochondrial (glycolysis) and mitochondrial e.g., oxidative phosphorylation and fatty acid oxidation) means. In addition, their internal cofactors such as mTOR, PPAR and HIF1α allow Treg cells to respond to substrate/oxygen changes in the microenvironment. Dietary modification or systemic infusions of drugs/metabolites could be used to augment Treg cell metabolism and function in an inflammatory allograft. Cellular therapy: Cell therapy involves the isolation of autologous Treg cells, which undergo expansion under sterile Good Manufacturing Principle (GMP) conditions. During this expansion process, the function and metabolism of Treg cells can be modified through drugs or change the substrate composition of metabolites. After the expansion process, the Treg cells could be returned to the patient or infused into an organ reperfusion circuit. Organ reperfusion: The recent introduction of organ reperfusion machines into clinical practice is changing the modus operandi of transplantation. Extended-criteria organs can be re-conditioned using different oxygen-delivery molecules, cytokines, drugs and metabolites to reduce their intrinsic ischemia/inflammatory burden as well as support the function of resident Treg cells. In parallel, recipient-expanded Treg cells could be infused during the reperfusion process to further optimize the reconditioning process. The recovery of an organ can then be measured through objective criteria e.g., pH, bile acid, lactate) and a decision made to implant or discard the organ.