Table 3:

Potential advantages and disadvantages of administration of an mTOR inhibitor in xenotransplantation

A. Advantages
Suppresses both cellular and antibody-mediated rejection (T cells, B cells, and antibody-producting cells) Associated with an increase in Tregs (especially when combined with CD40/CD154 co-stimulation pathway blockade) Inhibits the primate and pig IL-6/IL-6Rα/STAT3 pathway and suppresses inflammatory gene expression Decreases proinflammatory cytokines (e.g., IL-2, IFN-γ, and IL-6) Reduces pig organ growth Anti-viral/anti-cancer activity
B. Disadvantages
Increases IgM production (to specific antigens at low-concentration of mTOR-I) May inhibit wound healing (though this has never been a problem in our pig-to-NHP model) Not always tolerated by patients (but many side-effects are dose-dependent) Can be associated with proteinuria (though we have not seen this) May increase the risk of cardiovascular disease (e.g., dyslipidemia and hyperglycemia) May need supportive medications (e.g., erythropoietin, statin/fibrate, and insulin)