Research Project
7672176
DESCRIPTION (provided by applicant): Indolamine 2,3-deoxygenase enzymes (IDO-1 and IDO-2) play important counter-regulatory roles in the immune system. IDO-mediated tryptophan catabolism induces T cell suppression, which plays a physiological role in suppressing autoimmune and allergic diseases, as well as in facilitating maternal/fetal tolerance. IDO also plays a pathophysiological role in suppressing immune responses to tumors. Newlink Genetics Corporation has developed an IDO inhibitor, 1- methyl tryptophan (1-MT), as an immune stimulatory agent for cancer therapy. A multi-center phase I trial of 1-MT is currently underway. Compelling Preliminary Data indicate that IDO also plays biologically important, opposing roles (inhibition of the host response;inhibition of microbial replication) during diverse chronic infections. Specifically, our data indicate that: (a) IDO is counter-regulatory in cutaneous leishmaniasis (restraining inflammation and parasite clearance);(b) IDO is an antimicrobial effector in toxoplasmosis;and (c) IDO does not appear to alter the course of HSVI or Chlamydia pneumoniae infection. Of note, tuberculosis (TB) is associated with dramatic upregulation of IDO in lung lesions. Therapy for leishmaniasis, which causes a large burden of morbidity and mortality in the tropics, is prolonged;drug resistance is on the rise. The counter-regulatory activity of IDO provides a novel therapeutic target: inhibition should allow for shorter duration, more successful antibiotic therapy. Treatment of TB, one of the top infectious causes of death in the world, is hampered by the need for using multiple drugs for long periods and by increasing drug resistance. Whether IDO is counter-regulatory or antimicrobial in TB remains to be defined;either activity may provide a useful therapeutic target. In this Project, we aim to validate the scientific merit and technical feasibility of therapeutic targeting of IDO in leishmaniasis and TB, by: (1) validating preliminary data indicating therapeutic benefit for 1-MT in experimental leishmaniasis;and (2) defining the biological role of IDO in, and the utility of adjunctive 1-MT during antibiotic treatment of, experimental TB. PUBLIC HEALTH RELEVANCE: This proposal aims to validate the scientific merit and technical feasibility of therapeutic targeting of indolamine 2,3- deoxygenase (IDO) enzymes in leishmaniasis and TB, using an IDO inhibitor, 1-methyl tryptophan (1-MT), developed by Newlink Genetics Corporation as an immune stimulatory agent for cancer therapy.
