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.