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.
巨噬细胞诱导 T 细胞抑制的机制之一是色
氨酸的选择性消除和/或局部巨噬细胞微环境中一种或多种色
氨酸代谢物的增加 研究表明,
IDO 的表达可作为抑制 T 细胞活化的标志物,并可能在异体妊娠和其他类型的移植中发挥重要作用;当 T 细胞因妊娠、恶性肿瘤或 HIV 等病毒而受到抑制时,
IDO 抑制剂可用于激活 T 细胞,从而增强 T 细胞的活化。因此,抑制色
氨酸降解(从而增加色
氨酸浓度,同时降低色
氨酸代谢物浓度)或补充色
氨酸浓度,可作为
IDO 抑制剂的补充或替代物。同样,增加色
氨酸降解(从而降低色
氨酸浓度并增加色
氨酸代谢物浓度),例如通过增加
IDO 浓度或
IDO 活性,可以抑制 T 细胞。虽然特别提到了
IDO 的调节,但人们也可以操纵局部色
氨酸的浓度,和/或调节高亲和性色
氨酸转运体的活性,和/或管理其他色
氨酸降解酶。还可以使用细胞因子,如巨噬细胞集落刺激因子、γ干扰素,单独或与抗原或其他细胞因子结合使用,进一步进行调节。