Regulation of t cell-mediated immunity by tryptophan

Abstract

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 Expression of IDO can serve as a marker of suppression of T cell activation, and may play a significant role in allogeneic pregnancy and other types of transplantation. Inhibitors of IDO can be used to activate T cells. Inhibiting tryptophan degradation, or supplementing tryptophan concentration, can be used in addition to, or in place of, inhibitors of IDO. 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. One can manipulate local tryptophan concentrations, and/or modulate the activity of the high affinity tryptophan transporter, and/or administer tryptophan degrading enzymes. Regulation can be further manipulated using cytokines such as MCSF, IFNγ, alone or in combination with antigen or other cytokines.

1 .- 48 . (canceled) 
     
     
         49 . A method of altering an autoimmune response in a patient, the method comprising administering to the patient an effective amount of a pharmaceutical composition for decreasing extracellular concentrations of tryptophan. 
     
     
         50 . The method of  claim 49 , wherein the composition comprises an enzyme that degrades tryptophan. 
     
     
         51 . The method of  claim 50 , wherein the enzyme is selected from the group consisting of recombinant IDO and indolyl-3-alkane-alpha-hydroxylase. 
     
     
         52 . The method of  claim 49 , wherein the extracellular tryptophan concentrations are decreased to below physiological levels. 
     
     
         53 . The method of  claim 49 , further comprising administering to the patient a cytokine. 
     
     
         54 . The method of  claim 53 , wherein the cytokine increases tryptophan degradation. 
     
     
         55 . The method of  claim 54 , wherein the cytokine is MCSF. 
     
     
         56 . The method of  claim 49 , further comprising a pharmaceutically acceptable carrier. 
     
     
         57 . The method of  claim 49 , wherein the composition is formulated for parenteral administration. 
     
     
         58 . The method of  claim 49 , wherein the composition is formulated for injection into synovial joints.