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

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

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

JCI Insight ; 9(15)2024 Jul 02.

Article en En | MEDLINE | ID: mdl-39114981

ABSTRACT

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.

Asunto(s)

Coinfección; Indolamina-Pirrol 2,3,-Dioxigenasa; Macaca mulatta; Mycobacterium tuberculosis; Síndrome de Inmunodeficiencia Adquirida del Simio; Triptófano; Indolamina-Pirrol 2,3,-Dioxigenasa/antagonistas & inhibidores; Indolamina-Pirrol 2,3,-Dioxigenasa/metabolismo; Animales; Síndrome de Inmunodeficiencia Adquirida del Simio/inmunología; Síndrome de Inmunodeficiencia Adquirida del Simio/tratamiento farmacológico; Coinfección/tratamiento farmacológico; Coinfección/inmunología; Triptófano/metabolismo; Triptófano/análogos & derivados; Tuberculosis/inmunología; Tuberculosis/tratamiento farmacológico; Virus de la Inmunodeficiencia de los Simios/inmunología; Modelos Animales de Enfermedad; Linfocitos T CD8-positivos/inmunología; Infecciones por VIH/tratamiento farmacológico; Infecciones por VIH/inmunología; Infecciones por VIH/complicaciones; Antirretrovirales/uso terapéutico; Antirretrovirales/farmacología; Masculino; Pulmón/inmunología; Pulmón/patología; Humanos; Linfocitos T CD4-Positivos/inmunología

Palabras clave

Immunology; Infectious disease; Tuberculosis

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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Triptófano / Síndrome de Inmunodeficiencia Adquirida del Simio / Indolamina-Pirrol 2,3,-Dioxigenasa / Coinfección / Macaca mulatta / Mycobacterium tuberculosis Límite: Animals / Humans / Male Idioma: En Revista: JCI Insight Año: 2024 Tipo del documento: Article Pais de publicación: Estados Unidos

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