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Projekt
Antimicrobial effects mediated by the regulation of the local tryptophan concentration: diverse effects mediated by different tryptophan degrading enzymes in mice and men
Antragsteller
Professor Dr. Walter Däubener
Fachliche Zuordnung
Immunologie
Förderung
Förderung von 2007 bis 2014
Projektkennung
Deutsche Forschungsgemeinschaft (DFG) - Projektnummer 21644054
The regulation of the local concentration of the essential amino acid tryptophan by the IFN-γ inducible enzyme indoleamine 2,3-dioxygenase (IDO) is an important tool in the induction of tolerance and in the mediation of antimicrobial effects. In animal models with mice and in in vitro and in ex vivo experiments with human cells or tissues, IDO is a remarkable regulator of T cell tolerance. In in vitro experiments with human cells, but also in several animal models (e.g. pigs, cattle), IDO is an important antimicrobial effector mechanism directed against parasites (Toxoplasma gondii, Neospora caninum) bacteria (Staphylococcus aureus, Enterococcus faecalis) and viruses (herpes simplex virus, cytomegalovirus). Therefore it was surprising that, although in the murine system IDO mRNA and IDO protein were also found elevated in infected tissues, IDO-deficient animals show no deleterious phenotype in infectious diseases. This discrepancy might be explained by the activity of other tryptophan degrading enzymes like the recently discovered IDO2 or the tryptophan 2,3-dioxygenase (TDO) which are usually not analysed in models of infectious diseases. In our project we aim to define the antimicrobial and immunoregulatory capacity of these two enzymes. Hereby we will focus mainly on the lung or on lung cells, since in vivo studies have shown that the lung is the organ with the most dramatic changes in tryptophan concentrations during infectious diseases in mice. It is a defined clinical intent to use the IDO inhibitor 1-methyl-tryptophan (1-MT) in cancer therapy, but it is completely unclear whether the enhancement of T cell immunoreactivity by an inhibition of IDO would be accompanied by an enhanced risk of infectious diseases. Therefore, we plan to analyse the influence of 1-MT on antimicrobial effects mediated by IDO, IDO2 and TDO. Considerable differences of the L- and D isoform activity of 1-MT observed between in vitro and in vivo systems might also be explained by a diverse activity of 1-MT on IDO, IDO2 and TDO and this discrepancy will also be addressed in our proposed project.
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