Indoleamine-2,3-dioxygenase inhibition improves immunity and is safe for concurrent use with cART during Mtb/SIV coinfection
Bindu Singh, Riti Sharan, Gayathri Ravichandran, Ruby Escobedo, Vinay Shivanna, Edward J. Dick Jr., Shannan Hall-Ursone, Garima Arora, Xavier Alvarez, Dhiraj K. Singh, Deepak Kaushal, Smriti Mehra
Bindu Singh, Riti Sharan, Gayathri Ravichandran, Ruby Escobedo, Vinay Shivanna, Edward J. Dick Jr., Shannan Hall-Ursone, Garima Arora, Xavier Alvarez, Dhiraj K. Singh, Deepak Kaushal, Smriti Mehra
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Research Article Immunology Infectious disease

Indoleamine-2,3-dioxygenase inhibition improves immunity and is safe for concurrent use with cART during Mtb/SIV coinfection

Abstract

Chronic immune activation promotes tuberculosis (TB) reactivation in the macaque Mycobacterium tuberculosis (M. tuberculosis)/SIV coinfection model. Initiating combinatorial antiretroviral therapy (cART) early lowers the risk of TB reactivation, but immune activation persists. Studies of host-directed therapeutics (HDTs) that mitigate immune activation are, therefore, required. Indoleamine 2,3, dioxygenase (IDO), a potent immunosuppressor, is one of the most abundantly induced proteins in NHP and human TB granulomas. Inhibition of IDO improves immune responses in the lung, leading to better control of TB, including adjunctive to TB chemotherapy. The IDO inhibitor D-1 methyl tryptophan (D1MT) is, therefore, a bona fide TB HDT candidate. Since HDTs against TB are likely to be deployed in an HIV coinfection setting, we studied the effect of IDO inhibition in M. tuberculosis/SIV coinfection, adjunctive to cART. D1MT is safe in this setting, does not interfere with viral suppression, and improves the quality of CD4+ and CD8+ T cell responses, including reconstitution, activation and M. tuberculosis–specific cytokine production, and access of CD8+ T cells to the lung granulomas; it reduces granuloma size and necrosis, type I IFN expression, and the recruitment of inflammatory IDO+ interstitial macrophages (IMs). Thus, trials evaluating the potential of IDO inhibition as HDT in the setting of cART in M. tuberculosis/HIV coinfected individuals are warranted.

Authors

Bindu Singh, Riti Sharan, Gayathri Ravichandran, Ruby Escobedo, Vinay Shivanna, Edward J. Dick Jr., Shannan Hall-Ursone, Garima Arora, Xavier Alvarez, Dhiraj K. Singh, Deepak Kaushal, Smriti Mehra

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Figure 9

Dynamics of T cells and macrophages in the lung granulomas after D1MT+cART and cART treatment.

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Dynamics of T cells and macrophages in the lung granulomas after D1MT+cA...
(A–H) Lung sections obtained at necropsy of RMs from all the study groups were stained for CD4, CD8, CD68, and IDO1. The multilabel confocal images of the lung granulomas of the D1MT+cART- and cART-treated macaques depicting CD4/CD8 (green), CD68 (red), IDO1 (magenta), and nucleus (gray) captured at ×10 (A, C, E, and G) and ×20 (B, D, F, H) magnification. Representative images of CD4, CD68, and IDO1 in D1MT+cART RM are shown (A and B) as well as in cART-treated RM (C and D). Representative images of CD8, CD68, and IDO1 in D1MT+cART (E and F) and in cART (G and H) groups. These representative images were captured using Zeiss LSM-800 confocal microscope. The whole-tissue sections were scanned and quantified for CD4+ T cells, CD8+ T cells, total IDO1 expressing cells, and IDO1+ macrophages using HALO. (I–L) Graph showing the comparison of percentages of CD4+ T cells (I), CD8+ T cells (J), IDO1+ cells (K), and IDO1+ macrophages (L) in lung granuloma of D1MT+cART and cART-only group. Scale bars: 200 mm (×10 magnification; A, C, E and G) and 100 mm (×20 magnification; B, D, F and H). P values are indicated above the plots as obtained from unpaired t test (I–L). Data are represented as mean ± SEM.