A mechanism of macrophage-induced
T cell suppression is the selective
elimination of
tryptophan and / or increase in one or more
tryptophan metabolites within the local macrophage microenvironment Studies demonstrate that expression of IDO can serve as a marker of suppression of
T cell activation, and may play a significant role in allogeneic
pregnancy and therefore other types of
transplantation, and that inhibitors of IDO can be used to activate T cells and therefore enhance
T cell activation when the T cells are suppressed by
pregnancy,
malignancy or a
virus such as HIV. Inhibiting
tryptophan degradation (and thereby increasing tryptophan concentration while decreasing tryptophan
metabolite concentration), or supplementing tryptophan concentration, can therefore be used in addition to, or in place of, inhibitors of IDO. Similarly, increasing tryptophan degradation (thereby , decreasing tryptophan concentration and increasing tryptophan
metabolite concentration), for example, by increasing IDO concentration or IDO activity, can suppress T cells. Although described particularly with reference to IDO regulation, one can instead manipulate local tryptophan concentrations, and / or modulate the activity of the high affinity tryptophan
transporter, and / or administer other tryptophan degrading enzymes. Regulation can be further manipulated using cytokines such as
macrophage colony stimulating factor,
interferon gamma, alone or in combination with
antigen or other cytokines.