title: Immunotherapy Added to Antibiotic Treatment Reduces Relapse of Disease in a Mouse Model of Tuberculosis.
abstract: Immune-modulating drugs that target myeloid-derived suppressor cells or stimulate natural killer T cells have been shown to reduce mycobacterial loads in tuberculosis (TB). We aimed to determine if a combination of these drugs as adjunct immunotherapy to conventional antibiotic treatment could also increase therapeutic efficacy against TB. In our model of pulmonary TB in mice, we applied treatment with isoniazid, rifampicin, and pyrazinamide for 13 weeks alone or combined with immunotherapy consisting of all-trans retinoic acid, 1,25(OH)2-vitamin D3, and α-galactosylceramide. Outcome parameters were mycobacterial load during treatment (therapeutic activity) and 13 weeks after termination of treatment (therapeutic efficacy). Moreover, cellular changes were analyzed using flow cytometry and cytokine expression was assessed at the mRNA and protein levels. Addition of immunotherapy was associated with lower mycobacterial loads after 5 weeks of treatment and significantly reduced relapse of disease after a shortened 13-week treatment course compared with antibiotic treatment alone. This was accompanied by reduced accumulation of immature myeloid cells in the lungs at the end of treatment and increased TNF-α protein levels throughout the treatment period. We demonstrate, in a mouse model of pulmonary TB, that immunotherapy consisting of three clinically approved drugs can improve the therapeutic efficacy of standard antibiotic treatment.
authors.affiliation: 1 Department of Medical Microbiology and Infectious Diseases.
authors.forename: Bas C
authors.initials: BC
authors.lastname: Mourik
authors.affiliation: 2 Department of Immunology, and.
authors.forename: Pieter J M
authors.initials: PJ
authors.lastname: Leenen
authors.affiliation: 1 Department of Medical Microbiology and Infectious Diseases.
authors.forename: Gerjo J
authors.initials: GJ
authors.lastname: de Knegt
authors.affiliation: 2 Department of Immunology, and.
authors.forename: Ruth
authors.initials: R
authors.lastname: Huizinga
authors.affiliation: 3 Department of Internal Medicine, Erasmus MC, University Medical Center, Rotterdam, the Netherlands; and.
authors.forename: Bram C J
authors.initials: BC
authors.lastname: van der Eerden
authors.affiliation: 4 Department of Nutritional Science and Toxicology, University of California, Berkeley, California.
authors.forename: Jinshan
authors.initials: J
authors.lastname: Wang
authors.affiliation: 4 Department of Nutritional Science and Toxicology, University of California, Berkeley, California.
authors.forename: Charles R
authors.initials: CR
authors.lastname: Krois
authors.affiliation: 4 Department of Nutritional Science and Toxicology, University of California, Berkeley, California.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Napoli
authors.affiliation: 1 Department of Medical Microbiology and Infectious Diseases.
authors.forename: Irma A J M
authors.initials: IA
authors.lastname: Bakker-Woudenberg
authors.affiliation: 1 Department of Medical Microbiology and Infectious Diseases.
authors.forename: Jurriaan E M
authors.initials: JE
authors.lastname: de Steenwinkel
mesh_terms: D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology / Q000627:therapeutic use*; D000995:Antitubercular Agents / Q000494:pharmacology / Q000627:therapeutic use; D002762:Cholecalciferol / Q000494:pharmacology / Q000627:therapeutic use; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D005260:Female; D005699:Galactosylceramides / Q000494:pharmacology / Q000627:therapeutic use; D007111:Immunity, Cellular / Q000187:drug effects; D007167:Immunotherapy; D008168:Lung / Q000382:microbiology / Q000473:pathology; D008807:Mice, Inbred BALB C; D012008:Recurrence; D014212:Tretinoin / Q000097:blood; D014376:Tuberculosis / Q000097:blood / Q000188:drug therapy / Q000276:immunology* / Q000628:therapy*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: D000900:Anti-Bacterial Agents; D000995:Antitubercular Agents; D005699:Galactosylceramides; D014409:Tumor Necrosis Factor-alpha; C493154:alpha-galactosylceramide; D002762:Cholecalciferol; D014212:Tretinoin
keywords: Mycobacterium tuberculosis; antibiotics; host-directed therapy; inflammation