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Inhibition of indoleamine dioxygenase leads to better control of tuberculosis adjunctive to chemotherapy
Bindu Singh, … , Xavier Alvarez, Smriti Mehra
Bindu Singh, … , Xavier Alvarez, Smriti Mehra
Published January 24, 2023
Citation Information: JCI Insight. 2023;8(2):e163101. https://doi.org/10.1172/jci.insight.163101.
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Research Article Immunology Infectious disease

Inhibition of indoleamine dioxygenase leads to better control of tuberculosis adjunctive to chemotherapy

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Abstract

The expression of indoleamine 2,3-dioxygenase (IDO), a robust immunosuppressant, is significantly induced in macaque tuberculosis (TB) granulomas, where it is expressed on IFN-responsive macrophages and myeloid-derived suppressor cells. IDO expression is also highly induced in human TB granulomas, and products of its activity are detected in patients with TB. In vivo blockade of IDO activity resulted in the reorganization of the granuloma with substantially greater T cells being recruited to the core of the lesions. This correlated with better immune control of TB and reduced lung M. tuberculosis burdens. To study if the IDO blockade strategy can be translated to a bona fide host-directed therapy in the clinical setting of TB, we studied the effect of IDO inhibitor 1-methyl-d-tryptophan adjunctive to suboptimal anti-TB chemotherapy. While two-thirds of controls and one-third of chemotherapy-treated animals progressed to active TB, inhibition of IDO adjunctive to the same therapy protected macaques from TB, as measured by clinical, radiological, and microbiological attributes. Although chemotherapy improved proliferative T cell responses, adjunctive inhibition of IDO further enhanced the recruitment of effector T cells to the lung. These results strongly suggest the possibility that IDO inhibition can be attempted adjunctive to anti-TB chemotherapy in clinical trials.

Authors

Bindu Singh, Chivonne Moodley, Dhiraj K. Singh, Ruby A. Escobedo, Riti Sharan, Garima Arora, Shashank R. Ganatra, Vinay Shivanna, Olga Gonzalez, Shannan Hall-Ursone, Edward J. Dick Jr., Deepak Kaushal, Xavier Alvarez, Smriti Mehra

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Figure 6

No significant differences are observed for total T cell counts in lungs of the 3 study groups.

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No significant differences are observed for total T cell counts in lungs...
Lungs at the endpoint were processed to obtain single cells, which were subsequently stained for T cells and other functional markers. (A–I) The graphs illustrate the percentages of total CD3+ T cells (A), CD4+ T cells (B), CD8+ T cells (C), CD4+ effector T cells (D), CD4+ memory T cells (E), CD4+Ki67+ T cells (F), CD8+ effector T cells (G), CD8+ memory T cells (H), and CD8+Ki67+ T cells (I) in lungs at the endpoint. P values are indicated above the plots as obtained from 1-way ANOVA with Tukey’s multiple-comparison test. Data are represented as mean ± SEM.

Copyright © 2023 American Society for Clinical Investigation
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